To what extent can traditional medicine contribute a complementary or alternative solution to malaria control programmes?

Recent studies on traditional medicine (TM) have begun to change perspectives on TM effects and its role in the health of various populations. The safety and effectiveness of some TMs have been studied, paving the way to better collaboration between modern and traditional systems. Traditional medicines still remain a largely untapped health resource: they are not only sources of new leads for drug discoveries, but can also provide lessons and novel approaches that may have direct public-health and economic impact. To optimize such impact, several interventions have been suggested, including recognition of TM's economic and medical worth at academic and health policy levels; establishing working relationships with those prescribing TM; providing evidence for safety and effectiveness of local TM through appropriate studies with malaria patients; spreading results for clinical recommendations and health policy development; implementing and evaluating results of new health policies that officially integrate TM

Plasmodium falciparum clearance with artemisinin-based combination therapy (ACT) in patients with glucose-6-phosphate dehydrogenase deficiency in Mali

URL : http://www.malariajournal.com/content/9/1/332Background: Artemisinin-based combination therapy (ACT) is currently the most effective medicine for the treatment of uncomplicated malaria. Artemisinin has previously been shown to increase the clearance of Plasmodium falciparum in malaria patients with haemoglobin E trait, but it did not increase parasite inhibition in an in vitro study using haemoglobin AS erythrocytes. The current study describes the efficacy of artemisinin derivatives on P. falciparum clearance in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), a haemoglobin enzyme deficiency, not yet studied in the same context, but nonetheless is a common in malaria endemic areas, associated with host protection against uncomplicated and severe malaria. The impact of G6PD deficiency on parasite clearance with ACT treatment was compared between G6PD-deficient patients and G6PD-normal group. Methods: Blood samples from children and adults participants (1 to 70 years old) with uncomplicated P. falciparum malaria residing in Kambila, Mali were analysed. Study participants were randomly assigned to receive either artemether-lumefantrine (Coartem®) or artesunate plus mefloquine (Artequin™). A restriction-fragment length polymorphism analysis of PCR-amplified DNA samples was used to identify the (A-) allele of the gene mutation responsible for G6PD deficiency (G6PD*A-). 470 blood samples were thus analysed and of these, DNA was extracted from 315 samples using the QIAamp kit for PCR to identify the G6PD*A- gene. Results

Reconstitution of the Costunolide Biosynthetic Pathway in Yeast and Nicotiana benthamiana

The sesquiterpene costunolide has a broad range of biological activities and is the parent compound for many other biologically active sesquiterpenes such as parthenolide. Two enzymes of the pathway leading to costunolide have been previously characterized: germacrene A synthase (GAS) and germacrene A oxidase (GAO), which together catalyse the biosynthesis of germacra-1(10),4,11(13)-trien-12-oic acid. However, the gene responsible for the last step toward costunolide has not been characterized until now. Here we show that chicory costunolide synthase (CiCOS), CYP71BL3, can catalyse the oxidation of germacra-1(10),4,11(13)-trien-12-oic acid to yield costunolide. Co-expression of feverfew GAS (TpGAS), chicory GAO (CiGAO), and chicory COS (CiCOS) in yeast resulted in the biosynthesis of costunolide. The catalytic activity of TpGAS, CiGAO and CiCOS was also verified in planta by transient expression in Nicotiana benthamiana. Mitochondrial targeting of TpGAS resulted in a significant increase in the production of germacrene A compared with the native cytosolic targeting. When the N. benthamiana leaves were co-infiltrated with TpGAS and CiGAO, germacrene A almost completely disappeared as a result of the presence of CiGAO. Transient expression of TpGAS, CiGAO and CiCOS in N. benthamiana leaves resulted in costunolide production of up to 60 ng.g−1 FW. In addition, two new compounds were formed that were identified as costunolide-glutathione and costunolide-cysteine conjugates

Role of Transferrin Receptor and the ABC Transporters ABCB6 and ABCB7 for Resistance and Differentiation of Tumor Cells towards Artesunate

The anti-malarial artesunate also exerts profound anti-cancer activity. The susceptibility of tumor cells to artesunate can be enhanced by ferrous iron. The transferrin receptor (TfR) is involved in iron uptake by internalization of transferrin and is over-expressed in rapidly growing tumors. The ATP-binding cassette (ABC) transporters ABCB6 and ABCB7 are also involved in iron homeostasis. To investigate whether these proteins play a role for sensitivity towards artesunate, Oncotest's 36 cell line panel was treated with artesunate or artesunate plus iron(II) glycine sulfate (Ferrosanol®). The majority of cell lines showed increased inhibition rates, for the combination of artesunate plus iron(II) glycine sulfate compared to artesunate alone. However, in 11 out of the 36 cell lines the combination treatment was not superior. Cell lines with high TfR expression significantly correlated with high degrees of modulation indicating that high TfR expressing tumor cells would be more efficiently inhibited by this combination treatment than low TfR expressing ones. Furthermore, we found a significant relationship between cellular response to artesunate and TfR expression in 55 cell lines of the National Cancer Institute (NCI), USA. A significant correlation was also found for ABCB6, but not for ABCB7 in the NCI panel. Artesunate treatment of human CCRF-CEM leukemia and MCF7 breast cancer cells induced ABCB6 expression but repressed ABCB7 expression. Finally, artesunate inhibited proliferation and differentiation of mouse erythroleukemia (MEL) cells. Down-regulation of ABCB6 by antisense oligonucleotides inhibited differentiation of MEL cells indicating that artesunate and ABCB6 may cooperate. In conclusion, our results indicate that ferrous iron improves the activity of artesunate in some but not all tumor cell lines. Several factors involved in iron homeostasis such as TfR and ABCB6 may contribute to this effect

Artesunate induces necrotic cell death in schwannoma cells

Established as a potent anti-malaria medicine, artemisinin-based drugs have been suggested to have anti-tumour activity in some cancers. Although the mechanism is poorly understood, it has been suggested that artemisinin induces apoptotic cell death. Here, we show that the artemisinin analogue artesunate (ART) effectively induces cell death in RT4 schwannoma cells and human primary schwannoma cells. Interestingly, our data indicate for first time that the cell death induced by ART is largely dependent on necroptosis. ART appears to inhibit autophagy, which may also contribute to the cell death. Our data in human schwannoma cells show that ART can be combined with the autophagy inhibitor chloroquine (CQ) to potentiate the cell death. Thus, this study suggests that artemisinin-based drugs may be used in certain tumours where cells are necroptosis competent, and the drugs may act in synergy with apoptosis inducers or autophagy inhibitors to enhance their anti-tumour activity

A short educational intervention diminishes causal illusions and specific paranormal beliefs in undergraduates

Cognitive biases such as causal illusions have been related to paranormal and pseudoscientific beliefs and, thus, pose a real threat to the development of adequate critical thinking abilities. We aimed to reduce causal illusions in undergraduates by means of an educational intervention combining training-in-bias and training-in-rules techniques. First, participants directly experienced situations that tend to induce the Barnum effect and the confirmation bias. Thereafter, these effects were explained and examples of their influence over everyday life were provided. Compared to a control group, participants who received the intervention showed diminished causal illusions in a contingency learning task and a decrease in the precognition dimension of a paranormal belief scale. Overall, results suggest that evidence-based educational interventions like the one presented here could be used to significantly improve critical thinking skills in our students

How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials?

Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds

The effect of clinical experience, judgment task difficulty and time pressure on nurses’ confidence calibration in a high fidelity clinical simulation

Background: Misplaced or poorly calibrated confidence in healthcare professionals’ judgments compromises the quality of health care. Using higher fidelity clinical simulations to elicit clinicians’ confidence 'calibration' (i.e. overconfidence or underconfidence) in more realistic settings is a promising but underutilized tactic. In this study we examine nurses’ calibration of confidence with judgment accuracy for critical event risk assessment judgments in a high fidelity simulated clinical environment. The study also explores the effects of clinical experience, task difficulty and time pressure on the relationship between confidence and accuracy. Methods: 63 student and 34 experienced nurses made dichotomous risk assessments on 25 scenarios simulated in a high fidelity clinical environment. Each nurse also assigned a score (0–100) reflecting the level of confidence in their judgments. Scenarios were derived from real patient cases and classified as easy or difficult judgment tasks. Nurses made half of their judgments under time pressure. Confidence calibration statistics were calculated and calibration curves generated. Results: Nurse students were underconfident (mean over/underconfidence score −1.05) and experienced nurses overconfident (mean over/underconfidence score 6.56), P = 0.01. No significant differences in calibration and resolution were found between the two groups (P = 0.80 and P = 0.51, respectively). There was a significant interaction between time pressure and task difficulty on confidence (P = 0.008); time pressure increased confidence in easy cases but reduced confidence in difficult cases. Time pressure had no effect on confidence or accuracy. Judgment task difficulty impacted significantly on nurses’ judgmental accuracy and confidence. A 'hard-easy' effect was observed: nurses were overconfident in difficult judgments and underconfident in easy judgments. Conclusion: Nurses were poorly calibrated when making risk assessment judgments in a high fidelity simulated setting. Nurses with more experience tended toward overconfidence. Whilst time pressure had little effect on calibration, nurses’ over/underconfidence varied significantly with the degree of task difficulty. More research is required to identify strategies to minimize such cognitive biases