Publications

The suitability of laboratory-bred Anopheles cracens for the production of Plasmodium vivax sporozoites

A stenogamous colony of Anopheles cracens (A. dirus B) established 20 years ago in a Thai insectary proved susceptible to Plasmodium vivax. However, routine sporozoite production by feeding on field-collected blood samples has not been described. The setting-up of an A. cracens colony in an insectary on the Thai-Myanmar border and the process of using P. vivax field samples for the production of infectious sporozoites are described.

Short Communication: An assessment of the use of malaria rapid tests by village health volunteers in rural Laos

Summary Rapid malaria diagnosis, a key component of malaria control strategies, is hampered by the expense and training requirements of reliable microscopy. Rapid malaria antigen tests may improve the diagnosis of malaria in the rural tropics. After 1 h training 64 village health volunteers (VHVs) from rural Laos, with no previous laboratory experience, performed two malaria rapid diagnostic tests (ParacheckPf TM and OptiMAL TM ) accurately. The reliability of six VHVs was assessed longitudinally, over 10 months with different frequencies of retraining. Compared with microscopy, error rates in dipstick interpretation were low (<2%) for both tests and were not associated with retraining frequency ( P > 0.2). Previously untrained Lao VHVs performed malaria rapid tests reliably with high sensitivity and specificity after minimal training.

Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial

Background Most malaria deaths occur in rural areas. Rapid progression from illness to death can be interrupted by prompt, effective medication. Antimalarial treatment cannot rescue terminally ill patients but could be effective if given earlier. If patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate can be given before referral and acts rapidly on parasites. We investigated whether this intervention reduced mortality and permanent disability. Methods In Bangladesh, Ghana, and Tanzania, patients with suspected severe malaria who could not be treated orally were allocated randomly to a single artesunate (n=8954) or placebo (n=8872) suppository by taking the next numbered box, then referred to clinics at which injections could be given. Those with antimalarial injections or negative blood smears before randomisation were excluded, leaving 12 068 patients (6072 artesunate, 5996 placebo) for analysis. Primary endpoints were mortality, assessed 7–30 days later, and permanent disability, reassessed periodically. All investigators were masked to group assignment. Analysis was by intention to treat. This study is registered in all three countries, numbers ISRCTN83979018, 46343627, and 76987662. Results Mortality was 154 of 6072 artesunate versus 177 of 5996 placebo (2·5% vs 3·0%, p=0·1). Two versus 13 (0·03% vs 0·22%, p=0·0020) were permanently disabled; total dead or disabled: 156 versus 190 (2·6% vs 3·2%, p=0·0484). There was no reduction in early mortality (56 vs 51 deaths within 6 h; median 2 h). In patients reaching clinic within 6 h (median 3 h), pre-referral artesunate had no significant effect on death after 6 h or permanent disability (71/4450 [1·6%] vs 82/4426 [1·9%], risk ratio 0·86 [95% CI 0·63–1·18], p=0·35). In patients still not in clinic after more than 6 h, however, half were still not there after more than 15 h, and pre-referral rectal artesunate significantly reduced death or permanent disability (29/1566 [1·9%] vs 57/1519 [3·8%], risk ratio 0·49 [95% CI 0·32–0·77], p=0·0013). Interpretation If patients with severe malaria cannot be treated orally and access to injections will take several hours, a single inexpensive artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability. Funding UNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases (WHO/TDR); WHO Global Malaria Programme (WHO/GMP); Sall Family Foundation; the European Union (QLRT-2000-01430); the UK Medical Research Council; USAID; Irish Aid; the Karolinska Institute; and the University of Oxford Clinical Trial Service Unit (CTSU).

Preventing Antimalarial Drug Resistance with Triple Artemisinin-Based Combination Therapies

Background: Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs) which combine artemisinin derivatives with two partner drugs are efficacious and well tolerated in clinical trials, including in areas of multidrug-resistant malaria. Whether early TACT adoption could delay the emergence and spread of antimalarial drug resistance is a question of vital importance.Methods: Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use.Findings: In countries with 1% P. falciparum prevalence, immediate adoption of TACTs would result in substantially lower frequency of artemisinin-resistant alleles 10 years later. Median estimates were 70%, 33%, and 18% lower allele frequency for countries currently deploying dihydroartemisinin-piperaquine, artesunate-amodiaquine, or artemether-lumefantrine, respectively. Corresponding median treatment failure rate decreases are 74%, 34%, and 17%. Delaying TACT introduction increases future resistance frequencies and treatment failure rates. The most significant threat to the success of TACTs is the emergence of a triple-resistant genotype. which if above 0.01 frequency may undermine elimination efforts in low-prevalence regions.Interpretation: Introduction of TACTs could delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs and improving the chances of malaria elimination. Immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance.Funding: This research falls under the auspices of the Development of Triple Artemisinin-based Combination Therapies (DeTACT) project funded by UK Aid and the UK Government’s Foreign, Commonwealth and Development Office. Funding from Wellcome Trust (220211) is also acknowledged. MFB, TDN, TN-AT acknowledge funding from the National Institutes of Health grant NIAID R01AI153355 and The Bill and Melinda Gates Foundation INV-005517 grant awarded to Pennsylvania State University. RA acknowledges funding from the Bill and Melinda Gates Foundation (OPP1193472).Declaration of Interest: None to declare.

Pulmonary oedema in vivax malaria

Journal Article Pulmonary oedema in vivax malaria Get access S. Pukrittayakamee, S. Pukrittayakamee 1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Chantra, A. Chantra 1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar S. Vanijanonta, S. Vanijanonta 1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar N.J. White N.J. White ∗ 1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK ∗Address for correspondence: Professor N. J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand; phone +66 2 246 0832, fax +66 2 246 7795. fnnjw@diamond.mahidol.ac.th Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 92, Issue 4, July-August 1998, Pages 421–422, https://doi.org/10.1016/S0035-9203(98)91075-6 Published: 01 July 1998 Article history Received: 23 March 1998 Accepted: 29 April 1998 Published: 01 July 1998

Laboratory Detection of Artemisinin-Resistant Plasmodium falciparum

Conventional 48-h in vitro susceptibility tests have low sensitivity in identifying artemisinin-resistant Plasmodium falciparum, defined phenotypically by low in vivo parasite clearance rates. We hypothesized originally that this discrepancy was explained by a loss of ring-stage susceptibility and so developed a simple field-adapted 24-h trophozoite maturation inhibition (TMI) assay focusing on the ring stage and compared it to the standard 48-h schizont maturation inhibition (WHO) test. In Pailin, western Cambodia, where artemisinin-resistant P. falciparum is prevalent, the TMI test mean (95% confidence interval) 50% inhibitory concentration (IC50) for artesunate was 6.8 (5.2 to 8.3) ng/ml compared with 1.5 (1.2 to 1.8) ng/ml for the standard 48-h WHO test (P = 0.001). TMI IC50s correlated significantly with the in vivo responses to artesunate (parasite clearance time [r = 0.44, P = 0.001] and parasite clearance half-life [r = 0.46, P = 0.001]), whereas the standard 48-h test values did not. On continuous culture of two resistant isolates, the artemisinin-resistant phenotype was lost after 6 weeks (IC50s fell from 10 and 12 ng/ml to 2.7 and 3 ng/ml, respectively). Slow parasite clearance in falciparum malaria in western Cambodia results from reduced ring-stage susceptibility.

Meeting contribution: Visual interference observations of sub-arcsecond double stars

No abstract is provided for this article.

Effect of Serotonin Depletion Induced by <i>p</i>-Chloroamphetamine on Changes in Rats’ Activity Levels Produced by Lithium

The role of serotonin (5-HT) transmission in the production of changes in rats' activity levels induced by 0.15 and 1.50 mEq/kg LiCl was assessed by selectively depleting 5-HT brain levels with p-chloroamphetamine prior to chronic administration of LiCl for 21 days. While p-chloroamphetamine pretreatment decreased 5-HT levels by 56%, irrespective of the fact that the animals had been administered either saline, 0.15, or 1.50 mEq/kg LiCl for 21 days, it did not alter the effects that each LiCl dose alone had on activity levels. Both LiCl administrations produced an 18% increase in 5-HT levels in rats pretreated with saline, yet diametrically opposed effects on activity levels. A parallel is drawn between these biochemical findings and previously reported data indicating that both LiCl doses produce an improvement in selective attention, yet opposed effects on rats' activity levels. The hypothesis that 5-HT transmission might be crucially involved in mediating the dose-independent effect of lithium on selective attention is proposed for future research.

Erratum to: Malaria parasite clearance

Modes d'action et caractéristiques pharmacologiques des antipaludiques

The treatment for Plasmodium falciparum malaria is too often based on empirical notions of the efficacy and toxicity of drugs. Understanding the pharmacokinetic-pharmacodynamic relationships and antimalarial drugs' modes of action allows one to better understand the therapeutic responses observed in the treatment of severe or uncomplicated P. falciparum infections. The authors discuss the variations of parasitemia and their influencing factors (prevention, synchronism, virulence, and pretreatment). These factors are to be taken into account when first considering therapy. Many variables are defined to analyze the pharmacodynamic-efficacy interactions of anti-malarial drugs: minimal parasiticidal concentration (MPC) of a drug, minimum concentration in blood which produces a maximal inhibition (or maximum efficacy [Emax]), the parasitic reduction ratio (PRR), which is the relationship between the initial parasitemia over the parasitemia 48 hours after onset of treatment. These variables are specific to each drug and are useful in selecting the therapeutic answer and to better use antimalarial drugs. The main drugs and their combinations are reviewed (quinine, chloroquine, sulfadoxine-pyrimethamine, biguanides, mefloquine, halofantrine, artemisinine-based drugs), taking into account these pharmacological concepts.

Thiamine deficiency and malaria in adults from southeast Asia

Background Thiamine deficiency (beriberi) is common in some parts of southeast Asia. Acute thiamine deficiency can mimic many complications of malaria, such as encephalopathy and lactic acidosis. We examined the incidence of thiamine deficiency in adults admitted to hospital with malaria in Thailand. Methods For this prospective study, we recruited consecutive patients with malaria or other febrile illness who presented to Paholpolpayuhasena Hospital, Kanchanaburi, Thailand, between May and July, 1992. We used the activation coefficient (α) for transketolase activity in erythrocytes to measure thiamine deficiency (defined as α>1·31) in patients with severe and uncomplicated malaria and in controls (patients” relatives and healthy volunteers). To exclude the possibility of interference in the assays, transketolase activity was also measured in erythrocytes used to culture parasites. Findings 12 (52%) of 23 patients with severe malaria and ten (19%) of 54 patients with uncomplicated malaria had α values above the normal range (p<0·0001 and p=0·0014, respectively, compared with controls), which indicated severe thiamine deficiency. Thiamine deficiency was more severe in patients with cerebral malaria than in those with uncomplicated malaria and the controls (p=0·008). Interpretation In adults admitted to hospital in Thailand, thiamine deficiency commonly complicates acute falciparum malaria, particularly in severe infections, and could contribute to dysfunction of the central nervous system.

Increased food availability raises eviction rate in a cooperative breeding mammal

In group-living mammals, the eviction of subordinate females from breeding groups by dominants may serve to reduce feeding competition or to reduce breeding competition. Here, we combined both correlational and experimental approaches to investigate whether increases in food intake by dominant females reduces their tendency to evict subordinate females in wild meerkats ( Suricata suricatta ). We used 20 years of long-term data to examine the association between foraging success and eviction rate, and provisioned dominant females during the second half of their pregnancy, when they most commonly evict subordinates. We show that rather than reducing the tendency for dominants to evict subordinates, foraging success of dominant females is positively associated with the probability that pregnant dominant females will evict subordinate females and that experimental feeding increased their rates of eviction. Our results suggest that it is unlikely that the eviction of subordinate females serves to reduce feeding competition and that its principal function may be to reduce reproductive competition. The increase in eviction rates following experimental feeding also suggests that rather than feeding competition, energetic constraints may normally constrain eviction rates.

Antifungal susceptibilities of Cryptococcus neoformans in north-east Thailand

Journal Article Antifungal susceptibilities of Cryptococcus neoformans in north-east Thailand Get access V. Wuthiekanun, V. Wuthiekanun 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar P.A. Howe, P.A. Howe 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar A.J.H. Simpson, A.J.H. Simpson 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar M.D. Smith, M.D. Smith 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar A.L. Walsh, A.L. Walsh 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar B.J. Angus, B.J. Angus 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Rajchanuwong, A. Rajchanuwong 3Department of Medicine, Sappasitprasong Hospital, Ubon Ratchathani, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar N.J. White N.J. White 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Address for correspondence: Professor N. J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand; phone +662 246 0832, fax +66 2 246 7795. fnnjw@diamond.mahidol.ac.th Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 93, Issue 1, January-February 1999, Pages 96–97, https://doi.org/10.1016/S0035-9203(99)90195-5 Published: 01 January 1999 Article history Received: 17 August 1998 Revision received: 24 September 1998 Accepted: 08 October 1998 Published: 01 January 1999

Letters to the editors

Dear Editors and readers, We thank Dr Verhoef very much for his interesting letter and for raising this important statistical point. We agree that we should have used a method, such as that of Oldham, to examine the relationship. However, using Oldham's method (Tu and Gilthorpe 2007) does not change the conclusion. Patients with higher mean of admission and day 42 α have a greater reduction in alpha in convalescence (Figure 1, y = −67x + 76, R2 = 0.21, P < 0.001). Therefore, in this case statistical analysis using Oldham's method does not change the conclusion and the evidence indicates that the extent of improvement in thiamin status does depend on the degree of admission thiamin deficiency. Relationship between (admission α and convalescent α)/2 and percentage change in α. We are very grateful to Dr Sue Lee for her statistical advice on this response.

Patterns of association between mothers and offspring and their outcomes in a polygynous ungulate

Abstract Prolonged association between mothers and their offspring is common in ungulates, with the level of maternal investment likely to play a central role in shaping this trait. Here we examined patterns of association between mothers and offspring over time, the apparent benefits of association to offspring, and costs to mothers. We analyzed 40 years’ worth of census data from an individually-monitored, food-limited population of red deer ( Cervus elaphus ) on the Isle of Rum, Scotland. Starting from birth, female calves associated more frequently with their mothers than male calves in their first year. Calves also associated less with their mothers if the mother did not conceive a new calf. Association frequency decreased with mother’s age and population density, and survival over the first year was not related to mother-calf association. Yearlings, now in their second year, were more often associated with their mothers if they were female, if there was no subsequent calf (or the subsequent calf died as a neonate), and if they were still being suckled. Increased association between mothers and yearlings was associated with increased survival to adulthood at 28 months, but suckling a yearling did not improve its probability of survival. For individuals that reached maturity, increased association in the yearling year was associated with slightly shorter adult life spans. The level of association between a calf and mother was not associated with the mother’s immediate survival or fecundity. Our findings suggest that juveniles born to poor-condition mothers benefit from prolonged association through improved yearling survival.

Malaria

No abstract is provided for this article.

An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria

Background The artemisinins are potent and widely used antimalarial drugs that are eliminated rapidly. A simple concentration–effect pharmacometric model does not explain why dosing more frequently than once daily fails to augment parasite clearance and improve therapeutic responses in vivo. Artemisinins can induce a temporary non-replicative or ‘dormant’ drug refractory state in Plasmodium falciparum malaria parasites which may explain recrudescences observed in clinical trials despite full drug susceptibility, but whether it explains the dosing–response relationship is uncertain. Objectives To propose a revised model of antimalarial pharmacodynamics that incorporates reversible asexual parasite injury and temporary drug refractoriness in order to explain the failure of frequent dosing to augment therapeutic efficacy in falciparum malaria. Methods The model was fitted using a Bayesian Markov Chain Monte Carlo approach with the parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from western Cambodia and 40 patients from northwestern Thailand reported previously. Results The revised model captured the dynamics of parasite clearance data. Its predictions are consistent with observed therapeutic responses. Conclusions A within-host pharmacometric model is proposed in which it is hypothesized that some malaria parasites enter a temporary drug refractory state after exposure to artemisinin antimalarials, which is followed by delayed parasite death or reactivation. The model fitted the observed sequential parasite density data from patients with acute P. falciparum malaria, and it supported reduced ring stage activity in artemisinin-resistant infections.

Failure of interferon alfa and tribavirin in rabies encephalitis.

OBJECTIVE--To test the effect of interferon alfa and tribavirin (ribavirin) in patients with rabies encephalitis. DESIGN--An open trial of chemotherapy and intensive care in patients with early rabies. SETTING--The intensive care unit of a Bangkok hospital. PATIENTS--Four conscious men with clinical rabies encephalitis. INTERVENTIONS--Rapid virological diagnosis of rabies. Treatment with intravenous and intraventricular injections of high doses of lymphoblastoid interferon alfa in three patients and tribavirin in one patient. Intensive care was given throughout. MAIN OUTCOME MEASURES--Rabies infection confirmed by antigen detection and virus isolation. Rabies neutralising antibody and specific IgM sought in serum and cerebrospinal fluid. Interferon concentrations monitored before and during treatment in three patients. RESULTS--Interferon alfa treatment produced high concentrations in serum and cerebrospinal fluid. All four patients died after 5 1/2 to 12 1/2 days of treatment with no evidence of virostatic or clinically beneficial effects from either treatment. CONCLUSION--Interferon alfa treatment is not effective in rabies encephalitis. The use of tribavirin warrants further study, possibly combined with new therapeutic methods.