Publications

Artemether-lumefantrine is a new fixed antimalarial combination effective against multidrug-resistant falciparum malaria. A prospective electrocardiographic study was conducted in 150 patients receiving artemetherlumefantrine and 50 treated with artesunate-mefloquine. There was no evidence for clinically significant changes in the electrocardiographic intervals and in particular no relationship between plasma concentrations of lumefantrine and QTc prolongation. Artemether-lumefantrine does not have significant cardiac effects at therapeutic doses.

Understanding how climate can interact with other factors in determining patterns of species abundance is a persistent challenge in ecology. Recent research has suggested that the dynamics exhibited by some populations may be a non-additive function of climate, with climate affecting population growth more strongly at high density than at low density. However, we lack methodologies to adequately explain patterns in population growth generated as a result of interactions between intrinsic factors and extrinsic climatic variation in non-linear systems. We present a novel method (the Functional Coefficient Threshold Auto-Regressive (FCTAR) method) that can identify interacting influences of climate and density on population dynamics from time-series data. We demonstrate its use on count data on the size of the Soay sheep population, which is known to exhibit dynamics generated by nonlinear and non-additive interactions between density and climate, living on Hirta in the St Kilda archipelago. The FCTAR method suggests that climate fluctuations can drive the Soay sheep population between different dynamical regimes--from stable population size through limit cycles and non-periodic fluctuations.

In the majority of mammals, gestation length is relatively consistent and seldom varies by more than 3%. In a few species, females can adjust gestation length by delaying the development of the embryo after implantation. Delays in embryonic development allow females to defer the rising energetic costs of gestation when conditions are unfavourable, reducing the risk of embryo loss. Dispersal in mammals that breed cooperatively is a period when food intake is likely to be suppressed and stress levels are likely to be high. Here, we show that pregnant dispersing meerkats ( Suricata suricatta ), which have been aggressively evicted from their natal group and experience weight loss and extended periods of social stress, prolong their gestation by means of delayed embryonic development. Repeated ultrasound scans of wild, unanaesthetized females throughout their pregnancies showed that pregnancies of dispersers were on average 6.3% longer and more variable in length (52–65 days) than those of residents (54–56 days). The variation in dispersers shows that, unlike most mammals, meerkats can adapt to stress by adjusting their pregnancy length by up to 25%. By doing so, they potentially rearrange the costs of gestation during adverse conditions of dispersal and enhance offspring survival.

In severe falciparum malaria cytoadherence of parasitised red blood cells (PRBCs) to vascular endothelium (causing sequestration) and to uninfected red cells (causing rosette formation) contribute to microcirculatory flow obstruction in vital organs. Heparin can reverse the underlying ligand-receptor interactions, but may increase the bleeding risks. As a heparin-derived polysaccharide, sevuparin has been designed to retain anti-adhesive properties, while the antithrombin-binding domains have been eliminated, substantially diminishing its anticoagulant activity. Sevuparin has been evaluated recently in patients with uncomplicated falciparum malaria, and is currently investigated in a clinical trial for sickle cell disease. The effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum isolates from Thailand were investigated. Trophozoite stages of P. falciparum-infected RBCs (Pf-iRBCs) were cultured from 49 patients with malaria. Pf-iRBCs were treated with sevuparin at 37°C and assessed in rosetting and in cytoadhesion assays with human dermal microvascular endothelial cells (HDMECs) under static and flow conditions. The proportion of Pf-iRBCs forming rosettes ranged from 6.5% to 26.0% (median = 12.2%). Rosetting was dose dependently disrupted by sevuparin (50% disruption by 250 μg/mL). Overall 57% of P. falciparum isolates bound to HDMECs under static conditions; median (interquartile range) Pf-iRBC binding was 8.5 (3.0-38.0) Pf-iRBCs/1000 HDMECs. Sevuparin in concentrations ≥ 100 μg/mL inhibited cytoadherence. Sevuparin disrupts P. falciparum rosette formation in a dose dependent manner and inhibits cytoadherence to endothelial cells. The data support assessment of sevuparin as an adjunctive treatment to the standard therapy in severe falciparum malaria.

Journal Article Polymorphonuclear leucocyte elastase in Plasmodium falciparum malaria Get access S. Pukrittayakamee, S. Pukrittayakamee ∗ 1Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand ∗Author for correspondence. Search for other works by this author on: Oxford Academic PubMed Google Scholar R. Clemens, R. Clemens 1Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar C. Pramoolsinsap, C. Pramoolsinsap 2Division of Gastroenterology and Tropical Medicine, Department of Medicine, Ramathibodi Hospital, Mahidol University, Rama IV Road, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar H.E. Karges, H.E. Karges 3Behringwerke AG, Marburg, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar S. Vanijanonta, S. Vanijanonta 1Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar D. Bunnag, D. Bunnag 1Bangkok Hospital for Tropical Diseases, 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 1Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand4Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 86, Issue 6, November-December 1992, Pages 598–601, https://doi.org/10.1016/0035-9203(92)90143-Z Published: 01 November 1992 Article history Received: 14 January 1992 Revision received: 09 March 1992 Accepted: 24 March 1992 Published: 01 November 1992

Artemisinin-based combination therapies (ACTs) have contributed substantially to the global decline in Plasmodium falciparum morbidity and mortality, but resistance to artemisinins and their partner drugs is increasing in Southeast Asia, threatening malaria control. New antimalarial compounds will not be generally available soon.

Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response ≤28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.

In male vertebrates, androgens are inextricably linked to reproduction, social dominance, and aggression, often at the cost of paternal investment or prosociality. Testosterone is invoked to explain rank-related reproductive differences, but its role within a status class, particularly among subordinates, is underappreciated. Recent evidence, especially for monogamous and cooperatively breeding species, suggests broader androgenic mediation of adult social interaction. We explored the actions of androgens in subordinate, male members of a cooperatively breeding species, the meerkat (Suricata suricatta). Although male meerkats show no rank-related testosterone differences, subordinate helpers rarely reproduce. We blocked androgen receptors, in the field, by treating subordinate males with the antiandrogen, flutamide. We monitored androgen concentrations (via baseline serum and time-sequential fecal sampling) and recorded behavior within their groups (via focal observation). Relative to controls, flutamide-treated animals initiated less and received more high-intensity aggression (biting, threatening, feeding competition), engaged in more prosocial behavior (social sniffing, grooming, huddling), and less frequently initiated play or assumed a ‘dominant’ role during play, revealing significant androgenic effects across a broad range of social behavior. By contrast, guarding or vigilance and measures of olfactory and vocal communication in subordinate males appeared unaffected by flutamide treatment. Thus, androgens in male meerkat helpers are aligned with the traditional trade-off between promoting reproductive and aggressive behavior at a cost to affiliation. Our findings, based on rare endocrine manipulation in wild mammals, show a more pervasive role for androgens in adult social behavior than is often recognized, with possible relevance for understanding tradeoffs in cooperative systems.

Seasonal influenza leads to 2–3 million infections and up to 650,000 global deaths annually, with particularly high mortality in Asia and relatively low annual vaccination rates for prevention. Relatively lower attention is paid to antiviral treatment as a facet of influenza response strategy both in research and national policy. This study compares national influenza treatment guidelines across countries in the Asia Pacific region, and assesses the antiviral recommendations, comprehensiveness, availability, and quality, compared with World Health Organisation (WHO) guidelines. Ministry of Health websites were searched, and key stakeholders were contacted to obtain national influenza treatment guidelines. Official guidelines detailing pharmacologic treatment for seasonal influenza were included. Key data for comparison were extracted and quality appraisal was conducted using the AGREE II instrument. Out of 49 countries and areas in the World Health Organisation Western Pacific and South-East Asia regions, under half (14/49; 28.6%) had established national influenza treatment guidelines. Nine (9/49; 18.4%) reported no seasonal flu guidelines at all, and information could not be obtained for 25 (51.0%). All guidelines recommend oseltamivir in line with WHO recommendations, although rationale and evidence reviews were often missing. There was variation in recommendations for other antivirals, indications for treatment, definitions of severity and recency of publication. The AGREE II tool quality assessments revealed the highest average scores were observed in the ‘presentation’ domain and lowest scores in ‘editorial independence’ and ‘rigour of development’ domains, demonstrating limited evidence-based guideline development. The variability in recommendations and definitions highlight the need for a stronger evidence base with direct comparisons of antiviral treatment for hard and soft endpoints, and improvements in systematic guideline development. Established treatment guidelines are a key component of national influenza response strategy and in the post-covid pandemic era, renewed attention to seasonal influenza management is surely warranted.