Publications

2,455 publications from this institution

Effect of magnesium sulphate on urinary catecholamine excretion in severe tetanus

Summary Severe tetanus is characterised by muscle spasms and autonomic dysfunction. We recently reported the results of a randomised placebo controlled trial of magnesium sulphate infusions for the treatment of severe tetanus which showed magnesium was associated with improved muscle spasm and cardiovascular control. We hypothesised that magnesium controlled autonomic dysfunction by reducing catecholamine release and thus urinary excretion. Urinary adrenaline and noradrenaline concentrations were measured during the first 24 h of therapy in 180 adults with severe tetanus randomised to treatment with magnesium ( n = 92) or placebo ( n = 88). Magnesium therapy was associated with lower urinary adrenaline excretion and higher urinary noradrenaline excretion. High urinary adrenaline concentrations were associated with documented autonomic dysfunction. Patients given magnesium had significantly less autonomic dysfunction, required less cardiovascular stabilising drugs, and had lower urinary concentrations of adrenaline. These findings suggest adrenaline is important in the pathophysiology of severe tetanus and magnesium controls autonomic dysfunction by reducing adrenaline release.

Louise Thwaites, Lam Minh Yen, Sally M. Cordon et al. 2008Article

Antimalarial chemoprophylaxis for forest goers in southeast Asia: an open-label, individually randomised controlled trial

Malaria in the eastern Greater Mekong subregion has declined to historic lows. Countries in the Greater Mekong subregion are accelerating malaria elimination in the context of increasing antimalarial drug resistance. Infections are now increasingly concentrated in remote, forested foci. No intervention has yet shown satisfactory efficacy against forest-acquired malaria. The aim of this study was to assess the efficacy of malaria chemoprophylaxis among forest goers in Cambodia.

Rupam Tripura, Lorenz von Seidlein, Siv Sovannaroth et al. 2022Article

Pharmaceutical development and optimization of azithromycin suppository for paediatric use

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought.

Tina Kauss, Alexandra Gaubert, Chantal Boyer et al. 2012Article

Does Artesunate Prolong the Electrocardiograph QT Interval in Patients with Severe Malaria?

Several antimalarials can cause significant prolongation of the electrocardiograph QT interval, which can be associated with an increased risk of potentially lethal ventricular arrhythmias. High doses of artemether and artemotil have been associated with QT prolongation in dogs, raising the possibility of a class effect with the artemisinin derivatives. Serial electrocardiograms were recorded, and QTc interval was calculated before and after administration of artesunate by intravenous injection in patients with severe falciparum malaria in Bangladesh. Of 21 adult patients with severe malaria enrolled, 8 (38%) died. The mean QTc interval was unaffected by bolus intravenous artesunate (2.4 mg/kg). In two patients, the QTc interval exceeded 0.5 seconds, but in both cases, an alternative explanation was plausible. No effect was observed on the JTc or PR interval, QRS width, blood pressure, or heart rate. Intravenous artesunate does not have significant cardiovascular effects in patients with severe falciparum malaria.

Richard J. Maude, Katherine Plewes, M Abul Faiz et al. 2009Article

Defective production of and response to IL-2 in acute human falciparum malaria.

Patients with acute Plasmodium falciparum malaria have defective cell-mediated immune responses to malaria-specific Ag (MA). This immunologic defect may partially explain the difficulty with which natural immunity to falciparum malaria develops and may have important implications for the efficacy of potential malaria vaccines in endemic areas. To investigate the basis of this immune defect, we have examined the capacity of PBMC from patients with acute falciparum malaria to produce IL-2 and to express I1-2R in response to Ag stimulation. The effect of exogenous IL-1 and IL-2 on lymphocyte proliferation was studied. Soluble IL-2R levels were measured in acute and convalescent sera. Our results showed that no detectable IL-2 was produced and no IL-2R were expressed by PBMC in response to MA during the acute infection. IL-2 production and IL-2R expression were also depressed when PBMC were exposed to streptococcal Ag. The specific immune defect was not reconstituted by the addition of graded doses of purified human IL-1 or IL-2 and could not be attributed to suppressor adherent cells. In contrast to the absence of IL-2 and cell-bound IL-2R, circulating soluble IL-2R was elevated in acute sera. These findings suggest that the lack of IL-2, through either a defect in its production or inhibition of its activity, may be the basis of the Ag-specific immune unresponsiveness in acute P. falciparum malaria.

M Ho, H. Kyle Webster, B Green et al. 1988Article

Effects of Malaria Heme Products on Red Blood Cell Deformability

In falciparum malaria, the deformability of the entire erythrocyte population is reduced in proportion to disease severity, and this compromises microcirculatory blood flow through vessels partially obstructed by cytoadherent parasitized erythrocytes. The cause of rigidity of uninfected erythrocytes in not known but could be mediated by malaria heme products. In this study, we show that red blood cell deformability (RBC-D), measured by laser-assisted optical rotational cell analyzer, decreased in a dose-dependent manner after incubation with hemin and hydrogen peroxide but not with hemoglobin or beta-hematin. Hemin also reduced mean red cell volume. Albumin decreased and N-acetylcysteine (NAC) both prevented and reversed rigidity induced by hemin. Hemin-induced oxidative damage of the membrane seems to be a more important contributor to pathology than cell shrinkage because the antioxidant NAC restored RBC-D but not red blood cell volume. The findings suggest novel approaches to the treatment of potentially lethal malaria.

Forradee Nuchsongsin, Kesinee Chotivanich, Prakaykaew Charunwatthana et al. 2007Article

Methaemoglobinaemia and the radical curative efficacy of 8-aminoquinoline antimalarials

Methaemoglobin results from the oxidation of ferrous to ferric iron in the centre of the haem moeity of haemoglobin. The production of dose-dependent methaemoglobinaemia by 8-aminoquinoline antimalarial drugs appears to be associated with, but is not directly linked to therapeutic efficacy against latent vivax and ovale malarias. Iatrogenic methaemoglobinaemia may be a useful pharmacodynamic measure in 8-aminoquinoline drug and dose optimization.

Sir Nicholas White, James A Watson, Kevin Baird 2021Preprint

Transmission-blocking activity of artesunate, chloroquine and methylene blue on Plasmodium vivax gametocytes.

Plasmodium vivax is now the main cause of malaria outside Africa. The gametocytocidal effects of antimalarial drugs are important to reduce malaria transmissibility, particularly in low transmission settings, but they are not well characterized for P. vivax . The transmission-blocking effects of chloroquine, artesunate and methylene blue on P. vivax gametocytes were assessed. Blood specimens were collected from patients presenting with vivax malaria, incubated with or without the tested drugs, and then fed to mosquitos from a laboratory-adapted colony of Anopheles dirus (a major malaria vector in Southeast Asia). The effects on oocyst and sporozoite development were analyzed under a multi-level Bayesian model accounting for assay variability and the heterogeneity of mosquito Plasmodium -infection. Artesunate and methylene blue, but not chloroquine, exhibited potent transmission-blocking effects. Gametocyte exposures to artesunate and methylene blue reduced the mean oocyst count 469 fold (95%CI: 345 to 650) and 1438 fold (95%CI: 970 to 2064) respectively. The corresponding estimates for the sporozoite stage were a 148 fold reduction (95%CI: 61 to 470) and a 536 fold reduction (95%CI: 246 to 1311) in the mean count, respectively. In contrast, high chloroquine exposures reduced the mean oocyst count by only 1.40 fold (95%CI: 1.20 to 1.64) and the mean sporozoite count 1.34 fold (95%CI: 1.12 to 1.66). This suggests that patients with vivax malaria often remain infectious to anopheline mosquitos after treatment with chloroquine. Immediate initiation of primaquine radical cure or use of artemisinin combination therapies would reduce the transmissibility of P. vivax infections.

Victor Chaumeau, Praphan Wasisakun, James A Watson et al. 2024Preprint

Development and Evaluation of Rapid Urinary Antigen Detection Tests for Diagnosis of Penicilliosis Marneffei

Penicilliosis, caused by the dimorphic fungus Penicillium marneffei, is an important opportunistic systemic fungal infection affecting immunocompromised individuals living in areas where penicilliosis is endemic. We have demonstrated previously that a urinary enzyme-linked immunosorbent assay (ELISA) with purified rabbit polyclonal antibody against killed whole-fission-form arthroconidia of P. marneffei was specific and highly sensitive for the diagnosis of penicilliosis. In this study, a dot blot ELISA and a latex agglutination (LA) test were developed with the same polyclonal antibody and compared with the ELISA for the detection of P. marneffei urinary antigen. Urine specimens from 37 patients with culture-proven penicilliosis and 300 controls (52 healthy subjects and 248 hospitalized patients without penicilliosis) were tested. Antigen was detected in urine from all 37 (100%) penicilliosis patients by the LA test, 35 (94.6%) penicilliosis patients by the dot blot ELISA, and 36 (97.3%) penicilliosis patients by the ELISA. False-positive results were found by the three assays for 2 (0.7%), 8 (2.7%), and 6 (2%) of 300 controls, respectively. The overall sensitivities of the diagnostic tests were as follows: dot blot ELISA, 94.6%; ELISA, 97.3%; and LA test, 100% (specificities, 97.3, 98, and 99.3%, respectively). The LA test is simple, robust, rapid, and convenient and should prove to be an important addition to the existing diagnostic tests for penicilliosis.

Varunee Desakorn, Andrew J. H. Simpson, Vanaporn Wuthiekanun et al. 2002Article

No Evidence for Spread of Plasmodium falciparum Artemisinin Resistance to Savannakhet Province, Southern Laos

We conducted an open-label, randomized clinical trial to assess parasite clearance times (PCT) and the efficacy of 4 mg/kg (group 1, n = 22) and 2 mg/kg (group 2, n = 22) of oral artesunate for three days followed by artemether-lumefantrine in patients with uncomplicated Plasmodium falciparum malaria at Xepon Interdistrict Hospital, Savannakhet Province in southern Laos. Slides were read in duplicate. The overall mean (95% confidence interval; range) PCT in hours was 23.2 (21.2–25.3; 12–46) and 22.4 (20.3–24.5; 12–46) for the first and second microscopists, respectively ( P = 0.57). Ten (23%) patients remained parasitemic on day 1 after treatment (4 [18%] in group 1 and 6 [27%] in group 2; P = 0.47). No patient had patent asexual parasitemia on the second and third days of treatment. The 42-day polymerase chain reaction–corrected cure rates were 100% in both treatment groups. Serious adverse events did not develop during or after treatment in any patients. In conclusion, no evidence of P. falciparum in vivo resistance to artesunate was found in southern Laos.

Mayfong Mayxay, Maniphone Khanthavong, Odai Chanthongthip et al. 2012Article

State-dependent life history evolution in Soay sheep: dynamic modelling of reproductive scheduling

Adaptive decisions concerning the scheduling of reproduction in an animal’s lifetime, including age at maturity and clutch or litter size, should depend on an animal’s body condition or state. In this statedependent case, we are concerned with the optimization of sequences of actions and so dynamic optimization techniques are appropriate. Here we show how stochastic dynamic programming can be used to study the reproductive strategies and population dynamics of natural populations, assuming optimal decisions. As examples we describe models based upon field data from an island population of Soay sheep on St.Kilda. This population shows persistent instability, with cycles culminating in high mortality every three or four years. We explore different assumptions about the extent to which Soay ewes use information about the population cycle in making adaptive decisions. We compare the observed distributions of strategies and population dynamics with model predictions; the results indicate that Soay ewes make optimal reproductive decisions given that they have no information about the population cycle. This study represents the first use of a dynamic optimization life history model of realistic complexity in the study of a field population. The techniques we use are potentially applicable to many other populations, and we discuss their extension to other species and other life history questions.

Paul Marrow, John M. McNamara, A I Houston et al. 1996Article

Signals of need in a cooperatively breeding mammal with mobile offspring

In many bird species with biparental care for young in the nest, hungry chicks beg repeatedly and parents adjust their feeding rate to the call rate of young. Repetitive calling also occurs in fledglings and in some mammals where offspring follow provisioners. It is not yet clear whether, in mobile systems with dispersed young where adults cannot compare the vocal behaviour of all young simultaneously, the calls represent a signal of need. We investigated repetitive begging by cooperatively reared meerkat, Suricata suricatta, pups that foraged with the group. Pups produced two types of begging calls: repeat calls over long periods and high-pitched calls mainly confined to feeding events. Food-deprived pups stayed closer to feeders, and begged for longer and more intensely by calling at a higher rate. Hungry pups increased both the rate of repeat calls, which were given continually, and the number of high-pitched bouts, but adults increased their food allocation only in relation to the rate of repeat calls. Our study indicates that hunger may lead to several changes in vocal behaviour, only some of which may be used by adults to assess need.

Marta B. Manser, Joah R. Madden, Hansjoerg P. Kunc et al. 2008Article

The mechanism of artemisinin resistance of Plasmodium falciparum malaria parasites originates in their initial transcriptional response.

The emergence and spread of artemisinin resistant Plasmodium falciparum , first in the Greater Mekong Subregion (GMS), and now in East Africa, is a major threat to global malaria eliminations ambitions. To investigate the artemisinin resistance mechanism, transcriptome analysis was conducted of 577 P. falciparum isolates collected in the GMS between 2016–2018. A specific artemisinin resistance-associated transcriptional profile was identified that involves a broad but discrete set of biological functions related to proteotoxic stress, host cytoplasm remodeling and REDOX metabolism. The artemisinin resistance-associated transcriptional profile evolved from initial transcriptional responses of susceptible parasites to artemisinin. The genetic basis for this adapted response is likely to be complex.

Lei Zhu, Rob W. van der Pluijm, Michal Kucharski et al. 2021Preprint

Reproductive rate, not dominance status, affects fecal glucocorticoid levels in breeding female meerkats

Glucocorticoid hormones (GCs) have been studied intensively to understand the associations between physiological stress and reproductive skew in animal societies. However, we have little appreciation of the range of either natural levels within and among individuals, or the associations among dominance status, reproductive rate and GCs levels during breeding. To address these shortcomings, we examined variation in fecal glucocorticoid metabolites (fGC) during breeding periods in free-ranging female meerkats (Suricata suricatta) over 11years. The vast majority of variation in fGC levels was found within breeding events by the same female (~87%), with the remaining variation arising among breeding events and among females. Concentrations of fGC generally tripled as pregnancy progressed. However, females with a high reproductive rate, defined as those conceiving within a month following parturition (mean=9days postpartum), showed significant reductions in fGC in the final 2weeks before parturition. Despite these reductions, females with a high reproductive rate had higher fGC levels at conception of the following litter than those breeding at a low rate. After controlling for the higher reproductive rate of dominants, we found no association between levels of fGC and either age or dominance status. Our results suggest that one should be cautious about interpreting associations between dominance status, reproductive skew and GCs levels, without knowledge of the natural variation in GCs levels within and among females.

Marie-France Barrette, Steven L. Monfort, Marco Festa‐Bianchet et al. 2011Article

Animal husbandry: Red velvet and venison

No abstract is provided for this article.

Tim Clutton-brock 1983Article

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