Publications

Cerebral malaria (CM) is a major cause of death in severe Plasmodium falciparum malaria. We present quantitative electron microscopic findings of the neuropathologic features in a prospective clinicopathologic study of 65 patients who died of severe malaria in Thailand and Vietnam. Sequestration of parasitized red blood cells (PRBCs) in cerebral microvessels was significantly higher in the brains of patients with CM compared with those with non-cerebral malaria (NCM) in all parts of the brain (cerebrum, cerebellum, and medulla oblongata). There was a hierarchy of sequestration with more in the cerebrum and cerebellum than the brain stem. When cerebral sequestration was compared with the peripheral parasitemia pre mortem, there were 26.6 times more PRBCs in the brain microvasculature than in the peripheral blood. The sequestration index was significantly higher in CM patients (median = 50.7) than in NCM patients (median = 6.9) (P = 0.042). The degree of sequestration of P. falciparum-infected erythrocytes in cerebral microvessels is quantitatively associated with pre-mortem coma.

Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.

No abstract is provided for this article.

Changing environmental conditions cause changes in the distributions of phenotypic traits in natural populations. However, determining the mechanisms responsible for these changes—and, in particular, the relative contributions of phenotypic plasticity versus evolutionary responses—is difficult. To our knowledge, no study has yet reported evidence that evolutionary change underlies the most widely reported phenotypic response to climate change: the advancement of breeding times. In a wild population of red deer, average parturition date has advanced by nearly 2 weeks in 4 decades. Here, we quantify the contribution of plastic, demographic, and genetic components to this change. In particular, we quantify the role of direct phenotypic plasticity in response to increasing temperatures and the role of changes in the population structure. Importantly, we show that adaptive evolution likely played a role in the shift towards earlier parturition dates. The observed rate of evolution was consistent with a response to selection and was less likely to be due to genetic drift. Our study provides a rare example of observed rates of genetic change being consistent with theoretical predictions, although the consistency would not have been detected with a solely phenotypic analysis. It also provides, to our knowledge, the first evidence of both evolution and phenotypic plasticity contributing to advances in phenology in a changing climate.

Pro- and antiinflammatory cytokines were measured on admission in 287 consecutive Vietnamese adults with severe falciparum malaria. Plasma interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations and the IL-6: IL-10 ratio were significantly higher in patients who died than in survivors (P<.001). On multivariate analysis, hyperparasitemia, jaundice, and shock were all associated independently with raised IL-6, IL-10, and interferon-gamma, and acute renal failure specifically with raised TNF-alpha levels. Cerebral malaria patients, particularly those without other vital organ dysfunction, had significantly lower levels of these cytokines (P=.006), reflecting a more localized pathology. Serial IL-6 and IL-10 measurements made on 43 patients who died and matched survivors indicated a relative deficiency in IL-10 production as death approached. Elevated plasma cytokines in severe malaria are associated with systemic pathologic abnormalities, not cerebral involvement. Both the overall magnitude of the cytokine responses and the eventual imbalance between the pro- and antiinflammatory responses are important determinants of mortality.

Recent changes in the seasonal timing (phenology) of familiar biological events have been one of the most conspicuous signs of climate change. However, the lack of a standardized approach to analysing change has hampered assessment of consistency in such changes among different taxa and trophic levels and across freshwater, terrestrial and marine environments. We present a standardized assessment of 25 532 rates of phenological change for 726 UK terrestrial, freshwater and marine taxa. The majority of spring and summer events have advanced, and more rapidly than previously documented. Such consistency is indicative of shared large scale drivers. Furthermore, average rates of change have accelerated in a way that is consistent with observed warming trends. Less coherent patterns in some groups of organisms point to the agency of more local scale processes and multiple drivers. For the first time we show a broad scale signal of differential phenological change among trophic levels; across environments advances in timing were slowest for secondary consumers, thus heightening the potential risk of temporal mismatch in key trophic interactions. If current patterns and rates of phenological change are indicative of future trends, future climate warming may exacerbate trophic mismatching, further disrupting the functioning, persistence and resilience of many ecosystems and having a major impact on ecosystem services.

Clinical studies have shown that adding a single 0.25 mg base/kg dose of primaquine to standard antimalarial regimens rapidly sterilizes Plasmodium falciparum gametocytes. However, the mechanism of action and overall impact on malaria transmission is still unknown. Using data from 81 adult Malians with P. falciparum gametocytemia who received the standard dihydroartemisinin-piperaquine treatment course and were randomized to receive either a single dose of primaquine between 0.0625 and 0.5 mg base/kg or placebo, we characterized the pharmacokinetic-pharmacodynamic relationships for transmission blocking activity. Both gametocyte clearance and mosquito infectivity were assessed. A mechanistically linked pharmacokinetic-pharmacodynamic model adequately described primaquine and carboxy-primaquine pharmacokinetics, gametocyte dynamics, and mosquito infectivity at different clinical doses of primaquine. Primaquine showed a dose-dependent gametocytocidal effect that precedes clearance. A single low dose of primaquine (0.25 mg/kg) rapidly prevented P. falciparum transmissibility.

Five male patients with acute Plasmodium falciparum or Plasmodium vivax infections were infused with chloroquine diphosphate (15 mg kg-1) over four hours. Further does of chloroquine diphosphate (5 mg kg-1) were given at 12, 24, 36 and 60 hours. Plasma chloroquine concentrations were determined before and four hours after each dose and then daily until discharge. No serious cardiovascular toxicity was observed, and plasma chloroquine concentrations exceeding the putative minimum inhibitory concentration (MIC) of sensitive P. falciparum strains were reached within four hours of starting treatment. Further doses produced plasma concentrations which were sustained above the putative MIC, but showed no rapid increase into the range associated with toxicity.

Background. Sequestration of infected red blood cells (iRBCs) in the microcirculation is central to the pathophysiology of falciparum malaria. It is caused by cytoadhesion of iRBCs to vascular endothelium, mediated through the binding of Plasmodium falciparum erythrocyte membrane protein–1 to several endothelial receptors. Binding to CD36, the major vascular receptor, is stabilized through dephosphorylation of CD36 by an alkaline phosphatase. This is inhibited by the alkaline phosphatase-inhibitor levamisole, resulting in decreased cytoadhesion.

The social organization of Damaraland and naked mole-rats is often suggested to resemble the societies of eusocial insects more closely than that of any other vertebrate. Eusocial insects feature queens that hardly contribute to the workforce, and specialized worker castes. However, in Damaraland and naked mole-rats, which live in family groups with a single breeding pair and multiple non-breeding helpers, the work division is still unclear. Previous studies, largely confined to laboratory settings, could not quantify their primary cooperative behaviour, which is digging extensive foraging tunnels. Here, we studied the distribution of workload in 11 wild Damaraland mole-rat groups, using body acceleration loggers to evaluate behavioural time budgets of 86 individuals. We found behavioural differences between breeders and non-breeders that emerged with increases in group size, such that in large groups, breeders spent less time digging, more time resting, and were overall less active than non-breeders. We did not find any indication of a caste system among non-breeders, though the amount of time individuals spent digging varied with age and sex. Overall, the lower contribution by breeders to the group’s workload is a pattern rarely observed in other cooperative vertebrates; nevertheless, the lack of evidence for castes suggests that eusociality may be limited to invertebrates. This article is part of the theme issue ‘Division of labour as key driver of social evolution’.

There is no published information on the causes of bacteremia in the Lao PDR (Laos). Between 2000 and 2004, 4512 blood culture pairs were taken from patients admitted to Mahosot Hospital, Vientiane, Laos, with suspected community-acquired bacteremia; 483 (10.7%) cultures grew a clinically significant community-acquired organism, most commonly Salmonella enterica serovar typhi (50.9%), Staphylococcus aureus (19.0%), and Escherichia coli (12.4%). S. aureus bacteremia was common among infants (69.2%), while children 1–5 years had a high frequency of typhoid (44%). Multi–drug-resistant S . Typhi was rare (6%). On multiple logistic regression analysis, typhoid was associated with younger age, longer illness, diarrhea, higher admission temperature, and lower peripheral white blood cell count than non-typhoidal bacteremia. Empirical parenteral ampicillin and gentamicin would have some activity against ~ 88% of clinically significant isolates at a cost of US $1.4/day, an important exception being B. pseudomallei . Bacteremic infants in this setting require an anti-staphylococcal antibiotic.

that 192,000 people died in China in 2001 as a consequence of fake drugs

Unvaccinated individuals throughout the world are vulnerable to tetanus, but there are few data regarding the impact of focused vaccination programmes and modern intensive care facilities on the disease, particularly in the developing world. The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam admitted 2422 patients with tetanus aged > or =1 year between April 1993 and December 2002, during which time vaccine coverage and treatment facilities improved. The proportion of children < or =10 years old admitted with tetanus fell from 11.1 to 5.6% over the 10 year period (P = 0.002). The proportion of women aged 20-40 years fell from 10.1 to 1.2% (P < 0.001). Mortality rates fell from a maximum of 27.81% in 1994 to 10.04% in 2002 (P < 0.001). Thus, a marked reduction in tetanus incidence has occurred in age groups specifically targeted by the national vaccination programme. However, tetanus continues to be a major cause of morbidity and mortality in individuals outside the target population. Improved intensive care facilities, such as mechanical ventilation and low-cost infection control procedures are associated with a significant reduction in mortality.