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Background: Interactions between the endothelium and infected erythrocytes play a major role in the pathogenesis of falciparum malaria, with microvascular dysfunction and parasite sequestration associated with worsening outcomes. The glycocalyx is a carbohydrate-rich layer that lines the endothelium, with multiple roles in vascular homeostasis. The role of the glycocalyx in falciparum malaria and the association with disease severity has not been investigated. Methods: We prospectively enrolled Indonesian inpatients (aged ≥18 years) with severe (SM) or moderately severe (MSM) falciparum malaria, as defined by World Health Organization criteria, and healthy controls (HCs). On enrollment, blood and urine samples were collected concurrently with measurements of vascular nitric oxide (NO) bioavailability. Urine was assayed for glycocalyx breakdown products (glycosaminoglycans) using a dimethylmethylene blue (GAG-DMMB) and liquid chromatography-tandem mass spectrometry (GAG-MS) assay. Results: A total of 129 patients (SM = 43, MSM = 57, HC=29) were recruited. GAG-DMMB and GAG-MS (g/mol creatinine) were increased in SM (mean, 95% confidence interval: 3.98, 2.44–5.53 and 6.82, 5.19–8.44) compared to MSM patients (1.78, 1.27–2.29 and 4.87, 4.27–5.46) and HCs (0.22, 0.06–0.37 and 1.24, 0.89–1.59; P < 0.001). In SM patients, GAG-DMMB and GAG-MS were increased in those with a fatal outcome (n = 3; median, interquartile range: 6.72, 3.80–27.87 and 12.15, 7.88–17.20) compared to survivors (n = 39; 3.10, 0.46–4.5 and 4.64, 2.02–15.20; P = 0.03). Glycocalyx degradation was significantly associated with parasite biomass in both MSM (r = 0.48, GAG-DMMB and r = 0.43, GAG-MS; P < 0.001) and SM patients (r = 0.47, P = 0.002 and r = 0.33, P = 0.04) and inversely associated with endothelial NO bioavailability. Conclusions: Increased endothelial glycocalyx breakdown is associated with severe disease and a fatal outcome in adults with falciparum malaria. National Medical Research Council (NMRC) Published version The study was supported by the National Health and Medical Research Council of Australia (grants 1132975, International Collaborative Research Grant 283321, HOTNORTH 1131932 [E. K.] and Fellowship 1135820 [N. A.]), the National Institutes of Health (grant 1R01 HL130763-01), the Durham VA Research Service (2772), the Wellcome Trust (ICRG ME928457MES), and the Singapore National Medical Research Council (award to T. W. Y., CSA INV 15nov007).

Although more than 40% of the world's population live in malaria endemic areas, there are only 6 available antimalarial drugs for the treatment of Plasmodium falciparum infections. Three of these have been developed in the last 20 years and are discussed in this review. Mefloquine is relatively well tolerated and has the advantage of a single day regimen. It has ideal properties for prophylactic use. However, although rare, serious adverse reactions do occur and the drug cannot be used in severe malaria. Resistance has already emerged in some parts of the world. Halofantrine is also well tolerated and has a rapid antimalarial activity. It is more expensive than other antimalarials and the existence of cross-resistance links its usefulness to the demise of mefloquine. The discovery of a potentially lethal cardiotoxicity associated with halofantrine casts a further shadow over its use. The artemisinin derivatives represent an exciting breakthrough in the treatment of malaria. They are cheap and have a very rapid action. They seem remarkably free from toxic adverse effects, although the neurotoxicity seen in animal studies with the liposoluble derivatives gives rise for concern. However, the lack of pharmacokinetic and toxicity data as yet preclude their approval by Western drug regulation authorities. All antimalarials are threatened by the emergence of parasite resistance. Combination therapy using mefloquine and an artemisinin derivative may provide a way in which resistance can be combated.

Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of l -arginine, the substrate for NO synthase. Supplementation with l -arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for l -arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g, l -arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received l -arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] = 52%) and a volume of distribution of 24 liters (CV = 19%). The natural time course of l -arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous l -arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the K m of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.

John Searle and Susanna Siegel have argued that cases of aspect-switching show that visual experience represents a richer range of properties than colours, shapes, positions and sizes. I respond that cases of aspect-switching can be explained without holding that visual experience represents rich properties. I also argue that even if Searle and Siegel are right, and aspect-switching does require visual experience to represent rich properties, there is reason to think those properties do not include natural-kind properties, such as being a tomato.

Using matching and regression analyses, we measure the difference in citations between articles posted to Academia.edu and other articles from similar journals, controlling for field, impact factor, and other variables. Based on a sample size of 31,216 papers, we find that a paper in a median impact factor journal uploaded to Academia.edu receives 16% more citations after one year than a similar article not available online, 51% more citations after three years, and 69% after five years. We also found that articles also posted to Academia.edu had 58% more citations than articles only posted to other online venues, such as personal and departmental home pages, after five years.

IntroductionMaternal mortality is high in developing countries, but there are few data in high-risk groups such as migrants and refugees in malaria-endemic areas. Trends in maternal mortality were followed over 25 years in antenatal clinics prospectively established in an area with low seasonal transmission on the north-western border of Thailand.Methods and findingsAll medical records from women who attended the Shoklo Malaria Research Unit antenatal clinics from 12(th) May 1986 to 31(st) December 2010 were reviewed, and maternal death records were analyzed for causality. There were 71 pregnancy-related deaths recorded amongst 50,981 women who attended antenatal care at least once. Three were suicide and excluded from the analysis as incidental deaths. The estimated maternal mortality ratio (MMR) overall was 184 (95%CI 150-230) per 100,000 live births. In camps for displaced persons there has been a six-fold decline in the MMR from 499 (95%CI 200-780) in 1986-90 to 79 (40-170) in 2006-10, pConclusionsFrequent antenatal clinic screening allows early detection and treatment of falciparum malaria and substantially reduces maternal mortality from P. falciparum malaria. No significant decline has been observed in deaths from sepsis or other causes in refugee and migrant women on the Thai-Myanmar border.

Malaria continues to exert a huge global burden both in public health and economic terms. Although Plasmodium falciparum infections have been the focus of research and control efforts, there is a growing awareness that the burden of, and morbidity and mortality associated with, Plasmodium vivax infections are also substantial [1-4]. Control strategies for both species have been confounded by the emergence of antimalarial drug resistance to multiple drugs. Although chloroquine resistant P. falciparum was first documented >50 years ago in Cambodia, the first cases of chloroquine-resistant P. vivax infection were not reported until 1989 from Papua New Guinea [5] and northern Papua, Indonesia [6]. In the last decade, chloroquine resistance has continued to emerge, with failure rates after monotherapy exceeding 70% in Papua [7-9]. Other reports suggest declining chloroquine efficacy across much of Asia and South America [1, 10]. Few studies have specifically addressed the clinical efficacy of other antimalarial regimens against P. vivax, although the available data suggest that in western Indonesia mefloquine retains clinical efficacy [11], whereas amodiaquine efficacy is waning, particularly in the eastern province of Papua [12] and Papua New Guinea [13]. The dearth of clinical studies of P. vivax reflects both the inherent difficulties associated with the in vivo test for relapsing malaria [14] and the difficulties in differentiating between reinfection, recrudescence, and relapse after treatment failure [15, 16]. To better define the drug-susceptibility profile of P. vivax, we recently developed a standardized in vitro assay [17] and validated it using isolates of P. vivax from Indonesia, where P. vivax is known to be highly resistant to chloroquine, and from Thailand, where strains remain susceptible to chloroquine [18]. The aim of the present study was to define the in vitro susceptibility profile of P. vivax for a wider range of antimalarial drugs and correlate this with pvmdr1 copy number and a polymorphism known to be prevalent in both Thailand and Indonesia [18].

Background Multidrug resistance has emerged to both Plasmodium vivax and Plasmodium falciparum and yet the comparative epidemiology of these infections is poorly defined. Methods All laboratory-confirmed episodes of malaria in Timika, Papua, Indonesia, presenting to community primary care clinics and an inpatient facility were reviewed over a two-year period. In addition information was gathered from a house-to-house survey to quantify the prevalence of malaria and treatment-seeking behaviour of people with fever. Results Between January 2004 and December 2005, 99,158 laboratory-confirmed episodes of malaria were reported, of which 58% (57,938) were attributable to P. falciparum and 37% (36,471) to P. vivax. Malaria was most likely to be attributable to pure P. vivax in children under one year of age (55% 2,684/4,889). In the household survey, the prevalence of asexual parasitaemia was 7.5% (290/3,890) for P. falciparum and 6.4% (248/3,890) for P. vivax. The prevalence of P. falciparum infection peaked in young adults aged 15–25 years (9.8% 69/707), compared to P. vivax infection which peaked in children aged 1 to 4 years (9.5% 61/642). Overall 35% (1,813/5,255) of people questioned reported a febrile episode in the preceding month. Of the 60% of people who were estimated to have had malaria, only 39% would have been detected by the surveillance network. The overall incidence of malaria was therefore estimated as 876 per 1,000 per year (Range: 711–906). Conclusion In this region of multidrug-resistant P. vivax and P. falciparum, both species are associated with substantial morbidity, but with significant differences in the age-related risk of infection.

Source Citation von Seidlein L, Milligan P, Pinder M, et al. Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, contro...