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The coexistence of multiple independently circulating strains in pathogen populations that undergo sexual recombination is a central question of epidemiology with profound implications for control. An agent-based model is developed that extends earlier 'strain theory' by addressing the var gene family of Plasmodium falciparum. The model explicitly considers the extensive diversity of multi-copy genes that undergo antigenic variation via sequential, mutually exclusive expression. It tracks the dynamics of all unique var repertoires in a population of hosts, and shows that even under high levels of sexual recombination, strain competition mediated through cross-immunity structures the parasite population into a subset of coexisting dominant repertoires of var genes whose degree of antigenic overlap depends on transmission intensity. Empirical comparison of patterns of genetic variation at antigenic and neutral sites supports this role for immune selection in structuring parasite diversity.DOI:http://dx.doi.org/10.7554/eLife.00093.001.

BACKGROUND: Malaria triggers a high inflammatory response in the host that mediates most of the associated pathologies and contributes to death. The identification of pro-inflammatory molecules derived from Plasmodium is essential to understand the mechanisms of pathogenesis and to develop targeted interventions. Uric acid derived from hypoxanthine accumulated in infected erythrocytes has been recently proposed as a mediator of inflammation in rodent malaria. METHODS AND FINDINGS: We found that human erythrocytes infected with Plasmodium falciparum gradually accumulate hypoxanthine in their late stages of development. To analyze the role of hypoxanthine-derived uric acid induced by P. falciparum on the inflammatory cytokine response from human blood mononuclear cells, cultures were treated with allopurinol, to inhibit uric acid formation from hypoxanthine, or with uricase, to degrade uric acid. Both treatments significantly reduce the secretion of TNF, IL-6, IL-1beta and IL-10 from human cells. CONCLUSIONS AND SIGNIFICANCE: Uric acid is a major contributor of the inflammatory response triggered by P. falciparum in human peripheral blood mononuclear cells. Since the inflammatory reaction induced by P. falciparum is considered a major cause of malaria pathogenesis, identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.

The production of acute phase proteins during infection is an important part of innate immunity and limits inflammation. However, little is known of the acute phase response in malaria. We measured acute phase proteins in plasma in children attending clinics and admitted to hospital with acute malaria in Papua New Guinea. Plasma ferritin concentration increased progressively with disease severity with markedly elevated levels in the most severely ill children. Plasma ferritin was >500 ng/ml in 7/99 (7.1%) outpatients with uncomplicated malaria, 22/100 (22.0%) hospital non-severe cases, 64/175 (36.6%) severe malaria cases who survived and 7/9 (77.8%) severe malaria deaths (P < 0.001). The greatest concentration of ferritin (3561 ng/ml) was observed in a child who died. By contrast, C-reactive protein concentration was markedly increased in 153 children with uncomplicated malaria [median 203 (interquartile range 51-365) µg/ml] but, surprisingly, was only moderately increased in 135 children with one or more severe manifestations of malaria [47 (17-97) µg/ml; P < 0.001] and in 6 children who died [41 (22-280) µg/ml]. Excessive free-radical damage resulting from a combination of iron-induced oxidant stress and reduced levels of C-reactive protein may be an important pathological mechanism in severe malaria and amenable to therapeutic intervention. © 2009 Royal Society of Tropical Medicine and Hygiene.

Infection of erythrocytes with the Plasmodium parasite causes the pathologies associated with malaria, which result in at least one million deaths annually. The rupture of infected erythrocytes triggers an inflammatory response, which is induced by parasite-derived factors that still are not fully characterized. Induced secretion of inflammatory cytokines by these factors is considered a major cause of malaria pathogenesis. In particular, the inflammatory cytokine tumor necrosis factor (TNF) is thought to mediate most of the life-threatening pathologies of the disease. Here we describe the molecular characterization of a novel pathway that results in the secretion of TNF by host cells. We found that erythrocytes infected by Plasmodium accumulate high concentrations of hypoxanthine and xanthine. Degradation of Plasmodium-derived hypoxanthine/xanthine results in the formation of uric acid, which triggers the secretion of TNF. Since uric acid is considered a "danger signal" released by dying cells to alert the immune system, Plasmodium appears to have co-evolved to exploit this warning system. Identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.

OBJECTIVE: This study reviewed whether participants who were given a continence education package, which included a Continence Educational Brochure (CEB), and who indicated that they were bothered by incontinence symptoms changed health-seeking behaviors about their incontinence problem because of being given the brochure. METHOD(S): This study used a descriptive and exploratory design. Participants were given the CEB and asked to read the information. They were also asked to complete a continence questionnaire and mail this back to the research team. Participants who indicated that they were bothered by a continence problem and consented to being interviewed were telephoned 2 to 3 months later. They were asked questions to determine their actions and progress in relation to managing their continence problem and whether the CEB had influenced their behavior. SETTING AND SUBJECT: A total of 631 participants (352 females, 55.8%; 279 males, 44.2%) from 4 rural and regional settings in Victoria, Australia, participated. Of this sample, 111 participants (78 females, 70.3%; 33 males, 29.7%) who reported that they were bothered by a continence problem were interviewed 3 months after being given the CEB. RESULT(S): Two thirds of the total sample of participants (n = 111) sought help for their continence problem. Approximately 70.3% (n = 78) continued to have a continence problem. Of this group, 84.6% were still bothered by the continence problem and 65.4% had taken action to treat their incontinence. Forty-nine participants (44.1%) indicated that they had discussed the issue of bladder or bowel problems with someone directly because of this study or the information contained in the brochure. More than 94% of participants who remembered the CEB indicated that they believed the brochure would be helpful if given to other people. CONCLUSION(S): These findings suggest that the CEB prompted individuals to discuss their continence problem and in fewer cases to seek professional h

Author Posting. © Cambridge University Press, 2004. This article is posted here by permission of Cambridge University Press for personal use, not for redistribution. The definitive version was published in Parasitology 128 (2004): 577-584, doi:10.1017/S0031182004005025., Human serum high-density lipoprotein (HDL) is necessary and sufficient for the short-term maintenance of Plasmodium falciparum in in vitro culture. However, at high concentrations it is toxic to the parasite. A heat-labile component is apparently responsible for the stage-specific toxicity to parasites within infected erythrocytes 12–42 h after invasion, i.e. during trophozoite maturation. The effects of HDL on parasite metabolism (as determined by nucleic acid synthesis) are evident at about 30 h after invasion. Parasites treated with HDL show gross abnormalities by light and electron microscopy., Professor Hajduk was supported by NIH. Professor Day was supported by a Research Leave Fellowship from The Wellcome Trust. Dr Imrie and Ms Carter were supported by Programme Grant funding awarded to Professor Day from The Wellcome Trust. Dr Ferguson was supported by an equipment grant from The Wellcome Trust.

The upper Arkansas River south of Leadville, Colorado, contains deposits of fluvial tailings from historical mining operations. A stable-metal isotope (111Cd) was used to study metal retention and release mechanisms affecting metal transport from the deposits to shallow groundwater systems. An intact core was excavated from a small deposit and subjected to column experiments to examine the amount of metals leaching through the core. Deionised water was continuously applied to the top of the core and effluent collected from the bottom for a period of about two months. Unsaturated, partially saturated and fully saturated conditions were studied. Partial and complete saturation of the core resulted in the development of reducing conditions. During the unsaturated leaching phase, core effluents were acidic (pH 2.8-3.5) and contained elevated metal concentrations. During a portion of the unsaturated leaching phase isotope spikes and conservative tracers were simultaneously applied to the top of the core. During the unsaturated leaching phase, the isotope spikes did not exhibit breakthrough with the simultaneous addition of conservative tracers. However, some of the isotope spikes did break through when reducing conditions occurred in the core under partial and complete saturation conditions. The results indicate that there is a large reservoir of water-soluble material within the fluvial tailings deposit, which yields elevated metal concentrations and high acidity and which may degrade adjacent ground- and surface-water quality., The upper Arkansas River south of Leadville, Colorado, contains deposits of fluvial tailings from historical mining operations. A stable-metal isotope (111Cd) was used to study metal retention and release mechanisms affecting metal transport from the deposits to shallow groundwater systems. An intact core was excavated from a small deposit and subjected to column experiments to examine the amount of metals leaching through the core. Deionised water was continuously applied to the top of the core and effluent collected from the bottom for a period of about two months. Unsaturated, partially saturated and fully saturated conditions were studied. Partial and complete saturation of the core resulted in the development of reducing conditions. During the unsaturated leaching phase, core effluents were acidic (pH 2.8-3.5) and contained elevated metal concentrations. During a portion of the unsaturated leaching phase isotope spikes and conservative tracers were simultaneously applied to the top of the core. During the unsaturated leaching phase, the isotope spikes did not exhibit breakthrough with the simultaneous addition of conservative tracers. However, some of the isotope spikes did break through when reducing conditions occurred in the core under partial and complete saturation conditions. The results indicate that there is a large reservoir of water-soluble material within the fluvial tailings deposit, which yields elevated metal concentrations and high acidity and which may degrade adjacent ground- and surface-water quality.

Angiogenesis is critical for the growth and metastasis of endometrial cancer and is therefore an important therapeutic target. Vascular endothelial growth factor-A (VEGF-A) is a key molecule in angiogenesis, but the identification of related molecules and the angiopoietins suggests a more complex picture. We investigated the presence of transcripts for VEGF-A, VEGF-B, VEGF-C, VEGF-D, Angiopoietin-1 and Angiopoietin-2 in benign endometrium, atypical complex hyperplasia (ACH) and endometrioid endometrial carcinoma using in situ hybridisation. We confirmed the presence of VEGF-A mRNA in the epithelial cells of cancers examined (13 out of 13), but not in benign endometrium or ACH. We also demonstrate, using quantitative polymerase chain reaction, that levels of VEGF-B mRNA are significantly lower in endometrial cancer than benign endometrium. We conclude that loss of VEGF-B may contribute to the development of endometrial carcinoma by modulating availability of receptors for VEGF-A.