Designing a VAR2CSA-based vaccine to prevent placental malaria

AbstractPlacental malaria (PM) due to Plasmodium falciparum is a major cause of maternal, fetal and infant mortality, but the mechanisms of pathogenesis and protective immunity are relatively well-understood for this condition, providing a path for vaccine development. P. falciparum parasites bind to chondroitin sulfate A (CSA) to sequester in the placenta, and women become resistant over 1–2 pregnancies as they acquire antibodies that block adhesion to CSA. The protein VAR2CSA, a member of the PfEMP1 variant surface antigen family, mediates parasite adhesion to CSA, and is the leading target for a vaccine to prevent PM. Obstacles to PM vaccine development include the large size (∼350kD), high cysteine content, and sequence variation of VAR2CSA. A number of approaches have been taken to identify the combination of VAR2CSA domains and alleles that can induce broadly active antibodies that block adhesion of heterologous parasite isolates to CSA. This review summarizes these approaches, which have examined VAR2CSA fragments for binding activity, antigenicity with naturally acquired antibodies, and immunogenicity in animals for inducing anti-adhesion or surface-reactive antibodies. Two products are expected to enter human clinical studies in the near future based on N-terminal VAR2CSA fragments that have high binding affinity for CSA, and additional proteins preferentially expressed by placental parasites are also being examined for their potential contribution to a PM vaccine

Volition and Action in the Human Brain: Processes, Pathologies, and Reasons

Humans seem to decide for themselves what to do, and when to do it. This distinctive capacity may emerge from an ability, shared with other animals, to make decisions for action that are related to future goals, or at least free from the constraints of immediate environmental inputs. Studying such volitional acts proves a major challenge for neuroscience. This review highlights key mechanisms in the generation of voluntary, as opposed to stimulus-driven actions, and highlights three issues. The first part focuses on the apparent spontaneity of voluntary action. The second part focuses on one of the most distinctive, but elusive, features of volition, namely, its link to conscious experience, and reviews stimulation and patient studies of the cortical basis of conscious volition down to the single-neuron level. Finally, we consider the goal-directedness of voluntary action, and discuss how internal generation of action can be linked to goals and reasons

A Single-Neuron Correlate of Change Detection and Change Blindness in the Human Medial Temporal Lobe

Observers are often unaware of changes in their visual environment when attention is not focused at the location of the change [1,2,3,4]. Because of its rather intriguing nature, this phenomenon, known as change blindness, has been extensively studied with psychophysics [5,6,7] as well as with fMRI [8,9,10,11]. However, whether change blindness can be tracked in the activity of single cells is not clear. To explore the neural correlates of change detection and change blindness, we recorded from single neurons in the human medial temporal lobe (MTL) during a change-detection paradigm. The preferred pictures of the visually responsive units elicited significantly higher firing rates on the attended trials when subjects correctly identified a change (change detection) compared to the unattended trials when they missed it (change blindness). On correct trials, the firing activity of individual units allowed us to predict the occurrence of a change, on a trial-by-trial basis, with 67% accuracy. In contrast, this prediction was at chance for incorrect, unattended trials. The firing rates of visually selective MTL cells thus constitute a neural correlate of change detection

Development of Personalized Health Messages to Promote Engagement in Advance Care Planning

Objectives: To develop and test the acceptability of personalized intervention materials to promote advance care planning (ACP) based on the Transtheoretical Model (TTM), in which readiness to change is a critical organizing construct. Design: Development study creating an expert system delivering TTM‐personalized feedback reports and stage‐matched brochures with more‐general information on ACP and modifications based on participant reviews. Setting: Senior centers. Participants: Community‐living persons aged 65 and older (N = 77). Measurements: Participant ratings of length, attractiveness, and trustworthiness of and reactions to reports and brochures. Results: The expert system assessed participants’ readiness to engage in each of four ACP behaviors: completion of a living will, naming a health care proxy, communication with loved ones about quality vs quantity of life, and communication with clinicians about quality vs quantity of life. The system also assessed pros and cons of engagement and values and beliefs that influence engagement. The system provided individualized feedback based on the assessment, with brochures providing additional general information. Initial participant review indicating unacceptable length led to revision of feedback reports from full‐sentence paragraph format to bulleted format. After review, the majority of participants rated the materials as easy to read, trustworthy, providing new information, making them more comfortable reading about ACP, and increasing interest in participating in ACP. Conclusion: Older adults found an expert system individualized feedback report and accompanying brochure to promote ACP engagement to highly acceptable and engaging. Additional research is necessary to examine the effects of these materials on behavior change

Maternal peripheral blood level of IL-10 as a marker for inflammatory placental malaria

Background: Placental malaria (PM) is an important cause of maternal and foetal mortality in tropical areas, and severe sequelae and mortality are related to inflammation in the placenta. Diagnosis is difficult because PM is often asymptomatic, peripheral blood smear examination detects parasitemia as few as half of PM cases, and no peripheral markers have been validated for placental inflammation. Methods: In a cohort of Tanzanian parturients, PM was determined by placental blood smears and placental inflammation was assessed by histology and TNF mRNA levels. Maternal peripheral blood levels of several immune mediators previously implicated in PM pathogenesis, as well as ferritin and leptin were measured. The relationship between the levels of these soluble factors to PM and placental inflammation was examined. Results: Peripheral levels of TNF, TNF-RI, TNF-RII, IL-1, IL-10, and ferritin were elevated during PM, whereas levels of IFN-[gamma], IL-4, IL-5 and IL-6 were unchanged and levels of leptin were decreased. In receiver operating characteristic curve analysis, IL-10 had the greatest area under the curve, and would provide a sensitivity of 60% with a false positive rate of 10%. At a cut off level of 15 pg/mL, IL-10 would detect PM with a sensitivity of 79.5% and a specificity of 84.3%. IL-10 levels correlated with placental inflammatory cells and placental TNF mRNA levels in first time mothers. Conclusion: These data suggest that IL-10 may have utility as a biomarker for inflammatory PM in research studies, but that additional biomarkers may be required to improve clinical diagnosis and management of malaria during pregnancy.This work was supported by grants from Bill and Melinda Gates Foundation (grant 29202), NIH (R01 AI52059 and TW05509) and Puget Sound Partners for Global Health to P.E.D

Magnetic Resonance Imaging for the in Vivo Evaluation of Gastric-Retentive Tablets

Purpose. To develop a magnetic resonance imaging (MRI) technique for assessing in vivo properties of orally ingested gastric-retentive tablets under physiologic conditions. Methods. Tablets with different floating characteristics (tablet A-C) were marked with superparamagnetic Fe3O4 particles to analyze intragastric tablet position and residence time in human volunteers. Optimal Fe3O4 concentration was determined in vitro. Intragastric release characteristic of one slow-release tablet (tablet D) was analyzed by embedding gadolinium chelates (Gd-DOTA) as a drug model into the tablet. All volunteers underwent MRI in the sitting position. Tablet performance was analyzed in terms of relative position of tablet to intragastric meal level (with 100% at meal surface), intragastric residence time (min) and Gd-DOTA distribution volume (% of meal volume). Results. Intragastric tablet floating performance and residence time of tablets (tablet A-D) as well as the intragastric Gd-DOTA distribution of tablet D could be monitored using MRI. Tablet floating performance was different between the tablets (A, 93%(95 − 9%); B, 80%(80 − 68%); C, 38%(63 − 32%); p < 0.05). The intragastric distribution volume of Gd-DOTA was 19.9% proximally and 35.5% distally. Conclusions. The use of MRI allows the assessment of galenic properties of orally ingested tablets in humans in seated positio

Manifestation of a gap due to the exchange energy in a spinor condensate

We investigate the dynamic response of population transfer between two components of a finite temperature spinor Bose condensed gas to a time-dependent coupling potential. Comparison between results obtained in the Bogoliubov-Popov approximation (BPA) and in the generalized random phase approximation (GRPA) shows noticeable discrepancies. In particular, the inter-component current response function calculated in the GRPA displays a gapped spectrum due to the exchange interaction energy whereas the corresponding density response function is gapless. We argue that the GRPA is superior since, contrary to the BPA, it preserves the SU(2) symmetry and the f-sum rule associated to the spinor gas. In order to validate the approximation, we propose an experimental setup that allows the observation of the predicted gap.Comment: 5 pages, 2 figure

Fetal origins of malarial disease: cord blood cytokines as risk markers for pediatric severe malarial anemia.

BACKGROUND: Severe malarial anemia (SMA) remains a major cause of pediatric illness and mortality in Sub-Saharan Africa. Here we test the hypothesis that prenatal exposures, reflected by soluble inflammatory mediators in cord blood, can condition an individual's susceptibility to SMA. METHODS: In a Tanzanian birth cohort (n = 743), we measured cord blood concentrations of tumor necrosis factor (TNF), TNF receptors I and II (TNF-RI and TNF-RII), interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-10, and interferon gamma (IFN-γ). After adjusting for conventional covariates, we calculated the hazard ratios (HR) for time to first SMA event with log(e) cytokine concentrations dichotomized at the median, by quartile, and per standard deviation (SD) increase. RESULTS: Low levels of TNF, TNF-RI, IL-1β, and IL-5 and high levels of TNF-RII were associated statistically significantly and respectively with approximately 3-fold, 2-fold, 8-fold, 4-fold, and 3-fold increased risks of SMA (Hb < 50 g/L). TNF, TNF-RI, and IL-1β concentrations were inversely and log-linearly associated with SMA risk; the HR (95% confidence interval [CI]) per 1-SD increase were respectively 0.81 (.65, 1.02), 0.76 (.62, .92), and 0.50 (.40, .62). CONCLUSIONS: These data suggest that proinflammatory cytokine levels at birth are inversely associated with SMA risk and support the hypothesis that pediatric malarial disease has fetal origins

Parasite Burden and Severity of Malaria in Tanzanian Children

BACKGROUND: Severe Plasmodium falciparum malaria is a major cause of death in children. The contribution of the parasite burden to the pathogenesis of severe malaria has been controversial. METHODS: We documented P. falciparum infection and disease in Tanzanian children followed from birth for an average of 2 years and for as long as 4 years. RESULTS: Of the 882 children in our study, 102 had severe malaria, but only 3 had more than two episodes. More than half of first episodes of severe malaria occurred after a second infection. Although parasite levels were higher on average when children had severe rather than mild disease, most children (67 of 102) had high-density infection (>2500 parasites per 200 white cells) with only mild symptoms before severe malaria, after severe malaria, or both. The incidence of severe malaria decreased considerably after infancy, whereas the incidence of high-density infection was similar among all age groups. Infections before and after episodes of severe malaria were associated with similar parasite densities. Nonuse of bed nets, placental malaria at the time of a woman’s second or subsequent delivery, high-transmission season, and absence of the sickle cell trait increased severe-malaria risk and parasite density during infections. CONCLUSIONS: Resistance to severe malaria was not acquired after one or two mild infections. Although the parasite burden was higher on average during episodes of severe malaria, a high parasite burden was often insufficient to cause severe malaria even in children who later were susceptible. The diverging rates of severe disease and high-density infection after infancy, as well as the similar parasite burdens before and after severe malaria, indicate that naturally acquired resistance to severe malaria is not explained by improved control of parasite density. (Funded by the National Institute of Allergy and Infectious Diseases and others.