Plasmodium vivax but not Plasmodium falciparum blood-stage infection in humans is associated with the expansion of a CD8+ T cell population with cytotoxic potential

P. vivax and P. falciparum parasites display different tropism for host cells and induce very different clinical symptoms and pathology, suggesting that the immune responses required for protection may differ between these two species. However, no study has qualitatively compared the immune responses to P. falciparum or P. vivax in humans following primary exposure and infection. Here, we show that the two species differ in terms of the cellular immune responses elicited following primary infection. Specifically, P. vivax induced the expansion of a subset of CD8+ T cells expressing the activation marker CD38, whereas P. falciparum induced the expansion of CD38+ CD4+ T cells. The CD38+ CD8+ T cell population that expanded following P. vivax infection displayed greater cytotoxic potential compared to CD38- CD8+ T cells, and compared to CD38+ CD8+ T cells circulating during P. falciparum infection. We hypothesize that P. vivax infection leads to a stronger CD38+ CD8+ T cell activation because of its preferred tropism for MHC-I-expressing reticulocytes that, unlike mature red blood cells, can present antigen directly to CD8+ T cells. This study provides the first line of evidence to suggest an effector role for CD8+ T cells in P. vivax blood-stage immunity. It is also the first report of species-specific differences in the subset of T cells that are expanded following primary Plasmodium infection, suggesting that malaria vaccine development may require optimization according to the target parasite

Safety and Immunogenicity of a Malaria Vaccine, Plasmodium falciparum AMA-1/MSP-1 Chimeric Protein Formulated in Montanide ISA 720 in Healthy Adults

The P. falciparum chimeric protein 2.9 (PfCP-2.9) consisting of the sequences of MSP1-19 and AMA-1 (III) is a malaria vaccine candidate that was found to induce inhibitory antibodies in rabbits and monkeys. This was a phase I randomized, single-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the PfCP-2.9 formulated with a novel adjuvant Montanide ISA720. Fifty-two subjects were randomly assigned to 4 dose groups of 10 participants, each receiving the test vaccine of 20, 50, 100, or 200 µg respectively, and 1 placebo group of 12 participants receiving the adjuvant only.The vaccine formulation was shown to be safe and well-tolerated, and none of the participants withdrew. The total incidence of local adverse events (AEs) was 75%, distributed among 58% of the placebo group and 80% of those vaccinated. Among the vaccinated, 65% had events that were mild and 15% experienced moderate AEs. Almost all systemic adverse reactions observed in this study were graded as mild and required no therapy. The participants receiving the test vaccine developed detectable antibody responses which were boosted by the repeated vaccinations. Sixty percent of the vaccinated participants had high ELISA titers (>1∶10,000) of antigen-specific antibodies which could also recognize native parasite proteins in an immunofluorescence assay (IFA).This study is the first clinical trial for this candidate and builds on previous investigations supporting PfCP-2.9/ISA720 as a promising blood-stage malaria vaccine. Results demonstrate safety, tolerability (particularly at the lower doses tested) and immunogenicity of the formulation. Further clinical development is ongoing to explore optimizing the dose and schedule of the formulation to decrease reactogenicity without compromising immunogenicity.

Impact of the Method of G6PD Deficiency Assessment on Genetic Association Studies of Malaria Susceptibility

BACKGROUND:Clinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency. METHODOLOGY/PRINCIPAL FINDINGS:We compared the association between uncomplicated malaria incidence and G6PD deficiency in a cohort of 601 Ugandan children using two different diagnostic methods, enzyme activity and G6PD genotype (G202A, the predominant East African allele). Although roughly the same percentage of males were identified as deficient using enzyme activity (12%) and genotype (14%), nearly 30% of males who were enzymatically deficient were wild-type at G202A. The number of deficient females was three-fold higher with assessment by genotype (21%) compared to enzyme activity (7%). Heterozygous females accounted for the majority (46/54) of children with a mutant genotype but normal enzyme activity. G6PD deficiency, as determined by G6PD enzyme activity, conferred a 52% (relative risk [RR] 0.48, 95% CI 0.31-0.75) reduced risk of uncomplicated malaria in females. In contrast, when G6PD deficiency was defined based on genotype, the protective association for females was no longer seen (RR = 0.99, 95% CI 0.70-1.39). Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37-0.88 for females). CONCLUSIONS/SIGNIFICANCE:This study underscores the impact that the method of identifying G6PD deficient individuals has upon association studies of G6PD deficiency and uncomplicated malaria. We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity. These observations may help to explain the discrepancy in some published association studies involving G6PD deficiency and uncomplicated malaria

Secondary fibrosarcoma of the brain stem treated with cyclophosphamide and Imatinib

Radiation-induced midbrain fibrosarcoma is a rare, highly aggressive tumor, which is associated with poor prognosis. We present the case of a 48-year old man with brainstem fibrosarcoma 20 years following radiation therapy received for a pituitary tumor. We discuss this case in the context of the diagnostic criteria for these tumors, and previous reports of secondary and primary sarcomas of the central nervous system

Induction of labour versus expectant management in women with preterm prelabour rupture of membranes between 34 and 37 weeks (the PPROMEXIL-trial)

Contains fulltext : 53155.pdf ( ) (Open Access)BACKGROUND: Preterm prelabour rupture of the membranes (PPROM) is an important clinical problem and a dilemma for the gynaecologist. On the one hand, awaiting spontaneous labour increases the probability of infectious disease for both mother and child, whereas on the other hand induction of labour leads to preterm birth with an increase in neonatal morbidity (e.g., respiratory distress syndrome (RDS)) and a possible rise in the number of instrumental deliveries. METHODS/DESIGN: We aim to determine the effectiveness and cost-effectiveness of immediate delivery after PPROM in near term gestation compared to expectant management. Pregnant women with preterm prelabour rupture of the membranes at a gestational age from 34+0 weeks until 37+0 weeks will be included in a multicentre prospective randomised controlled trial. We will compare early delivery with expectant monitoring.The primary outcome of this study is neonatal sepsis. Secondary outcome measures are maternal morbidity (chorioamnionitis, puerperal sepsis) and neonatal disease, instrumental delivery rate, maternal quality of life, maternal preferences and costs. We anticipate that a reduction of neonatal infection from 7.5% to 2.5% after induction will outweigh an increase in RDS and additional costs due to admission of the child due to prematurity. Under these assumptions, we aim to randomly allocate 520 women to two groups of 260 women each. Analysis will be by intention to treat. Additionally a cost-effectiveness analysis will be performed to evaluate if the cost related to early delivery will outweigh those of expectant management. Long term outcomes will be evaluated using modelling. DISCUSSION: This trial will provide evidence as to whether induction of labour after preterm prelabour rupture of membranes is an effective and cost-effective strategy to reduce the risk of neonatal sepsis. CONTROLLED CLINICAL TRIAL REGISTER: ISRCTN29313500

“Keeping Moving”: factors associated with sedentary behaviour among older people recruited to an exercise promotion trial in general practice

Background Sedentary behaviour is detrimental to health, even in those who achieve recommended levels of physical activity. Efforts to increase physical activity in older people so that they reach beneficial levels have been disappointing. Reducing sedentary behaviour may improve health and be less demanding of older people, but it is not clear how to achieve this. We explored the characteristics of sedentary older people enrolled into an exercise promotion trial to gain insights about those who were sedentary but wanted to increase activity. Method Participants in the ProAct65+ trial (2009–2013) were categorised as sedentary or not using a self-report questionnaire. Demographic data, health status, self-rated function and physical test performance were examined for each group. 1104 participants aged 65 & over were included in the secondary analysis of trial data from older people recruited via general practice. Results were analysed using logistic regression with stepwise backward elimination. Results Three hundred eighty seven (35 %) of the study sample were characterised as sedentary. The likelihood of being categorised as sedentary increased with an abnormal BMI (25 kg/m2) (Odds Ratio 1.740, CI 1.248–2.425), ever smoking (OR 1.420, CI 1.042–1.934) and with every additional medication prescribed (OR 1.069, CI 1.016–1.124). Participants reporting better self-rated physical health (SF-12) were less likely to be sedentary; (OR 0.961, 0.936–0.987). Participants’ sedentary behaviour was not associated with gender, age, income, education, falls, functional fitness, quality of life or number of co-morbidities. Conclusion Some sedentary older adults will respond positively to an invitation to join an exercise study. Those who did so in this study had poor self-rated health, abnormal BMI, a history of smoking, and multiple medication use, and are therefore likely to benefit from an exercise intervention