Journals
2012 EN
Joanne G. Lisciandro · Susan L. Prescott · Marie G. NadalSims
+7 more
Studies addressing the ontogeny of the innate immune system in early life have reported mainly on Toll-like receptor (TLR) responses in infants living in high-income countries, with little or even no information on other pattern recognition receptors or on early life innate immune responses in children living under very different environmental conditions in less-developed parts of the world. In this study, we describe whole blood innate immune responses to both Toll-like and nucleotide-binding oligomerization domain (NOD)-like receptor agonists including the widely used vaccine adjuvant ‘alum’ in a group of Papua New Guinean infants aged 1–3 (n = 18), 4–6 (n = 18), 7–12 (n = 21) and 13–18 (n = 10) months old. Depending on the ligands and cytokines studied, different age-related patterns were found: alum-induced IL-1β and CXCL8 responses were found to significantly decline with increasing age; inflammatory (IL-6, IL-1β, IFN-γ) responses to TLR2 and TLR3 agonists increased; and IL-10 responses remained constant or increased during infancy, while TNF-α responses either declined or remained the same. We report for the first time that whole blood innate immune responses to the vaccine adjuvant alum decrease with age in infancy; a finding that may imply that the adjuvant effect of alum in pediatric vaccines could be age-related. Our findings further suggest that patterns of innate immune development may vary between geographically diverse populations, which in line with the ‘hygiene hypothesis’ particularly involves persistence of innate IL-10 responses in populations experiencing higher infectious pressure.
Public Library of Science
Journals
2012 EN
S. Pédeboscq · Christophe Rey · Muriel Petit
+4 more
The antioxidant properties of α-tocopherol have been proposed to play a beneficial chemopreventive role against cancer. However, emerging data also indicate that it may exert contrasting effects on the efficacy of chemotherapeutic treatments when given as dietary supplement, being in that case harmful for patients. This dual role of α-tocopherol and, in particular, its effects on the efficacy of anticancer drugs remains poorly documented. For this purpose, we studied here, using high throughput flow cytometry, the direct impact of α-tocopherol on apoptosis and cell cycle arrest induced by different cytotoxic agents on various models of cancer cell lines in vitro . Our results indicate that physiologically relevant concentrations of α-tocopherol strongly compromise the cytotoxic and cytostatic action of various protein kinase inhibitors (KI), while other classes of chemotherapeutic agents or apoptosis inducers are unaffected by this vitamin. Interestingly, these anti-chemotherapeutic effects of α-tocopherol appear to be unrelated to its antioxidant properties since a variety of other antioxidants were completely neutral toward KI-induced cell cycle arrest and cell death. In conclusion, our data suggest that dietary α-tocopherol could limit KI effects on tumour cells, and, by extent, that this could result in a reduction of the clinical efficacy of anti-cancer treatments based on KI molecules.
Public Library of Science
Journals
2012 EN
Catherine Riou · Blas Peixoto · Lindi Roberts
+8 more
Background Sputum Mycobacterium tuberculosis (Mtb) culture is commonly used to assess response to antibiotic treatment in individuals with pulmonary tuberculosis (TB). Such techniques are constrained by the slow growth rate of Mtb, and more sensitive methods to monitor Mtb clearance are needed. The goal of this study was to evaluate changes in plasma cytokines in patients undergoing treatment for TB as a means of identifying candidate host markers associated with microbiologic response to therapy. Methods Twenty-four plasma cytokines/chemokines were measured in 42 individuals diagnosed with active pulmonary TB, 52% were HIV co-infected. Individuals, undergoing a 26-week standard TB treatment, were followed longitudinally over 18 months and measurements were associated with HIV status and rates of sputum culture conversion. Results Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status. By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p = 0.02). Moreover, in HIV negative patients, plasma VEGF concentrations, measured as early as 2-weeks post TB treatment initiation, positively correlated with the time of sputum conversion (p = 0.0017). No significant changes were observed in other studied immune mediators. Conclusions These data suggest that VEGF plasma concentration, measured during early TB treatment, could represent a surrogate marker to monitor sputum culture conversion in HIV uninfected individuals.
Public Library of Science
Journals
2012 EN
Laëtitia Fabre · Jian Zhang · Ghislaine Guigon
+14 more
Laboratory surveillance systems for salmonellosis should ideally be based on the rapid serotyping and subtyping of isolates. However, current typing methods are limited in both speed and precision. Using 783 strains and isolates belonging to 130 serotypes, we show here that a new family of DNA repeats named CRISPR (clustered regularly interspaced short palindromic repeats) is highly polymorphic in Salmonella . We found that CRISPR polymorphism was strongly correlated with both serotype and multilocus sequence type. Furthermore, spacer microevolution discriminated between subtypes within prevalent serotypes, making it possible to carry out typing and subtyping in a single step. We developed a high-throughput subtyping assay for the most prevalent serotype, Typhimurium. An open web-accessible database was set up, providing a serotype/spacer dictionary and an international tool for strain tracking based on this innovative, powerful typing and subtyping tool.
Public Library of Science
Journals
2012 EN
Catherine Hindi Attar · Matthias M. Müller
A number of studies have shown that emotionally arousing stimuli are preferentially processed in the human brain. Whether or not this preference persists under increased perceptual load associated with a task at hand remains an open question. Here we manipulated two possible determinants of the attentional selection process, perceptual load associated with a foreground task and the emotional valence of concurrently presented task-irrelevant distractors. As a direct measure of sustained attentional resource allocation in early visual cortex we used steady-state visual evoked potentials (SSVEPs) elicited by distinct flicker frequencies of task and distractor stimuli. Subjects either performed a detection (low load) or discrimination (high load) task at a centrally presented symbol stream that flickered at 8.6 Hz while task-irrelevant neutral or unpleasant pictures from the International Affective Picture System (IAPS) flickered at a frequency of 12 Hz in the background of the stream. As reflected in target detection rates and SSVEP amplitudes to both task and distractor stimuli, unpleasant relative to neutral background pictures more strongly withdrew processing resources from the foreground task. Importantly, this finding was unaffected by the factor ‘load’ which turned out to be a weak modulator of attentional processing in human visual cortex.
Public Library of Science
Journals
2012 EN
Aude Rémot · X. Roux · Catherine C. Dubuquoy
+6 more
Background The human respiratory syncytial virus (hRSV) is the leading cause of severe bronchiolitis in infants worldwide. The most severe RSV diseases occur between 2 and 6 months-of-age, so pediatric vaccination will have to be started within the first weeks after birth, when the immune system is prone to Th2 responses that may turn deleterious upon exposure to the virus. So far, the high risk to prime for immunopathological responses in infants has hampered the development of vaccine. In the present study we investigated the safety and efficacy of ring-nanostructures formed by the recombinant nucleoprotein N of hRSV (N SRS ) as a mucosal vaccine candidate against RSV in BALB/c neonates, which are highly sensitive to immunopathological Th2 imprinting. Methodology and Principal Findings A single intranasal administration of N SRS with detoxified E.coli enterotoxin LT(R192G) to 5–7 day old neonates provided a significant reduction of the viral load after an RSV challenge at five weeks of age. However, neonatal vaccination also generated an enhanced lung infiltration by neutrophils and eosinophils following the RSV challenge. Analysis of antibody subclasses and cytokines produced after an RSV challenge or a boost administration of the vaccine suggested that neonatal vaccination induced a Th2 biased local immune memory. This Th2 bias and the eosinophilic reaction could be prevented by adding CpG to the vaccine formulation, which, however did not prevent pulmonary inflammation and neutrophil infiltration upon viral challenge. Conclusions/Significance In conclusion, protective vaccination against RSV can be achieved in neonates but requires an appropriate combination of adjuvants to prevent harmful Th2 imprinting.
Public Library of Science
Journals
2012 EN
Amanda Tivnan · W. Shan Orr · Vladimir Gubala
+12 more
Background Neuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in paediatric oncology, underlining the need for novel therapeutic approaches. Typically, patients with high risk disease undergo an initial remission in response to treatment, followed by disease recurrence that has become refractory to further treatment. Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model. These tumors express high levels of the cell surface antigen disialoganglioside GD2 (GD 2 ), providing a target for tumor-specific delivery. Principal Findings Nanoparticles encapsulating miR-34a and conjugated to a GD 2 antibody facilitated tumor-specific delivery following systemic administration into tumor bearing mice, resulted in significantly decreased tumor growth, increased apoptosis and a reduction in vascularisation. We further demonstrate a novel, multi-step molecular mechanism by which miR-34a leads to increased levels of the tissue inhibitor metallopeptidase 2 precursor (TIMP2) protein, accounting for the highly reduced vascularisation noted in miR-34a-treated tumors. Significance These novel findings highlight the potential of anti-GD 2 -nanoparticle-mediated targeted delivery of miR-34a for both the treatment of GD 2 -expressing tumors, and as a basic discovery tool for elucidating biological effects of novel miRNAs on tumor growth.
Public Library of Science
Journals
2012 EN
Georgia Paxton · Katrina Sangster · Ellen Maxwell
+2 more
Objective To document the prevalence of nutritional deficiencies, infectious diseases and susceptibility to vaccine preventable diseases in Karen refugees in Australia. Design Retrospective audit of pathology results. Setting Community based cohort in Melbourne over the period July 2006–October 2009. Participants 1136 Karen refugee children and adults, representing almost complete local area settlement and 48% of total Victorian Karen humanitarian intake for the time period. Main Outcome Measures Prevalence of positive test results for refugee health screening, with breakdown by age group (<6 years, 6–11 years, 12–17 years, 18 years and older). Results Overall prevalence figures were: anaemia 9.2%, microcytosis 19.1%, iron deficiency 13.1%, low vitamin B 12 1.5%, low folate 1.5%, abnormal thyroid function tests 4.4%, vitamin D<50 nmol/L 33.3%, hypocalcaemia 7.4%, raised alkaline phosphatase 5.2%, abnormal liver transaminases 16.1%, hepatitis B surface antigen positive 9.7%, hepatitis B surface antibody positive 49.5%, isolated hepatitis B core antibody positive 9.0%, hepatitis C positive 1.9%, eosinophilia 14.4%, Schistosoma infection 7%, Strongyloides infection 20.8%, malaria 0.2%, faecal parasites 43.4%. Quantiferon-gold screening was positive in 20.9%. No cases of syphilis or HIV were identified. Serological immunity to vaccine preventable diseases was 87.1% for measles, 95% for mumps and 66.4% for rubella; 56.9% of those tested had seroimmunity to all three. Conclusions Karen refugees have high rates of nutritional deficiencies and infectious diseases and may be susceptible to vaccine preventable diseases. These data support the need for post-arrival health screening and accessible, funded catch-up immunisation.
Public Library of Science
Journals
2012 EN
James D. Gilardi · Catherine A. Toft
Background Generalist herbivores are challenged not only by the low nitrogen and high indigestibility of their plant foods, but also by physical and chemical defenses of plants. This study investigated the foods of wild parrots in the Peruvian Amazon and asked whether these foods contain dietary components that are limiting for generalist herbivores (protein, lipids, minerals) and in what quantity; whether parrots chose foods based on nutrient content; and whether parrots avoid plants that are chemically defended. Methodology/Principal Findings We made 224 field observations of free-ranging parrots of 17 species in 8 genera foraging on 102 species of trees in an undisturbed tropical rainforest, in two dry seasons (July-August 1992–1993) and one wet season (January-February1994). We performed laboratory analyses of parts of plants eaten and not eaten by parrots and brine shrimp assays of toxicity as a proxy for vertebrates. Parrots ate seeds, fruits, flowers, leaves, bark, and insect larvae, but up to 70% of their diet comprised seeds of many species of tropical trees, in various stages of ripeness. Plant parts eaten by parrots were rich in protein, lipid, and essential minerals, as well as potentially toxic chemicals. Seeds were higher than other plant materials in protein and lipid and lower in fiber. Large macaws of three species ate foods higher in protein and lipids and lower in fiber compared to plant parts available but not eaten. Macaws ate foods that were lower in phenolic compounds than foods they avoided. Nevertheless, foods eaten by macaws contained measurable levels of toxicity. Macaws did not appear to make dietary selections based on mineral content. Conclusions/Significance Parrots represent a remarkable example of a generalist herbivore that consumes seeds destructively despite plant chemical defenses. With the ability to eat toxic foods, rainforest-dwelling parrots exploited a diversity of nutritious foods, even in the dry season when food was scarce for other frugivores and granivores.
Public Library of Science
Journals
2012 EN
Christine E. McLaren · Stela McLachlan · Chad Garner
+11 more
The existence of multiple inherited disorders of iron metabolism suggests genetic contributions to iron deficiency. We previously performed a genome-wide association study of iron-related single nucleotide polymorphisms (SNPs) using DNA from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤12 µg/L (cases) and controls (SF >100 µg/L in men, SF >50 µg/L in women). We report a follow-up study of white, African-American, Hispanic, and Asian HEIRS participants, analyzed for association between SNPs and eight iron-related outcomes. Three chromosomal regions showed association across multiple populations, including SNPs in the TF and TMPRSS6 genes, and on chromosome 18q21. A novel SNP rs1421312 in TMPRSS6 was associated with serum iron in whites (p = 3.7×10 −6 ) and replicated in African Americans (p = 0.0012).Twenty SNPs in the TF gene region were associated with total iron-binding capacity in whites (p<4.4×10 −5 ); six SNPs replicated in other ethnicities (p<0.01). SNP rs10904850 in the CUBN gene on 10p13 was associated with serum iron in African Americans (P = 1.0×10 −5 ). These results confirm known associations with iron measures and give unique evidence of their role in different ethnicities, suggesting origins in a common founder.
Public Library of Science