Pre-/post-otic rhombomeric interactions control the emergence of a fetal-like respiratory rhythm in the mouse embryo

How regional patterning of the neural tube in vertebrate embryos may influence the emergence and the function of neural networks remains elusive. We have begun to address this issue in the embryonic mouse hindbrain by studying rhythmogenic properties of different neural tube segments. We have isolated pre- and post-otic hindbrain segments and spinal segments of the mouse neural tube, when they form at embryonic day (E) 9, and grafted them into the same positions in stage-matched chick hosts. Three days after grafting, in vitro recordings of the activity in the cranial nerves exiting the grafts indicate that a high frequency (HF) rhythm (order: 10 bursts/min) is generated in post-otic segments while more anterior pre-otic and more posterior spinal territories generate a low frequency (LF) rhythm (order: 1 burst/min). Comparison with homo-specific grafting of corresponding chick segments points to conservation in mouse and chick of the link between the patterning of activities and the axial origin of the hindbrain segment. This HF rhythm is reminiscent of the respiratory rhythm known to appear at E15 in mice. We also report on pre-/post-otic interactions. The pre-otic rhombomere 5 prevents the emergence of the HF rhythm at E12. Although the nature of the interaction with r5 remains obscure, we propose that ontogeny of fetal-like respiratory circuits relies on: (i) a selective developmental program enforcing HF rhythm generation, already set at E9 in post-otic segments, and (ii) trans-segmental interactions with pre-otic territories that may control the time when this rhythm appears.     

Early Response to Sibutramine in Patients Not Meeting Current Label Criteria: Preliminary Analysis of SCOUT Lead‐in Period

The Sibutramine Cardiovascular Outcomes (SCOUT) trial protocol defines a patient population predominantly outside current European Union label criteria. This article explores responses to sibutramine during the 6‐week, single‐blind, lead‐in period between patients who conformed to the label requirements (“conformers”) and those who did not (“nonconformers”). SCOUT is an ongoing, randomized, double‐blind, placebo‐controlled outcome trial in overweight/obese patients at high risk of a cardiovascular event. In total, 10,742 patients received sibutramine and weight management during the lead‐in period. Initial responses were assessed post hoc in label conformers and nonconformers. Of that 8.1% patients met label criteria; 91.9%, the majority with cardiovascular disease and/or blood pressure >145/90 mm Hg, were nonconformers. Conformers and nonconformers had similar reductions in body weight (median change ?2.2 kg) and waist circumference (women: ?2.0 cm for both groups; men: ?1.5 cm vs. ?2.0 cm for conformers and nonconformers, respectively) over the 6‐week period. Greater blood pressure falls were evident in nonconformers (median change ?3.5/?1.0 vs. ?1.0/0.0 mm Hg). Both groups had small pulse rate increases; median 1.5 bpm (nonconformers) vs. 3.0 bpm (conformers). There was a low incidence of serious adverse events (conformers: 1.0%; nonconformers: 2.8%) and ～93% of patients in both groups completed the 6‐week period. The SCOUT lead‐in period evaluating weight management with sibutramine confirms its good tolerability and efficacy in patients who meet current label criteria. Preliminary data from high‐risk patients for whom sibutramine is currently contraindicated suggest a low discontinuation rate and few serious adverse events but confirmation from the SCOUT outcome data is needed.     

Fusarium ananatum sp. nov. in the Gibberella fujikuroi species complex from pineapples with fruit rot in South Africa

Pineapple (Ananas comosus) is native to South America and widely planted as a fruit crop in the tropics and sub-tropics. This plant is susceptible to a number of fungal diseases of which the most severe is fusariosis. The disease is caused by Fusarium guttiforme and occurs only in South and Central America. The occurrence of a similar disease on pineapples in South Africa has prompted a re-evaluation of the Fusarium sp. associated with pineapple fruit rot. Phylogenetic relationships of isolates from pineapples collected in Brazil and South Africa were assessed based on sequence data for the translation elongation factor-1-α, histone H3 and β-tubulin gene regions. Analyses showed that the South African isolates represent a species distinct from Brazilian isolates. The South African isolates are characterised by a concentration of aerial mycelium at the centres of the colonies, different to the Brazilian isolates that have an even distribution of aerial mycelium. Both phylogenetic and morphological data show that the disease on pineapple in South Africa is caused by a new Fusarium species described here as F. ananatum sp. nov.     

Mycobacterium tuberculosis epitope-specific interferon-g production in healthy Brazilians reactive and non-reactive to tuberculin skin test

The interferon (IFN)-γ response to peptides can be a useful diagnostic marker of Mycobacterium tuberculosis (MTB) latent infection. We identified promiscuous and potentially protective CD4⁺ T-cell epitopes from the most conserved regions of MTB antigenic proteins by scanning the MTB antigenic proteins GroEL2, phosphate-binding protein 1 precursor and 19 kDa antigen with the TEPITOPE algorithm. Seven peptide sequences predicted to bind to multiple human leukocyte antigen (HLA)-DR molecules were synthesised and tested with IFN-γ enzyme-linked immunospot (ELISPOT) assays using peripheral blood mononuclear cells (PBMCs) from 16 Mantoux tuberculin skin test (TST)-positive and 16 TST-negative healthy donors. Eighty-eight percent of TST-positive donors responded to at least one of the peptides, compared to 25% of TST-negative donors. Each individual peptide induced IFN-γ production by PBMCs from at least 31% of the TST-positive donors. The magnitude of the response against all peptides was 182 ± 230 x 10⁶ IFN-γ spot forming cells (SFC) among TST-positive donors and 36 ± 62 x 10⁶ SFC among TST-negative donors (p = 0.007). The response to GroEL2 (463-477) was only observed in the TST-positive group. This combination of novel MTB CD4 T-cell epitopes should be tested in a larger cohort of individuals with latent tuberculosis (TB) to evaluate its potential to diagnose latent TB and it may be included in ELISPOT-based IFN-γ assays to identify individuals with this condition.     

Risk of symptomatic dengue for foreign visitors to the 2014 FIFA World Cup in Brazil

Brazil will host the FIFA World Cup™, the biggest single-event competition in the world, from June 12-July 13 2014 in 12 cities. This event will draw an estimated 600,000 international visitors. Brazil is endemic for dengue. Hence, attendees of the 2014 event are theoretically at risk for dengue. We calculated the risk of dengue acquisition to non-immune international travellers to Brazil, depending on the football match schedules, considering locations and dates of such matches for June and July 2014. We estimated the average per-capita risk and expected number of dengue cases for each host-city and each game schedule chosen based on reported dengue cases to the Brazilian Ministry of Health for the period between 2010-2013. On the average, the expected number of cases among the 600,000 foreigner tourists during the World Cup is 33, varying from 3-59. Such risk estimates will not only benefit individual travellers for adequate pre-travel preparations, but also provide valuable information for public health professionals and policy makers worldwide. Furthermore, estimates of dengue cases in international travellers during the World Cup can help to anticipate the theoretical risk for exportation of dengue into currently non-infected areas.     

SNPs in DNA repair genes associated to meningitis and host immune response

In vitro and in animal models, APE1, OGG1, and PARP-1 have been proposed as being involved with inflammatory response. In this work, we have investigated if the SNPs APE1 Asn148Glu, OGG1 Ser326Cys, and PARP-1 Val762Ala are associated to meningitis. The patient genotypes were investigated by PIRA-PCR or PCR-RFLP. DNA damages were detected in genomic DNA by Fpg treatment. IgG and IgA were measured from plasma and the cytokines and chemokines were measured from cerebrospinal fluid samples using Bio-Plex assays. A higher frequency (P<0.05) of APE1 Glu allele in bacterial meningitis (BM) and aseptic meningitis (AM) patients was observed. The genotypes Asn/Asn in control group and Asn/Glu in BM group was also higher. For the SNP OGG1 Ser326Cys, the genotype Cys/Cys was more frequent (P<0.05) in BM group. The frequency of PARP-1 Val/Val genotype was higher in control group (P<0.05). The occurrence of combined SNPs is significantly higher in BM patients, indicating that these SNPs may be associated to the disease. Increasing in sensitive sites to Fpg was observed in carriers of APE1 Glu allele or OGG1 Cys allele, suggesting that SNPs affect DNA repair activity. Alterations in IgG production were observed in the presence of SNPs APE1 Asn148Glu, OGG1 Ser326Cys or PARP-1 Val762Ala. Moreover, reduction in the levels of IL-6, IL-1Ra, MCP-1/CCL2 and IL-8/CXCL8 was observed in the presence of APE1 Glu allele in BM patients. In conclusion, we obtained indications of an effect of SNPs in DNA repair genes on the regulation of immune response in meningitis.