Cardiopulmonary exercise testing in children with Cystic Fibrosis : one centre’s experience

Exercise testing is increasingly being used as a prognostic indicator in Cystic Fibrosis (CF) but it is reported to be underutilised in UK CF centres, particularly in children. Here, we evaluated the CPET results of our children with CF at the CF annual review and its possible clinical value

Chandra X-Ray Spectroscopy Of The Very Early O Supergiant HD 93129A: Constraints On Wind Shocks And The Mass-Loss Rate

We present an analysis of both the resolved X-ray emission-line profiles and the broad-band X-ray spectrum of the O-2 If* star HD 93129A, measured with the Chandra High Energy Transmission Grating Spectrometer ( HETGS). This star is among the earliest and most massive stars in the Galaxy, and provides a test of the embedded wind-shock scenario in a very dense and powerful wind. A major new result is that continuum absorption by the dense wind is the primary cause of the hardness of the observed X-ray spectrum, while intrinsically hard emission from colliding wind shocks contributes less than 10 per cent of the X-ray flux. We find results consistent with the predictions of numerical simulations of the line-driving instability, including line broadening indicating an onset radius of X-ray emission of several tenths of R-*. Helium-like forbidden-to-intercombination line ratios are consistent with this onset radius, and inconsistent with being formed in a wind-collision interface with the star\u27s closest visual companion at a distance of 100 au. The broad-band X-ray spectrum is fitted with a dominant emission temperature of just kT = 0.6 keV along with significant wind absorption. The broad-band wind absorption and the line profiles provide two independent measurements of the wind mass-loss rate:. M = 5.2(-1.5)(+1.8) x 10(-6) and 6.8(-2.2)(+2.8) x 10(-6) M-circle dot yr(-1), respectively. This is the first consistent modelling of the X-ray line-profile shapes and broad-band X-ray spectral energy distribution in a massive star, and represents a reduction of a factor of 3-4 compared to the standard H alpha mass-loss rate that assumes a smooth wind

The Open Navigation Surface Project

Many hydrographic and oceanographic agencies have moved or are moving towards gridded bathymetric products. However, there is no accepted format to allow these grids to be exchanged while maintaining data and metadata integrity. This paper describes the Open Navigation Surface (ONS) Project, which aims to fill this gap. The ONS Project is an open-source software project designed to provide a freely available, portable source-code library to encapsulate gridded bathymetric surfaces with associated uncertainty values. The data file format is called a Bathymetric Attributed Grid (BAG). The BAG is developed and maintained by the ONS Working Group (ONSWG), and the source code is available via the ONS websit

Systemic leukotriene B₄ receptor antagonism lowers arterial blood pressure and improves autonomic function in the spontaneously hypertensive rat

KEY POINTS: Evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B(4) (LTB(4)), a potent chemoattractant involved in the inflammatory response, but its mode of action is poorly understood. In the SHR, we observed an increase in T cells and macrophages in the brainstem; in addition, gene expression profiling data showed that LTB(4) production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. When LTB(4) receptor 1 (BLT1) receptors were blocked with CP‐105,696, arterial pressure was reduced in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in systolic blood pressure (BP) indicators. These data provide new evidence for the role of LTB(4) as an important neuro‐immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension. ABSTRACT: Accumulating evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B(4) (LTB(4)), a potent chemoattractant involved in the inflammatory response. However, the mechanism for LTB(4)‐mediated inflammation in hypertension is poorly understood. Here we report in the SHR, increased brainstem infiltration of T cells and macrophages plus gene expression profiling data showing that LTB(4) production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. Chronic blockade of the LTB(4) receptor 1 (BLT1) receptor with CP‐105,696, reduced arterial pressure in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in low and high frequency spectra of systolic blood pressure, and an increase in spontaneous baroreceptor reflex gain (sBRG). These data provide new evidence for the role of LTB(4) as an important neuro‐immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension

Evaluating the potential for the environmentally sustainable control of foot and mouth disease in Sub-Saharan Africa

Strategies to control transboundary diseases have in the past generated unintended negative consequences for both the environment and local human populations. Integrating perspectives from across disciplines, including livestock, veterinary and conservation sectors, is necessary for identifying disease control strategies that optimise environmental goods and services at the wildlife-livestock interface. Prompted by the recent development of a global strategy for the control and elimination of foot-and-mouth disease (FMD), this paper seeks insight into the consequences of, and rational options for potential FMD control measures in relation to environmental, conservation and human poverty considerations in Africa. We suggest a more environmentally nuanced process of FMD control that safe-guards the integrity of wild populations and the ecosystem dynamics on which human livelihoods depend while simultaneously improving socio-economic conditions of rural people. In particular, we outline five major issues that need to be considered: 1) improved understanding of the different FMD viral strains and how they circulate between domestic and wildlife populations; 2) an appreciation for the economic value of wildlife for many African countries whose presence might preclude the country from ever achieving an FMD-free status; 3) exploring ways in which livestock production can be improved without compromising wildlife such as implementing commodity-based trading schemes; 4) introducing a participatory approach involving local farmers and the national veterinary services in the control of FMD; and 5) finally the possibility that transfrontier conservation might offer new hope of integrating decision-making at the wildlife-livestock interface

Influence of age on respiratory modulation of muscle sympathetic nerve activity, blood pressure and baroreflex function in humans

New Findings What is the central question of this study? Does ageing influence the respiratory‐related bursting of muscle sympathetic nerve activity (MSNA) and the association between the rhythmic fluctuations in MSNA and blood pressure (Traube–Hering waves) that occur with respiration? What is the main finding and its importance? Despite the age‐related elevation in MSNA, the cyclical inhibition of MSNA during respiration is similar between young and older individuals. Furthermore, central respiratory–sympathetic coupling plays a role in the generation of Traube–Hering waves in both young and older humans. Healthy ageing and alterations in respiratory–sympathetic coupling have been independently linked with heightened sympathetic neural vasoconstrictor activity. We investigated how age influences the respiratory‐related modulation of muscle sympathetic nerve activity (MSNA) and the association between the rhythmic fluctuations in MSNA and blood pressure that occur with respiration (Traube–Hering waves; THW). Ten young (22 ± 2 years; mean ± SD) and 10 older healthy men (58 ± 6 years) were studied while resting supine and breathing spontaneously. MSNA, blood pressure and respiration were recorded simultaneously. Resting values were ascertained and respiratory cycle‐triggered averaging of MSNA and blood pressure measurements performed. The MSNA burst incidence was higher in older individuals [22.7 ± 9.2 versus 42.2 ± 13.7 bursts (100 heart beats)−1, P < 0.05], and was reduced to a similar extent in the inspiratory to postinspiratory period in young and older subjects (by ∼25% compared with mid‐ to late expiration). A similar attenuation of MSNA burst frequency (in bursts per minute), amplitude and total activity (burst frequency × mean burst amplitude) was also observed in the inspiratory to postinspiratory period in both groups. A significant positive correlation between respiratory‐related MSNA and the magnitude of Traube–Hering waves was observed in all young (100%) and most older subjects (80%). These data suggest that the strength of the cyclical inhibition of MSNA during respiration is similar between young and older individuals; thus, alterations in respiratory–sympathetic coupling appear not to contribute to the age‐related elevation in MSNA. Furthermore, central respiratory–sympathetic coupling plays a role in the generation of Traube–Hering waves in both healthy young and older humans

The chicken talpid3 gene encodes a novel protein that is essential for hedgehog signaling

Talpid(3) is a classical chicken mutant with abnormal limb patterning and malformations in other regions of the embryo known to depend on Hedgehog signaling. We combined the ease of manipulating chicken embryos with emerging knowledge of the chicken genome to reveal directly the basis of defective Hedgehog signal transduction in talpid(3) embryos and to identify the talpid(3) gene. We show in several regions of the embryo that the talpid(3) phenotype is completely ligand independent and demonstrate for the first time that talpid(3) is absolutely required for the function of both Gli repressor and activator in the intracellular Hedgehog pathway. We map the talpid(3) locus to chromosome 5 and find a frameshift mutation in a KIAA0586 ortholog (ENSGALG00000012025), a gene not previously attributed with any known function. We show a direct causal link between KIAA0586 and the mutant phenotype by rescue experiments. KIAA0586 encodes a novel protein, apparently specific to vertebrates, that localizes to the cytoplasm. We show that Gli3 processing is abnormal in talpid(3) mutant cells but that Gli3 can still translocate to the nucleus. These results suggest that the talpid(3) protein operates in the cytoplasm to regulate the activity of both Gli repressor and activator proteins

Palaeotectonic setting of the south-eastern Kédougou-Kéniéba Inlier, West Africa: new insights from igneous trace element geochemistry and U-Pb zircon ages

New U-Pb zircon ages and geochemistry from the eastern Kédougou-Kéniéba Inlier are presented and integrated with published data to generate a revised tectonic framework for the westernmost Birimian terranes. The Falémé Volcanic Belt and Kofi Series are highly prospective, hosting several multi-million ounce gold deposits and a significant iron ore resource, but remain under-researched. It is therefore important to constrain the fundamental geological setting. The igneous rocks of the eastern Kédougou-Kéniéba Inlier are dominantly of high-K calc-alkaline affinity, with fractionated REE patterns and negative Nb-Ta anomalies. The plutonic rocks in the Falémé Belt are dioritic to granodioritic in composition, with moderately fractionated REE patterns and metaluminous A/CNK signatures. Felsic, peraluminous granite stocks, dykes and plutons with fractionated REE patterns and negative Eu, Ti and P anomalies intruded both the Falémé Belt and Kofi Series. Albitisation masks the affinity of some units, although use of the Th-Co diagram shows that prior to albitisation, all igneous units belonged to the high-K calc-alkaline series. New U-Pb age data for the Boboti and Balangouma plutons indicate crystallisation at 2088.5 ± 8.5 Ma and at 2112 ± 13 Ma, respectively. Inherited zircons in the Boboti pluton indicate magmatic activity in the Falémé Belt at 2218 ± 83 Ma coincided with the oldest dated units in the Mako Belt to the West. Systematic changes in Dy/Yb, Sm/La, Nb/Zr, Rb concentration, Eu-anomaly and ɛNdt over ∼200 Ma reveal that the tectonic setting in the KKI evolved from a volcanic island arc environment to an active continental margin. Crustal thickening, as a result of a shift to collisional tectonic setting, combined with magmatic differentiation, led to the generation of peraluminous, granitic melts with a significant crustal component. A small suite of more basic intrusive and extrusive rocks on the eastern margin of the Dialé-Daléma basin are highly metaluminous and display limited LILE enrichment, with normalised HREE values close to unity. The Daléma igneous rocks may have formed in an extensional back arc, related to the arc system

The pneumococcal alpha-glycerophosphate oxidase enhances nasopharyngeal colonization through binding to host glycoconjugates

Streptococcus pneumoniae (the pneumococcus) is a major human pathogen, causing a broad spectrum of diseases including otitis media, pneumonia, bacteraemia and meningitis. Here we examined the role of a potential pneumococcal meningitis vaccine antigen, alpha-glycerophosphate oxidase (SpGlpO), in nasopharyngeal colonization. We found that serotype 4 and serotype 6A strains deficient in SpGlpO have significantly reduced capacity to colonize the nasopharynx of mice, and were significantly defective in adherence to human nasopharyngeal carcinoma cells in vitro. We also demonstrate that intranasal immunization with recombinant SpGlpO significantly protects mice against subsequent nasal colonization by wild type serotype 4 and serotype 6A strains. Furthermore, we show that SpGlpO binds strongly to lacto/neolacto/ganglio host glycan structures containing the GlcNAcβ1-3Galβ disaccharide, suggesting that SpGlpO enhances colonization of the nasopharynx through its binding to host glycoconjugates. We propose that SpGlpO is a promising vaccine candidate against pneumococcal carriage, and warrants inclusion in a multi-component protein vaccine formulation that can provide robust, serotype-independent protection against all forms of pneumococcal disease

A functional genomics catalogue of activated transcription factors during pathogenesis of pneumococcal disease

Background: Association analysis is an alternative to conventional family-based methods to detect the location of gene(s) or quantitative trait loci (QTL) and provides relatively high resolution in terms of defining the genome position of a gene or QTL. Seed protein and oil concentration are quantitative traits which are determined by the interaction among many genes with small to moderate genetic effects and their interaction with the environment. In this study, a genome-wide association study (GWAS) was performed to identify quantitative trait loci (QTL)controlling seed protein and oil concentration in 298 soybean germplasm accessions exhibiting a wide range of seed protein and oil content. Results: A total of 55,159 single nucleotide polymorphisms (SNPs) were genotyped using various methods including illumina Infinium and GoldenGate assays and 31,954 markers with minor allele frequency >0.10 were used to estimate linkage disequilibrium (LD) in heterochromatic and euchromatic regions. In euchromatic regions, the mean LD (r2) rapidly declined to 0.2 within 360 Kbp, whereas the mean LD declined to 0.2 at 9,600 Kbp in heterochromatic regions. The GWAS results identified 40 SNPs in 17 different genomic regions significantly associated with seed protein. Of these, the five SNPs with the highest associations and seven adjacent SNPs were located in the 27.6-30.0 Mbp region of Gm20. A major seed protein QTL has been previously mapped to the same location and potential candidate genes have recently been identified in this region. The GWAS results also detected 25 SNPs in 13 different genomic regions associated with seed oil. Of these markers, seven SNPs had a significant association with both protein and oil. Conclusions: This research indicated that GWAS not only identified most of the previously reported QTL controlling seed protein and oil, but also resulted in narrower genomic regions than the regions reported as containing these QTL. The narrower GWAS-defined genome regions will allow more precise marker-assisted allele selection and will expedite positional cloning of the causal gene(s)