Reference based contrast functions in a semi-blind context

International audienceWe deal with blind signal extraction in the framework of a convolutive mixture of independent sources. Considering so-called reference signals, we generalize former identifiability conditions. Based on this result, we propose to incorporate some a priori information in the references. We show the validity of reference based contrast functions in two semi-blind situations. The results are confirmed by computer simulation

Actinomyces spp. gene expression in root caries lesions

Background: studies of the distribution of Actinomyces spp. on carious and non-carious root surfaces have not been able to confirm the association of these bacteria with root caries, although they were extensively implicated as a prime suspect in root caries. Objective: the aim of this study was to observe the gene expression of Actinomyces spp. in the microbiota of root surfaces with and without caries. Design: the oral biofilms from exposed sound root surface (SRS; n=10) and active root caries (RC; n=30) samples were collected. The total bacterial RNA was extracted and the mRNA was isolated. Samples with low RNA concentration were pooled, yielding a final sample size of SRS=10 and RC=9. cDNA libraries were prepared and sequenced on the Illumina Hi-Seq2500. Sequence reads were mapped to eight Actinomyces genomes. Count data were normalized using DESeq2 to analyse differential gene expression applying the Benjamini-Hochberg correction (FDR0.05), except for Actinomyces OT178 (p=0.001) and A. gerencseriae (p=0.004), which had higher read count in the SRS. Genes that code for stress proteins (clp, dnaK and groEL), enzymes of glycolysis pathways (including, enolase and phosphoenolpyruvate carboxykinase), adhesion (Type-2 fimbrial and collagen-binding protein) and cell growth (EF-Tu) were highly, but not differentially (p>0.001) expressed in both groups. Genes with the most significant up-regulation in RC were those coding for hypothetical proteins and uracil DNA glycosylase (p=2.61E-17). The gene with the most significant up-regulation in SRS was a peptide ABC transporter substrate-binding protein (log2FC= -6.00, FDR= 2.37E-05). Conclusion: there were similar levels of Actinomyces gene expression in both sound and carious root biofilms. These bacteria can be commensal in root surface sites, but may be cariogenic due to survival mechanisms allowing them to exist in acid environment and metabolize sugars saving energy

The metatranscriptomes of root caries and sound root surface biofilms

There is limited knowledge of bacterial metabolism in root caries lesions. The aim of this study was to describe the bacterial metatranscriptomes associated with root caries and sound root surfaces using an RNA-seq analysis approach. The biofilms from exposed root surfaces were sampled from caries-free volunteers (n=10), and from the infected dentine of volunteers with root caries (n=30). Total bacterial RNA was extracted; cDNA libraries were prepared and sequenced on the Illumina Hi-Seq2500. The function and composition of the metabolically active microbiota were investigated using: a) MG-RAST, and b) denovo assembly of the read data and mapping to contigs. Differential gene expression analysis was done using the R package DESeq2 (padj <10−3). Transcripts with the highest expression levels were those coding for membrane transport systems, ribosomal proteins, enolase and glycolytic pathways in both groups. Differential analysis indicated that genes coding for the OmpA domain protein and metalloprotease domain protein were over-expressed in the caries samples (log2FoldChange = –12.2; padj= 3.5 × 10−13), whereas genes in the samples from healthy sites over-expressed pilus biosynthesis protein, thiamine diphosphokinase and transporter protein (log2FoldChange = 16.5; padj = 2.2 × 10−21). Metatranscriptomic analyses show unique gene expression profiles in sound root surface and carious biofilms

The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism

<p>Abstract</p> <p>Background</p> <p>Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na⁺/K⁺) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra^®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound.</p> <p>Methods</p> <p>The effect of eplerenone and PF-03882845 on urinary Na⁺/K⁺and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in healthy volunteers. Drug exposure-response data were modeled to evaluate the translatability of these biomarkers from rats to humans.</p> <p>Results</p> <p>In Sprague-Dawley rats, eplerenone elicited a rapid effect on urinary Na⁺/K⁺yielding an EC₅₀that was within 5-fold of the functional <it>in vitro </it>IC₅₀. More importantly, the effect of eplerenone on urinary Na⁺/K⁺in healthy volunteers yielded an EC₅₀that was within 2-fold of the EC₅₀generated in Sprague-Dawley rats. Similarly, the potency of PF-03882845 in elevating urinary Na⁺/K⁺in Sprague-Dawley rats was within 3-fold of its <it>in vitro </it>functional potency. The effect of MR antagonism on urinary Na⁺/K⁺was not sustained chronically; thus we studied the effect of the compounds on plasma aldosterone following chronic dosing in SHR. Modeling of drug exposure-response data for both eplerenone and PF-03882845 yielded EC₅₀values that were within 2-fold of that estimated from modeling of drug exposure with changes in urinary sodium and potassium excretion. Importantly, similar unbound concentrations of eplerenone in humans and SHR rats yielded the same magnitude of elevations in aldosterone, indicating a good translatability from rat to human.</p> <p>Conclusions</p> <p>Urinary Na⁺/K⁺and plasma aldosterone appear to be translatable biomarkers of MR antagonism following administration of single or multiple doses of compound, respectively.</p> <p>Trial Registration</p> <p>For clinical study reference EE3-96-02-004, this study was completed in 1996 and falls out scope for disclosure requirements.</p> <p>Clinical study reference A6141115: <url>http://clinicaltrials.gov</url>, <url>http://NIHclinicaltrails.gov</url>; NCTID: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00990223">NCT00990223</a></p

Surgical management, staging, and outcomes of Wilms tumours with intravascular extension: Results of the IMPORT study

PURPOSE: To review surgical management, tumour stage and clinical outcomes in children with intravascular extension of Wilms tumour (WT) registered in a national clinical study (2012-19). METHODS: WTs with presence/suspicion of tumour thrombus in the renal vein (RV) or beyond on radiology, surgery or pathology case report forms were identified. Only cases where thrombus was confirmed by surgeon and/or reference pathologist were included. Surgical management, disease stage, overall (OS) and event free survival (EFS) were investigated. RESULTS: 69/583 (11.8%) patients met the inclusion criteria. Forty-six (67%) had abdominal stage III due to thrombus-related reasons: 11 had macroscopically incomplete resection, including 8 cases where cavotomy was not performed; 20 had piecemeal complete resection of thrombus; 15 had microscopically positive resection margins at the RV. 66% of tumour thrombi contained viable tumour. There were eight relapses and five deaths. EFS, but not OS, was significantly associated with completeness of surgical resection (P<0.05). OS and EFS were also significantly associated with histological risk group (P<0.05) but not with viability of tumour thrombus (P=0.19; P=0.59). CONCLUSIONS: WTs with intravascular extension have a high risk of local stage III due to thrombus-related reasons. Controlled complete removal of the thrombus should be the aim of surgery. LEVEL OF EVIDENCE: Level II

The rise of dentine hypersensitivity and tooth wear in an ageing population

Our understanding of the aetiology of dentine hypersensitivity (DH) has changed dramatically over the past few decades. It is no longer an enigma, but other problems exist. The prevalence of DH in the world and in particular in the UK is increasing, predominately due to increases in tooth wear and the erosive dietary intake in the younger population. DH is increasingly reported in all age groups and is shown to provide clinical indication of an active erosive tooth wear. As the population ages and possibly retain teeth for longer, the likelihood of tooth wear and DH could increase. This paper describes the prevalence, aetiology, diagnosis and management of DH in relation to tooth wear, which work together through a surface phenomenon. The aim is to raise awareness of the conditions and to help inform a prevention strategy in an ageing population, which starts from younger age groups to reduce disease into older age