Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction

Aims. Galectin-3 is an emerging biomarker which has been studied in relatively small heart failure (HF) cohorts with predominantly systolic HF. We studied the prognostic value of base-line galectin-3 in a large HF cohort, with preserved and reduced left ventricular ejection fraction (LVEF), and compared this to other biomarkers. Methods. We studied 592 HF patients who had been hospitalized for HF and were followed for 18 months. The primary end-point was a composite of all-cause mortality and HF hospitalization. Results. A doubling of galectin-3 levels was associated with a hazard ratio (HR) of 1.97 (1.62-2.42) for the primary outcome (P <0.001). After correction for age, gender, BNP, eGFR, and diabetes the HR was 1.38 (1.07-1.78; P = 0.015). Galectin-3 levels were correlated with higher IL-6 and CRP levels (P <0.002). Changes of galectin-3 levels after 6 months did not add prognostic information to the base-line value (n = 291); however, combining plasma galectin-3 and BNP levels increased prognostic value over either biomarker alone (ROC analysis, P <0.05). The predictive value of galectin-3 was stronger in patients with preserved LVEF (n = 114) compared to patients with reduced LVEF (P <0.001). Conclusions. Galectin-3 is an independent marker for outcome in HF and appears to be particularly useful in HF patients with preserved LVEF

Degenerate Stars and Gravitational Collapse in AdS/CFT

We construct composite CFT operators from a large number of fermionic primary fields corresponding to states that are holographically dual to a zero temperature Fermi gas in AdS space. We identify a large N regime in which the fermions behave as free particles. In the hydrodynamic limit the Fermi gas forms a degenerate star with a radius determined by the Fermi level, and a mass and angular momentum that exactly matches the boundary calculations. Next we consider an interacting regime, and calculate the effect of the gravitational back-reaction on the radius and the mass of the star using the Tolman-Oppenheimer-Volkoff equations. Ignoring other interactions, we determine the "Chandrasekhar limit" beyond which the degenerate star (presumably) undergoes gravitational collapse towards a black hole. This is interpreted on the boundary as a high density phase transition from a cold baryonic phase to a hot deconfined phase.Comment: 75 page

Innate responses of the predatory mite Phytoseiulus persimilis to a herbivore-induced plant volatile

The responses of the predatory mite P. persimilis to herbivore-induced plant volatiles are at least partly genetically determined. Thus, there is potential for the evolution of this behaviour by natural selection. We tested whether distinct predator genotypes with contrasting responses to a specific herbivore-induced plant volatile, i.e. methyl salicylate (MeSa), could be found in a base population collected in the field (Sicily). To this end, we imposed purifying selection on individuals within iso-female lines of P. persimilis such that the lines were propagated only via the individual that showed either a preference or avoidance of MeSa. The responses of the lines were characterized as the mean proportion of individuals choosing MeSa when given a choice between MeSa and clean air. Significant variation in predator responses was detected among iso-female lines, thus confirming the presence of a genetic component for this behaviour. Nevertheless, we did not find a significant difference in the response to MeSa between the lines that were selected to avoid MeSa and the lines selected to prefer MeSa. Instead, in the course of selection the lines selected to avoid MeSa shifted their mean response towards a preference for MeSa. An inverse, albeit weaker, shift was detected for the lines selected to prefer MeSa. We discuss the factors that may have caused the apparent lack of a response to selection within iso-female line in this study and propose experimental approaches that address them

Circulating Acylcarnitines Associated with Hypertrophic Cardiomyopathy Severity: an Exploratory Cross-Sectional Study in MYBPC3 Founder Variant Carriers

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value

BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants-design and status

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited. AIM: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression. METHODS: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death). RESULTS: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects. CONCLUSION: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium

Increased retention of functional fusions to toxic genes in new two-hybrid libraries of the E. coli strain MG1655 and B. subtilis strain 168 genomes, prepared without passaging through E. coli

BACKGROUND: Cloning of genes in expression libraries, such as the yeast two-hybrid system (Y2H), is based on the assumption that the loss of target genes is minimal, or at worst, managable. However, the expression of genes or gene fragments that are capable of interacting with E. coli or yeast gene products in these systems has been shown to be growth inhibitory, and therefore these clones are underrepresented (or completely lost) in the amplified library. RESULTS: Analysis of candidate genes as Y2H fusion constructs has shown that, while stable in E. coli and yeast for genetic studies, they are rapidly lost in growth conditions for genomic libraries. This includes the rapid loss of a fragment of the E. coli cell division gene ftsZ which encodes the binding site for ZipA and FtsA. Expression of this clone causes slower growth in E. coli. This clone is also rapidly lost in yeast, when expressed from a GAL1 promoter, relative to a vector control, but is stable when the promoter is repressed. We have demonstrated in this report that the construction of libraries for the E. coli and B. subtilis genomes without passaging through E. coli is practical, but the number of transformants is less than for libraries cloned using E. coli as a host. Analysis of several clones in the libraries that are strongly growth inhibitory in E. coli include genes for many essential cellular processes, such as transcription, translation, cell division, and transport. CONCLUSION: Expression of Y2H clones capable of interacting with E. coli and yeast targets are rapidly lost, causing a loss of complexity. The strategy for preparing Y2H libraries described here allows the retention of genes that are toxic when inappropriately expressed in E. coli, or yeast, including many genes that represent potential antibacterial targets. While these methods are generally applicable to the generation of Y2H libraries from any source, including mammalian and plant genomes, the potential of functional clones interacting with host proteins to inhibit growth would make this approach most relevant for the study of prokaryotic genomes

Environmental occurrence, analysis, and toxicology of toxaphene compounds.

Toxaphene production, in quantities similar to those of polychlorinated biphenyls, has resulted in high toxaphene levels in fish from the Great Lakes and in Arctic marine mammals (up to 10 and 16 microg g-1 lipid). Because of the large variabiliity in total toxaphene data, few reliable conclusions can be drawn about trends or geographic differences in toxaphene concentrations. New developments in mass spectrometric detection using either negative chemical ionization or electron impact modes as well as in multidimensional gas chromatography recently have led researchers to suggest congener-specific approaches. Recently, several nomenclature systems have been developed for toxaphene compounds. Although all systems have specific advantages and limitations, it is suggested that an international body such as the International Union of Pure and Applied Chemistry make an attempt to obtain uniformity in the literature. Toxicologic information on individual chlorobornanes is scarce, but some reports have recently appeared. Neurotoxic effects of toxaphene exposure such as those on behavior and learning have been reported. Technical toxaphene and some individual congeners were found to be weakly estrogenic in in vitro test systems; no evidence for endocrine effects in vivo has been reported. In vitro studies show technical toxaphene and toxaphene congeners to be mutagenic. However, in vivo studies have not shown genotoxicity; therefore, a nongenotoxic mechanism is proposed. Nevertheless, toxaphene is believed to present a potential carcinogenic risk to humans. Until now, only Germany has established a legal tolerance level for toxaphene--0.1 mg kg-1 wet weight for fish

PET and MRI for the evaluation of regional myocardial perfusion and wall thickening after myocardial infarction

Deterioration of left ventricular (LV) function after myocardial infarction (MI) is a major cause of heart failure. Myocardial perfusion performance may play an important role in deterioration or improvement in LV function after MI. The aim of this study was to evaluate the myocardial perfusion reserve (MPR) and stress perfusion in deteriorating and non-deteriorating LV segments in patients after MI by PET and MRI, respectively. Regional wall thickening of 352 segments in 22 patients was assessed at 4 and 24 months after MI by cardiac MRI. PET was performed to evaluate MPR and adenosine stress N-13-ammonia perfusion 24 months after MI. Segments were divided into four groups according to deterioration or improvement in wall thickening. Normal functional segments at 4 months after MI that remained stable had a significantly higher mean MPR and mean stress perfusion PET value than deteriorated segments (p < 0.001). Furthermore, dysfunctional segments that improved had a significantly higher mean stress perfusion PET value than dysfunctional segments that remained dysfunctional (p < 0.001). This study demonstrated the additional value of myocardial perfusion assessment in relation to the functional integrity of the injured myocardium. Segmental functional LV improvement after MI was associated with better regional myocardial perfusion characteristics. Furthermore, the amount of wall thickening reduction was associated with regional myocardial perfusion abnormalities in patients after MI

Specifying enough light to feel reassured on pedestrian footpaths

This article discusses lighting for pedestrians and how investigation of reassurance might lead toward an understanding of the right amount of light. A conventional approach is to evaluate reassurance after dark under road lighting of different illuminance: this tends to show the trivial result that higher illuminances enhance reassurance, and that alone does not enable an optimum light level to be identified. One reason is that the category rating procedure widely used is prone to stimulus range bias; experimental results are presented that demonstrate stimulus range bias in reassurance evaluations. This article also recommends alternative methods for future research. One such method is the day–dark rating approach, which does not tend toward ever higher illuminances, and results are presented of two studies using this method

Practical Verification of Decision-Making in Agent-Based Autonomous Systems

We present a verification methodology for analysing the decision-making component in agent-based hybrid systems. Traditionally hybrid automata have been used to both implement and verify such systems, but hybrid automata based modelling, programming and verification techniques scale poorly as the complexity of discrete decision-making increases making them unattractive in situations where complex log- ical reasoning is required. In the programming of complex systems it has, therefore, become common to separate out logical decision-making into a separate, discrete, component. However, verification techniques have failed to keep pace with this devel- opment. We are exploring agent-based logical components and have developed a model checking technique for such components which can then be composed with a sepa- rate analysis of the continuous part of the hybrid system. Among other things this allows program model checkers to be used to verify the actual implementation of the decision-making in hybrid autonomous systems