A network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic heart failure

Aims Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non‐ischaemic HF, it is important to better understand differences in underlying molecular mechanisms. Methods and results We performed a biological physical protein–protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT‐CHF study, 715 of whom had ischaemic HF and 445 had non‐ischaemic HF. Second, we constructed an enriched physical protein–protein interaction network, followed by a pathway over‐representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non‐ischaemic HF patients. We found 21/92 proteins to be up‐regulated and 2/92 down‐regulated in ischaemic relative to non‐ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin‐like growth factor binding protein‐1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort. Conclusions Pathophysiological pathways distinguishing patients with ischaemic HF from those with non‐ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF

Divergences in Real-Time Classical Field Theories at Non-Zero Temperature

The classical approximation provides a non-perturbative approach to time-dependent problems in finite temperature field theory. We study the divergences in hot classical field theory perturbatively. At one-loop, we show that the linear divergences are completely determined by the classical equivalent of the hard thermal loops in hot quantum field theories, and that logarithmic divergences are absent. To deal with higher-loop diagrams, we present a general argument that the superficial degree of divergence of classical vertex functions decreases by one with each additional loop: one-loop contributions are superficially linearly divergent, two-loop contributions are superficially logarithmically divergent, and three- and higher-loop contributions are superficially finite. We verify this for two-loop SU(N) self-energy diagrams in Feynman and Coulomb gauges. We argue that hot, classical scalar field theory may be completely renormalized by local (mass) counterterms, and discuss renormalization of SU(N) gauge theories.Comment: 31 pages with 7 eps figure

Concentric vs. eccentric remodelling in heart failure with reduced ejection fraction:clinical characteristics, pathophysiology and response to treatment

Aims: Heart failure is traditionally classified by left ventricular ejection fraction (LVEF), rather than by left ventricular (LV) geometry, with guideline-recommended therapies in heart failure with reduced ejection fraction (HFrEF) but not heart failure with preserved ejection fraction (HFpEF). Most patients with HFrEF have eccentric LV hypertrophy, but some have concentric LV hypertrophy. We aimed to compare clinical characteristics, biomarker patterns, and response to treatment of patients with HFrEF and eccentric vs. concentric LV hypertrophy. Methods and results: We performed a retrospective post-hoc analysis including 1015 patients with HFrEF (LVEF <40%) from the multinational observational BIOSTAT-CHF study. LV geometry was classified using two-dimensional echocardiography. Network analysis of 92 biomarkers was used to investigate pathophysiologic pathways. Concentric LV hypertrophy was present in 142 (14%) patients, who were on average older and more likely hypertensive compared to those with eccentric LV hypertrophy. Network analysis revealed that N-terminal pro-B-type natriuretic peptide was an important hub in eccentric hypertrophy, whereas in concentric hypertrophy, tumour necrosis factor receptor 1, urokinase plasminogen activator surface receptor, paraoxonase and P-selectin were central hubs. Up-titration of beta-blockers was associated with a mortality benefit in HFrEF with eccentric but not concentric LV hypertrophy (P-value for interaction ≤0.001). For angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, the hazard ratio for mortality was higher in concentric hypertrophy, but the interaction was not significant. Conclusion: Patients with HFrEF with concentric hypertrophy have a clinical and biomarker phenotype that is distinctly different from those with eccentric hypertrophy. Patients with concentric hypertrophy may not experience similar benefit from up.-titration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers compared to patients with eccentric hypertrophy

Pathogenesis of Henoch-Schönlein purpura nephritis

The severity of renal involvement is the major factor determining the long-term outcome of children with Henoch-Schönlein purpura (HSP) nephritis (HSPN). Approximately 40% children with HSP develop nephritis, usually within 4 to 6 weeks after the initial onset of the typical purpuric rashes. Although the pathogenetic mechanisms are still not fully delineated, several studies suggest that galactose-deficient IgA1 (Gd-IgA1) is recognized by anti-glycan antibodies, leading to the formation of the circulating immune complexes and their mesangial deposition that induce renal injury in HSPN

Process for inhibiting the growth of a culture of lactic acid bacteria, and optionally lysing the bacterial cells, and uses of the resulting lysed culture

The invention provides a process for inhibiting the growth of a culture of lactic acid bacteria, or a product containing such culture e.g. a cheese product, in which in the cells of the lactic acid bacteria a holin obtainable from bacteriophages of Gram-positive bacteria, esp. from bacteriophages of lactic acid bacteria is produced in situ, the gene encoding said holin being under control of a first regulatable promoter, said holin being capable of exerting a bacteriostatic effect on the cells in which it is produced by means of a system, whereby the cell membrane is perforated, while preferably the natural production of autolysin is not impaired. It is preferable that additionally a lysin obtainable from lactic acid bacteria or their bacteriophages is produced in situ in the cells of the lactic acid bacteria, the gene encoding said lysin being under control of a second regulatable promoter, whereby the produced lysin effects lysis of the cells of the lactic acid bacteria. The second regulatable promoter can be the same as the first regulatable promoter and the genes encoding the holin and the lysin, respectively can be placed under the same regulatable promoter in one operon. Preferably the promoters are regulatable by the food-grade ingredients or parameters. Other uses of the invention include preparing a mixture of peptides which are modified by peptidases freed after the lysis, using the lysed culture as a bactericidal agent against spoiling bacteria or pathogenic bacteria for improving the shelf life of a product containing the lysed culture

Complex inducible promoter system derivable from a phage of a lactic acid bacterium (lab), and the use in a lab for production of a desired protein

The invention provides a complex inducible promoter system derivable from a phage of a lactic acid bacterium, especially one having the DNA sequence of SEQ. ID. NO: 3 given in Figure 2, or a DNA sequence essentially corresponding to those sequences, and a modification of (an essential part of) such promoter system in which the mitomycin C induction system is replaced by a food-grade system, e.g. a temperature-initiated induction system or a salt-initiated induction system. Also is provided a recombinant vector and a transformed lactic acid bacterium comprising (an essential part of) such promoter system. Further a process for producing a desired protein by such transformed bacterium is provided, comprising expressing a gene encoding said desired protein or a precursor thereof under control of such promoter system or an essential part thereof. Preferably the transformed lactic acid bacterium is made food-grade due to using food-grade DNA sequences and/or removing non-food-grade DNA sequences. When required, the desired protein can be secreted by the lactic acid bacterium if a DNA sequence fused to the gene encoding the desired protein is present which effects secretion of the desired protein or its precursor. The process can be used in a fermentation process, in which the desired protein causes lysis of the bacterial cells so that the contents of the cells can be released, or in which the desired protein is an enzyme involved in flavour formation, or in which the desired protein has a function in a cheese production process, such as chymosin or a precursor thereof, or an enzyme involved in flavour formation