Soluble triggering receptor expressed on myeloid cells-1 is a marker of organ injuries in cardiogenic shock : results from the CardShock Study

Aims Optimal outcome after cardiogenic shock (CS) depends on a coordinated healing response in which both debris removal and extracellular matrix tissue repair play a crucial role. Excessive inflammation can perpetuate a vicious circle, positioning leucocytes as central protagonists and potential therapeutic targets. High levels of circulating Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), were associated with death in acute myocardial infarction confirming excessive inflammation as determinant of bad outcome. The present study aims to describe the association of soluble TREM-1 with 90-day mortality and with various organ injuries in patients with CS. Methods and results This is a post-hoc study of CardShock, a prospective, multicenter study assessing the clinical presentation and management in patients with CS. At the time of this study, 87 patients had available plasma samples at either baseline, and/or 48 h and/or 96-120 h for soluble TREM-1 (sTREM-1) measurements. Plasma concentration of sTREM-1 was higher in 90-day non-survivors than survivors at baseline [median: 1392 IQR: (724-2128) vs. 621 (525-1233) pg/mL, p = 0.008), 48 h (p = 0.019) and 96-120 h (p = 0.029). The highest tertile of sTREM-1 at baseline (threshold: 1347 pg/mL) was associated with 90-day mortality with an unadjusted HR 3.08 CI 95% (1.48-6.42). sTREM-1 at baseline was not associated to hemodynamic parameters (heart rate, blood pressure, use of vasopressors or inotropes) but rather with organ injury markers: renal (estimated glomerular filtration rate, p = 0.0002), endothelial (bio-adrenomedullin, p = 0.018), myocardial (Suppression of Tumourigenicity 2, p = 0.002) or hepatic (bilirubin, p = 0.008). Conclusion In CS patients TREM-1 pathway is highly activated and gives an early prediction of vital organ injuries and outcome. [GRAPHICS] .Peer reviewe

NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) : characterisation of a novel cerebropulmonary disease

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.Peer reviewe

DEVELOPMENT OF HIGH STRENGTH COMPOSITE WIRES BASED ON CU-MG

Разработаны технологии по получению высокопрочных композитных проводов на основе Cu–Mg. Методом гидроэкструзии сформирован композитный провод с большим количеством волокон магния. Проведены эксперименты по получению композитного провода Cu–Mg путем введения смеси из порошков меди и магния. Исследована микроструктура полученных композитов. Проведены измерения электрических и механических свойств.The techniques to obtain high-strength Cu–Mg composite wires were developed. Hydrostatic extrusion method was used to obtain the Cu–Mg composite wire with lots of magnesium fibers. Also the experiments to acquire a composite wire from the mixture of copper and magnesium powders were conducted. The microstructure of obtained composites was investigated. The electrical and mechanical properties were measured.Работа выполнена в рамках государственного задания ФАНО России (тема «Деформация», № 01201463327)

Mitochondrial 2,4-dienoyl-CoA Reductase Deficiency in Mice Results in Severe Hypoglycemia with Stress Intolerance and Unimpaired Ketogenesis

The mitochondrial β-oxidation system is one of the central metabolic pathways of energy metabolism in mammals. Enzyme defects in this pathway cause fatty acid oxidation disorders. To elucidate the role of 2,4-dienoyl-CoA reductase (DECR) as an auxiliary enzyme in the mitochondrial β-oxidation of unsaturated fatty acids, we created a DECR–deficient mouse line. In Decr−/− mice, the mitochondrial β-oxidation of unsaturated fatty acids with double bonds is expected to halt at the level of trans-2, cis/trans-4-dienoyl-CoA intermediates. In line with this expectation, fasted Decr−/− mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C18:2), urinary excretion of unsaturated dicarboxylic acids, and hepatic steatosis, wherein unsaturated fatty acids accumulate in liver triacylglycerols. Metabolically challenged Decr−/− mice turned on ketogenesis, but unexpectedly developed hypoglycemia. Induced expression of peroxisomal β-oxidation and microsomal ω-oxidation enzymes reflect the increased lipid load, whereas reduced mRNA levels of PGC-1α and CREB, as well as enzymes in the gluconeogenetic pathway, can contribute to stress-induced hypoglycemia. Furthermore, the thermogenic response was perturbed, as demonstrated by intolerance to acute cold exposure. This study highlights the necessity of DECR and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state

Deletion of the Major Bullous Pemphigoid Epitope Region of Collagen XVII Induces Blistering, Autoimmunization, and Itching in Mice

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering skin disease with a characteristic of pruritus and blistering. BP patients carry inflammation-triggering autoantibodies against the collagen XVII (ColXVII, also known as BP180) juxtamembraneous extracellular noncollagenous 16A (NC16A) domain involved in ectodomain shedding. Deletion of the corresponding NC14A region in a genetically modified mouse model (ΔNC14A) decreased the amount of ColXVII in skin, but it did not prevent ectodomain shedding. Newborn ΔNC14A mice had no macroscopic phenotypic changes. However, subepidermal microblisters, rudimentary hemidesmosomes, and loose basement membrane zone were observed by microscopy. ΔNC14A mice grow normally, but at around 3 months of age they start to scratch themselves and develop crusted erosions. Furthermore, perilesional eosinophilic infiltrations in the skin, eosinophilia, and elevated serum IgE levels are detected. Despite the removal of the major BP epitope region, ΔNC14A mice developed IgG and IgA autoantibodies with subepidermal reactivity, indicating autoimmunization against a dermo-epidermal junction component. Moreover, IgG autoantibodies recognized a 180-kDa keratinocyte protein, which was sensitive to collagenase digestion. We show here that ΔNC14A mice provide a highly reproducible BP-related mouse model with spontaneous breakage of self-tolerance and development of autoantibodies