New technologies - new insights into the pathogenesis of hepatic encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome which frequently accompanies acute or chronic liver disease. It is characterized by a variety of symptoms of different severity such as cognitive deficits and impaired motor functions. Currently, HE is seen as a consequence of a low grade cerebral oedema associated with the formation of cerebral oxidative stress and deranged cerebral oscillatory networks. However, the pathogenesis of HE is still incompletely understood as liver dysfunction triggers exceptionally complex metabolic derangements in the body which need to be investigated by appropriate technologies. This review summarizes technological approaches presented at the ISHEN conference 2014 in London which may help to gain new insights into the pathogenesis of HE. Dynamic in vivo13C nuclear magnetic resonance spectroscopy was performed to analyse effects of chronic liver failure in rats on brain energy metabolism. By using a genomics approach, microRNA expression changes were identified in plasma of animals with acute liver failure which may be involved in interorgan interactions and which may serve as organ-specific biomarkers for tissue damage during acute liver failure. Genomics were also applied to analyse glutaminase gene polymorphisms in patients with liver cirrhosis indicating that haplotype-dependent glutaminase activity is an important pathogenic factor in HE. Metabonomics represents a promising approach to better understand HE, by capturing the systems level metabolic changes associated with disease in individuals, and enabling monitoring of metabolic phenotypes in real time, over a time course and in response to treatment, to better inform clinical decision making. Targeted fluxomics allow the determination of metabolic reaction rates thereby discriminating metabolite level changes in HE in terms of production, consumption and clearance

Circulating microRNAs Reveal Time Course of Organ Injury in a Porcine Model of Acetaminophen-Induced Acute Liver Failure

Acute liver failure is a rare but catastrophic condition which can progress rapidly to multi-organ failure. Studies investigating the onset of individual organ injury such as the liver, kidneys and brain during the evolution of acute liver failure, are lacking. MicroRNAs are short, non-coding strands of RNA that are released into the circulation following tissue injury. In this study, we have characterised the release of both global microRNA and specific microRNA species into the plasma using a porcine model of acetaminophen-induced acute liver failure. Pigs were induced to acute liver failure with oral acetaminophen over 19h±2h and death occurred 13h±3h thereafter. Global microRNA concentrations increased 4h prior to acute liver failure in plasma (P<0.0001) but not in isolated exosomes, and were associated with increasing plasma levels of the damage-associated molecular pattern molecule, genomic DNA (P<0.0001). MiR122 increased around the time of onset of acute liver failure (P<0.0001) and was associated with increasing international normalised ratio (P<0.0001). MiR192 increased 8h after acute liver failure (P<0.0001) and was associated with increasing creatinine (P<0.0001). The increase in miR124-1 occurred concurrent with the pre-terminal increase in intracranial pressure (P<0.0001) and was associated with decreasing cerebral perfusion pressure (P<0.002)

Characterization of Volcano-Sedimentary Rocks and Related Scraps for Design of Sustainable Materials

This work started as a joint academia and company research project with the aim of finding new applications for domestically sourced volcanic products and related waste (pumice, lapillus, zeolitic tuff and volcanic debris from Tessennano and Arlena quarry) by creating a database of secondary volcanic raw materials and their intrinsic characteristics to help industry replace virgin materials and enhance circularity. In this context, accurate chemical, mineralogical, morphological, granulometric and thermal characterizations were performed. Based on the results presented, it can be concluded that due to their lightness, these materials can be used in the design and preparation of lightweight aggregates for agronomic purposes or in the construction field. Furthermore, due to their aluminosilicate nature and amorphous fraction, pumice and lapillus can play the role of precursor or activator for geopolymer preparation. With its porous nature, zeolitic tuff can be exploited for flue gas treatment. Due to the presence of feldspathic phase (sanidine), these materials can be used in tile production as a fluxing component, and with their pozzolanic activity and calcium content, they have application in the binder field as supplementary cementitious material or as aggregates

Circulating microparticles: square the circle

Background: The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results: MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions: Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes

Application of Life Cycle Assessment in the Environmental Study of Sustainable Ceramic Bricks Made with 'alperujo' (Olive Pomace)

Investigations on the application of Life Cycle Assessment (LCA) to the construction sector have shown that the environmental impact of construction products can be significantly reduced. To achieve this, the use of best available techniques and eco-innovation in production plants must be promoted. In this way, the use of finite natural resources can be replaced by waste generated in other production processes, preferably available locally, stimulating the creation of more sustainable products. Conducting a comparative LCA study between the traditional ceramic brick manufacturing process and the ceramic brick manufacturing process incorporating 'alperujo' (waste generated in the virgin oil extraction process), is an inevitable step to achieve the integration of circularity and eco-innovation in the production system of traditional ceramic materials, through the CML(Centrum voor Milieukunde Leiden) and IPCC(The Intergovernmental Panel on Climate Change) methodology. The obtained results suggest that the environmental benefits in this practice are very limited, even taking into account the contribution of different amounts of this waste to the production of bricks

Improved Measurement of CPCP Violation Parameters in Bs0→J/ψK+K−B^0_s \rightarrow J/\psi K^+ K^- Decays in the Vicinity of the ϕ(1020) Resonance

The decay-time-dependent CP asymmetry in B_{s}^{0}→J/ψ(→μ^{+}μ^{-})K^{+}K^{-} decays is measured using proton-proton collision data, corresponding to an integrated luminosity of 6  fb^{-1}, collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 B_{s}^{0} signal decays with an invariant K^{+}K^{-} mass in the vicinity of the ϕ(1020) resonance, the CP-violating phase ϕ_{s} is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the B_{s}^{0}-B[over ¯]_{s}^{0} system, ΔΓ_{s}, and the difference of the average B_{s}^{0} and B^{0} meson decay widths, Γ_{s}-Γ_{d}. The values obtained are ϕ_{s}=-0.039±0.022±0.006  rad, ΔΓ_{s}=0.0845±0.0044±0.0024  ps^{-1}, and Γ_{s}-Γ_{d}=-0.0056_{-0.0015}^{+0.0013}±0.0014  ps^{-1}, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase ϕ_{s} is also measured independently for each polarization state of the K^{+}K^{-} system and shows no evidence for polarization dependence

Monitoring Procalcitonin in Febrile Neutropenia: What Is Its Utility for Initial Diagnosis of Infection and Reassessment in Persistent Fever?

Background: Management of febrile neutropenic episodes (FE) is challenged by lacking microbiological and clinical documentation of infection. We aimed at evaluating the utility of monitoring blood procalcitonin (PCT) in FE for initial diagnosis of infection and reassessment in persistent fever.Methods: PCT kinetics was prospectively monitored in 194 consecutive FE (1771 blood samples): 65 microbiologically documented infections (MDI, 33.5%; 49 due to non-coagulase-negative staphylococci, non-CNS), 68 clinically documented infections (CDI, 35%; 39 deep-seated), and 61 fever of unexplained origin (FUO, 31.5%).Results: At fever onset median PCT was 190 pg/mL (range 30-26'800), without significant difference among MDI, CDI and FUO. PCT peak occurred on day 2 after onset of fever: non-CNS-MDI/deep-seated-CDI (656, 80-86350) vs. FUO (205, 33-771; p&lt;0.001). PCT &gt;500 pg/mL distinguished non-CNS-MDI/deep-seated-CDI from FUO with 56% sensitivity and 90% specificity. PCT was &gt;500 pg/ml in only 10% of FUO (688, 570-771). A PCT peak &gt;500 pg/mL (1196, 524-11950) occurred beyond 3 days of persistent fever in 17/21 (81%) invasive fungal diseases (IFD). This late PCT peak identified IFD with 81% sensitivity and 57% specificity and preceded diagnosis according to EORTC-MSG criteria in 41% of cases. In IFD responding to therapy, median days to PCT &lt;500 pg/mL and defervescence were 5 (1-23) vs. 10 (3-22; p = 0.026), respectively.Conclusion: While procalcitonin is not useful for diagnosis of infection at onset of neutropenic fever, it may help to distinguish a minority of potentially severe infections among FUOs on day 2 after onset of fever. In persistent fever monitoring procalcitonin contributes to early diagnosis and follow-up of invasive mycose

Conformational preferences of a 14-residue fibrillogenic peptide from acetylcholinesterase

A 14-residue fragment from near the C-terminus of the enzyme acetylcholinesterase (AChE) is believed to have a neurotoxic/neurotrophic effect acting via an unknown pathway. While the peptide is α-helical in the full-length enzyme, the structure and association mechanism of the fragment are unknown. Using multiple molecular dynamics simulations, starting from a tetrameric complex of the association domain of AChE and systematicall disassembled subsets that include the peptide fragment, we show that the fragment is incapable of retaining its helicity in solution. Extensive replica exchange Monte Carlo folding and unfolding simulations in implicit solvent with capped and uncappted termini failed to converge to any consistent cluster of structures, suggesting that the fragment remains largely unstructured in solution under the conditions considered. Furthermore, extended molecular dynamics simulations of two steric zipper models show that the peptide is likely to form a zipper with antiparallel sheets and that peptides with mutations known to prevent fibril formation likely do so by interfering with this packing. The results demonstrate how the local environment of a peptide can stabilize a particular conformation