Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study

Background & AimsIn acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure.MethodsPigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure.ResultsThe Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen.ConclusionsThe survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients

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)

Responding to global challenges in food, energy, environment and water: Risks and options assessment for decision-Making

We analyse the threats of global environmental change, as they relate to food security. First, we review three discourses: (i) ‘sustainable intensification’, or the increase of food supplies without compromising food producing inputs, such as soils and water; (ii) the ‘nexus’ that seeks to understand links across food, energy, environment and water systems; and (iii) ‘resilience thinking’ that focuses on how to ensure the critical capacities of food, energy and water systems are maintained in the presence of uncertainties and threats. Second, we build on these discourses to present the causal, risks and options assessment for decision-making process to improve decision-making in the presence of risks. The process provides a structured, but flexible, approach that moves from problem diagnosis to better risk-based decision-making and outcomes by responding to causal risks within and across food, energy, environment and water systems

Modeling household decisions using longitudinal data from household panel surveys, with applications to residential mobility

Many events occurring to married or cohabiting individuals are the result of decisions made jointly by both partners. However, studies of life-course events usually take an individual or head-of-household perspective and so do not explicitly reflect the joint nature of these decisions. Household panel studies and population registers are a rich resource for the study of household events, but analyzing such data presents major analytical challenges. Models should ideally allow for the influence of both partners in a couple’s decision making and be flexible enough to handle the facts that individuals can change their partners and have periods when they are not in coresidential unions. In this article, the authors propose two types of multilevel random-effects models to address some of these issues: a “multiple-membership” model in which the outcome depends on a weighted combination of the random effects for each decision maker and a random-coefficients model that allows different random effects for individuals when they are single and partnered. All methods are discussed in terms of a binary household outcome before describing more general discrete-choice models for nominal outcomes. The proposed methods are compared with previously used approaches in a simulation study and illustrated in analyses of residential mobility using data from the British Household Panel Survey

Porcine model characterizing various parameters assessing the outcome after acetaminophen intoxication induced acute liver failure

AIM: To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen overdose. METHODS: Eight pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon autopsy. RESULTS: Acute liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 mL/min) increased to a maximum flow of 1873 ± 175 mL/min at manifestation of ALF, which was significantly elevated (P 0.01). CONCLUSION: Declining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model

BDNF mediates improvements in executive function following a 1-year exercise intervention

Executive function declines with age, but engaging in aerobic exercise may attenuate decline. One mechanism by which aerobic exercise may preserve executive function is through the up-regulation of brain-derived neurotropic factor (BDNF), which also declines with age. The present study examined BDNF as a mediator of the effects of a 1-year walking intervention on executive function in 90 older adults (mean age = 66.82). Participants were randomized to a stretching and toning control group or a moderate intensity walking intervention group. BDNF serum levels and performance on a task-switching paradigm were collected at baseline and follow-up. We found that age moderated the effect of intervention group on changes in BDNF levels, with those in the highest age quartile showing the greatest increase in BDNF after 1-year of moderate intensity walking exercise (p = .036). The mediation analyses revealed that BDNF mediated the effect of the intervention on task-switch accuracy, but did so as a function of age, such that exercise-induced changes in BDNF mediated the effect of exercise on task-switch performance only for individuals over the age of 71. These results demonstrate that both age and BDNF serum levels are important factors to consider when investigating the mechanisms by which exercise interventions influence cognitive outcomes, particularly in elderly populations

Levels of miR122, miR192 and miR124-1 in their respective tissues.

<p>Values are means ± SE of relative expression (2^-ΔΔCt) for APAP-treated animals to both the endogenous control (miR26a) and the time-matched controls; * <i>P</i> < 0.05 vs. baseline at -20h.</p

Assessment of potential endogenous controls, snRNA:U6, miR26a and miR191, for use in porcine studies of ALF, using miR122 as the target miRNA.

<p>Potential endogenous controls were quantified by qRT-PCR in plasma samples from acetaminophen-treated pigs (n = 3, raw Ct). The stability of the potential endogenous controls with progression of ALF was assessed using the following software packages: Normfinder [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128076#pone.0128076.ref028" target="_blank">28</a>]; BestKeeper [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128076#pone.0128076.ref029" target="_blank">29</a>]; geNorm [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128076#pone.0128076.ref030" target="_blank">30</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128076#pone.0128076.ref031" target="_blank">31</a>]; and Delta Ct method [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128076#pone.0128076.ref032" target="_blank">32</a>]. The results from these analyses were used to form the composite rank to determine the final choice of endogenous control. For a graphical representation of the stability of the endogenous controls see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128076#pone.0128076.s001" target="_blank">S1 Fig</a>.</p><p>Ct, threshold cycle; SD, standard deviation; CPs, crossing points; M-value, gene stability value; CV, coefficient of variance</p><p>Assessment of potential endogenous controls, snRNA:U6, miR26a and miR191, for use in porcine studies of ALF, using miR122 as the target miRNA.</p