The effect of fractal-like mechanical ventilation on vital signs in a rat model of acute-on-chronic liver failure

OBJECTIVE: The network of interactions between different organs is impaired in liver cirrhosis. Liver cirrhosis is associated with multi-system involvement, which eventually leads to multiple organ failure. This process is accelerated by a precipitating factor such as bacterial infection, which leads to respiratory distress, circulatory shock, neural dysfunction and very high mortality. Cirrhotic patients often have blunted respiratory sinus arrhythmia and impaired cardio-respiratory variability. Fractal-like mechanical ventilation is reported to enhance respiratory sinus arrhythmia and attenuate respiratory distress in experimental models. In the present study we hypothesise that fractal-like mechanical ventilation may improve the outcome of cirrhotic rats with multiple organ failure. APPROACH: Cirrhosis was induced by chronic biliary obstruction in rats. Acute multiple organ failure was induced by intraperitoneal injection of bacterial endotoxin in cirrhotic rats. The effect of conventional mechanical ventilation (with constant tidal volume and respiratory rate) or fractal-like ventilation (with the same average but variable tidal volume and respiratory rate) were assessed on vital signs, oxygen saturation and plasma alanine aminotransferase in anaesthetised cirrhotic rats. MAIN RESULTS: We demonstrated that fractal-like mechanical ventilation was accompanied by improved oxygen saturation, reduced heart rate and decreased liver injury following injection of bacterial endotoxin. Moreover, variable mechanical ventilation in cirrhotic rats reduced mortality and prevented a fall in short-term heart rate variability following endotoxin challenge in comparison with rats with constant mechanical ventilation. Significance: We suggest further investigations into the beneficial effects of fractal-like ventilation strategy in critically ill patients with liver failure requiring organ support and mechanical ventilation

Anti-melanocortin-4 receptor autoantibodies in obesity

Background: The melanocortin-4 receptor (MC4R) is part of an important pathway regulating energy balance. Here we report the existence of autoantibodies (autoAbs) against the MC4R in sera of obese patients. Methods: The autoAbs were detected after screening of 216 patients' sera by using direct and inhibition ELISA with an N-terminal sequence of the MC4R. Binding to the native MC4R was evaluated by flow cytometry and pharmacological effects by measuring adenylyl cyclase activity. Results: Positive results in all tests were obtained in patients with overweight or obesity (prevalence: 3.6%) but not in normal weight patients. The selective binding properties of anti-MC4R autoAbs were confirmed by surface plasmon resonance and by immunoprecipitation with the native MC4R. Finally it was demonstrated that these autoAbs increased food intake in rats after passive transfer via intracerebroventricular injection. Conclusion: These observations suggest that inhibitory anti-MC4R autoAbs might contribute to the development of obesity in a small subpopulation of patients

Empirical constraints on the origin of fast radio bursts: volumetric rates and host galaxy demographics as a test of millisecond magnetar connection

The localization of the repeating FRB 121102 to a low-metallicity dwarf galaxy at $z=0.193$, and its association with a quiescent radio source, suggests the possibility that FRBs originate from magnetars, formed by the unusual supernovae in such galaxies. We investigate this via a comparison of magnetar birth rates, the FRB volumetric rate, and host galaxy demographics. We calculate average volumetric rates of possible millisecond magnetar production channels such as superluminous supernovae (SLSNe), long and short gamma-ray bursts (GRBs), and general magnetar production via core-collapse supernovae. For each channel we also explore the expected host galaxy demographics using their known properties. We determine for the first time the number density of FRB emitters (the product of their volumetric birthrate and lifetime), $R_{\rm FRB}\tau\approx 10^4$Gpc$^{-3}$, assuming that FRBs are predominantly emitted from repetitive sources similar to FRB 121102 and adopting a beaming factor of 0.1. By comparing rates we find that production via rare channels (SLSNe, GRBs) implies a typical FRB lifetime of $\approx$30-300 yr, in good agreement with other lines of argument. The total energy emitted over this time is consistent with the available energy stored in the magnetic field. On the other hand, any relation to magnetars produced via normal core-collapse supernovae leads to a very short lifetime of $\approx$0.5yr, in conflict with both theory and observation. We demonstrate that due to the diverse host galaxy distributions of the different progenitor channels, many possible sources of FRB birth can be ruled out with $\lesssim 10$ host galaxy identifications. Conversely, targeted searches of galaxies that have previously hosted decades-old SLSNe and GRBs may be a fruitful strategy for discovering new FRBs and related quiescent radio sources, and determining the nature of their progenitors

A near-stationary subspace for ridge approximation

Response surfaces are common surrogates for expensive computer simulations in engineering analysis. However, the cost of fitting an accurate response surface increases exponentially as the number of model inputs increases, which leaves response surface construction intractable for high-dimensional, nonlinear models. We describe ridge approximation for fitting response surfaces in several variables. A ridge function is constant along several directions in its domain, so fitting occurs on the coordinates of a low-dimensional subspace of the input space. We review essential theory for ridge approximation---e.g., the best mean-squared approximation and an optimal low-dimensional subspace---and we prove that the gradient-based active subspace is near-stationary for the least-squares problem that defines an optimal subspace. Motivated by the theory, we propose a computational heuristic that uses an estimated active subspace as an initial guess for a ridge approximation fitting problem. We show a simple example where the heuristic fails, which reveals a type of function for which the proposed approach is inappropriate. We then propose a simple alternating heuristic for fitting a ridge function, and we demonstrate the effectiveness of the active subspace initial guess applied to an airfoil model of drag as a function of its 18 shape parameters

Increased sample asymmetry and memory of cardiac time-series following endotoxin administration in cirrhotic rats

Sepsis, and other causes of acute systemic inflammation, can reduce heart rate variability (HRV) and increase cardiac cycle regularity in mammals. Thus, HRV monitoring has been used for early detection of sepsis in adults and neonates. Liver cirrhosis is associated with reduced basal HRV and the development of tolerance to the cardiac chronotropic effects of bacterial endotoxin. This may pose limitations on the use of heart rate monitoring in early detection of sepsis in this patient population. In a study to develop a physiomarker for the detection of sepsis in cirrhosis, we observed that endotoxin administration in adult cirrhotic rats leads to the development of transient heart rate decelerations, a phenomenon which has been reported in neonates with sepsis, and quantified using sample asymmetry analysis. In the present study, cirrhosis was induced by surgical ligation of the bile duct in rats. Cirrhotic rats were given intraperitoneal injections of either saline or endotoxin (1 mg kg(-1)). Changes in sample asymmetry and memory length of cardiac time-series were studied in conscious rats using implanted telemetric probes. Cirrhotic (but not control) rats exhibited increased sample asymmetry following endotoxin injection, which was consistent with the development of transient heart rate deceleration. Endotoxin administration in cirrhotic rats was associated with prolongation of memory length for observing decelerating perturbations in the cardiac rhythm. These findings may have application in the development of an HRV monitoring system for early detection of sepsis in cirrhosis

Neonatal Sepsis Alters the Excitability of Regular Spiking Cells in the Nucleus of the Solitary Tract in Rats

OBJECTIVE: Sepsis is a leading cause of mortality and morbidity in infants. Although the measures of autonomic dysfunction (e.g. reduced heart rate variability) predict mortality in sepsis, the mechanism of sepsis-induced autonomic dysfunction has remained elusive. The nucleus of the solitary tract hjh(NTS) is a vital structure for the integrated autonomic response to physiological challenges. In the present study we hypothesized that sepsis alters the excitability of NTS neurons in a rat model of neonatal sepsis (14-day old rats). METHODS AND RESULTS: Sepsis was induced by intraperitoneal injection of cecal slurry (CS) in rat neonates. The presence of autonomic dysfunction was confirmed by observing a significant reduction in both short-term and long-term heart rate variably following CS injection. We investigated the effect of polymicrobial sepsis on the electrophysiological properties of the medial NTS neurons using a whole cell patch clamp recording. Our results showed that the resting membrane potential in regular spiking neurons was significantly less polarized in the septic group (-37.6 ± 1.76 mv) when compared with the control group (-54.7 ± 1.73 mv, P < 0.001). The number of spontaneous action potentials in the septic group, was also significantly higher than the control group (P < 0.05). In addition, the frequency and amplitude of the spontaneous excitatory post synaptic potentials (EPSPs) was significantly higher in neurons recorded in the septic group (P < 0.001). Interestingly, regular spiking cells in the CS group exhibited a rebound action potential following hyperpolarization. Injection of depolarizing currents was associated with lower first spike latency and changes in rise slope of action potential (P < 0.001). CONCLUSIONS: We showed that polymicrobial sepsis increases the excitability of regular spiking cells in the medial NTS. These alterations can potentially affect neural coding and thus may contribute to an abnormal homeostatic or allostatic physiological response to sepsis and systemic inflammation

Spitzer Space Telescope Infrared Observations of the Binary Neutron Star Merger GW170817

We present Spitzer Space Telescope 3.6 and 4.5 micron observations of the binary neutron star merger GW170817 at 43, 74, and 264 days post-merger. Using the final observation as a template, we uncover a source at the position of GW170817 at 4.5 micron with a brightness of 22.9+/-0.3 AB mag at 43 days and 23.8+/-0.3 AB mag at 74 days (the uncertainty is dominated by systematics from the image subtraction); no obvious source is detected at 3.6 micron to a 3-sigma limit of >23.3 AB mag in both epochs. The measured brightness is dimmer by a factor of about 2-3 times compared to our previously published kilonova model, which is based on UV, optical, and near-IR data at <30 days. However, the observed fading rate and color (m_{3.6}-m_{4.5}> 0 AB mag) are consistent with our model. We suggest that the discrepancy is likely due to a transition to the nebular phase, or a reduced thermalization efficiency at such late time. Using the Spitzer data as a guide, we briefly discuss the prospects of observing future binary neutron star mergers with Spitzer (in LIGO/Virgo Observing Run 3) and the James Webb Space Telescope (in LIGO/Virgo Observing Run 4 and beyond).Comment: 6 pages, 2 figures, submitted to ApJ