Experiments and numerical results on nonlinear vibrations of an impacting hertzian contact. Part 1: harmonic excitation

The purpose of this paper is to investigate experimental and numerical dynamic responses of a preloaded vibro-impacting Hertzian contact under sinusoidal excitation. Dynamic response under random excitation is analysed in the second part of this paper. A test rig is built corresponding to a double sphere-plane contact preloaded by the weight of a moving cylinder. Typical response curves are obtained for several input levels. Time traces and spectral contents are explored. Both amplitude and phase of harmonics of the dynamic response are investigated. Linearised resonance frequency and damping ratio are identified from the almost linear behaviour under very small input amplitude. Increasing the external input amplitude, the softening behaviour induced by Hertzian nonlinear stiffness is clearly demonstrated. Resonance peak is confined in a narrow frequency range. Jump discontinuities are identified for both amplitude and phase responses. Forced response spectrum exhibits several harmonics because of nonlinear Hertzian restoring force. Numerical simulations show a very good agreement with experimental results. For higher input amplitude, system exhibits vibro-impacts. Loss of contact non-linearity clearly dominates the dynamic behaviour of the vibroimpacting contact and leads to a wide frequency range softening resonance. Spectral content of the response is dominated by both the first and the second harmonics. Evolution of the experimental downward jump frequency versus input amplitude allows the identification of the nonlinear damping law during intermittent contact. Simulations of the vibroimpacting Hertzian contact are performed using a shooting method and show a very good agreement with experimental results

Response of an impacting hertzian contact to an order-2 subharmonic excitation : theory and experiments

Response of a normally excited preloaded Hertzian contact is investigated in order to analyze the subharmonic resonance of order 2. The nonlinearity associated with contact losses is included. The method of multiple scales is used to obtain the non-trivial steady state solutions, their stability, and the frequency-response curves. To this end, a third order Taylor series of the elastic Hertzian contact force is introduced over the displacement interval where the system remains in contact. A classical time integration method is also used in conjunction with a shooting method to take into account losses of contact. The theoretical results show that the subharmonic resonance constitutes a precursor of dynamic responses characterised by loss of contact, and consequently, the resonance establishes over a wide frequency range. Finally, experimental validations are also presented in this paper. To this end, a specific test rig is used. It corresponds to a double sphere-plane contact preloaded by the weight of a moving mass. Experimental results show good agreements with theoretical ones

Experiments and numerical results on nonlinear vibrations of an impacting hertzian contact. Part 2: random excitation

Non linear dynamic behaviour of a normally excited preloaded Hertzian contact (including possible contact losses) is investigated using an experimental test rig. It consists on a double sphere plane contact loaded by the weight of a rigid moving mass. Contact vibrations are generated by a external Gaussian white noise and exhibit vibroimpact responses when the input level is sufficiently high. Spectral contents and statistics of the stationary transmitted normal force are analysed. A single-degree-of-freedom non linear oscillator including loss of contact and Hertzian non linearities is built for modelling the experimental system. Theoretical responses are obtained by using the stationary Fokker-Planck equation and also Monte Carlo simulations. When contact loss occurrence is very occasional, numerical results shown a very good agreement with experimental ones. When vibroimpacts occur, results remain in reasonable agreement with experimental ones, that justify the modelling and the numerical methods described in this paper. The contact loss non linearity appears to be rather strong compared to the Hertzian non linearity. It actually induces a large broadening of the spectral contents of the response. This result is of great importance in noise generation for a lot of systems such as mechanisms using contacts to transform motions and forces (gears, ball-bearings, cam systems, to name a few). It is also of great importance for tribologists preoccupied to prevent surface dammage

The prognostic value of pulmonary artery compliance in cardiogenic shock.

The aim of this study was to evaluate the pathophysiological role and the prognostic significance of pulmonary artery compliance (C <sub>PA</sub> ), a measure of right ventricular pulsatile afterload, in cardiogenic shock. We retrospectively included 91 consecutive patients with cardiogenic shock due to primary left ventricular failure, monitored with a pulmonary artery catheter within the first 24 h. C <sub>PA</sub> was calculated as the ratio of stroke volume to pulmonary artery pulse pressure, and we determined whether C <sub>PA</sub> predicted mortality and whether it performed better than other pulmonary hemodynamic variables. The overall in-hospital mortality in our cohort was 27%. Survivors and nonsurvivors had comparable left ventricular ejection fraction, systolic, diastolic and mean pulmonary artery pressure, transpulmonary gradient, diastolic pressure gradient, and pulmonary vascular resistance at 24 h. In contrast, C <sub>PA</sub> was the only pulmonary artery variable significantly associated with mortality in univariate and multivariate analyses. Mortality increased from 4.5% at the highest quartile of C <sub>PA</sub> (3.6-6.5 mL/mmHg) to 43.5% at the lowest quartile (0.7-1.7 mL/mmHg). In 64 patients with a PAC inserted immediately upon admission, we calculated the trend of C <sub>PA</sub> between admission and 24 h. This trend was positive in survivors (+0.8 ± 1.3 ml/mmHg) but negative in nonsurvivors (-0.1 ± 1.0 mL/mmHg). The lower C <sub>PA</sub> in nonsurvivors was associated with more severe right ventricular systolic dysfunction. In conclusion, a reduced compliance of the pulmonary artery promotes right ventricular dysfunction and is independently associated with mortality in cardiogenic shock. Future studies should evaluate the impact on pulmonary arterial compliance and right ventricular afterload of therapies used in cardiogenic shock

Three-dimensional Ca2+ imaging advances understanding of astrocyte biology.

Astrocyte communication is typically studied by two-dimensional calcium ion (Ca2+) imaging, but this method has not yielded conclusive data on the role of astrocytes in synaptic and vascular function. We developed a three-dimensional two-photon imaging approach and studied Ca2+ dynamics in entire astrocyte volumes, including during axon-astrocyte interactions. In both awake mice and brain slices, we found that Ca2+ activity in an individual astrocyte is scattered throughout the cell, largely compartmented between regions, preponderantly local within regions, and heterogeneously distributed regionally and locally. Processes and endfeet displayed frequent fast activity, whereas the soma was infrequently active. In awake mice, activity was higher than in brain slices, particularly in endfeet and processes, and displayed occasional multifocal cellwide events. Astrocytes responded locally to minimal axonal firing with time-correlated Ca2+ spots

Cytokine hemoadsorption with CytoSorb^® in post-cardiac arrest syndrome, a pilot randomized controlled trial.

Hemoadsorption (HA) might mitigate the systemic inflammatory response associated with post-cardiac arrest syndrome (PCAS) and improve outcomes. Here, we investigated the feasibility, safety and efficacy of HA with CytoSorb <sup>®</sup> in cardiac arrest (CA) survivors at risk of PCAS. In this pilot randomized controlled trial, we included patients admitted to our intensive care unit following CA and likely to develop PCAS: required norepinephrine (> 0.2 µg/kg/min), and/or had serum lactate > 6 mmol/l and/or a time-to-return of spontaneous circulation (ROSC) > 25 min. Those requiring ECMO or renal replacement therapy were excluded. Eligible patients were randomly allocated to either receive standard of care (SOC) or SOC plus HA. Hemoadsorption was performed as stand-alone therapy for 24 h, using CytoSorb <sup>®</sup> and regional heparin-protamine anticoagulation. We collected feasibility, safety and clinical data as well as serial plasma cytokines levels within 72 h of randomization. We enrolled 21 patients, of whom 16 (76%) had out-of-hospital CA. Median (IQR) time-to-ROSC was 30 (20, 45) minutes. Ten were assigned to the HA group and 11 to the SOC group. Hemoadsorption was initiated in all patients allocated to the HA group within 18 (11, 23) h of ICU admission and conducted for a median duration of 21 (14, 24) h. The intervention was well tolerated except for a trend for a higher rate of aPTT elevation (5 (50%) vs 2 (18%) p = 0.18) and mild (100-150 G/L) thrombocytopenia at day 1 (5 (50%) vs 2 (18%) p = 0.18). Interleukin (IL)-6 plasma levels at randomization were low (< 100 pg/mL) in 10 (48%) patients and elevated (> 1000 pg/mL) in 6 (29%). The median relative reduction in IL-6 at 48 h was 75% (60, 94) in the HA group versus 5% (- 47, 70) in the SOC group (p = 0.06). In CA survivors at risk of PCAS, HA was feasible, safe and was associated with a nonsignificant reduction in cytokine plasma levels. Future trials are needed to further define the role of HA after CA. Those studies should include cytokine assessment to enrich the study population. NCT03523039, registered 14 May 2018

Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential

Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.

Cardiopulmonary bypass (CPB) is often associated with degrees of complex inflammatory response mediated by various cytokines. This response can, in severe cases, lead to systemic hypotension and organ dysfunction. Cytokine removal might therefore improve outcomes of patients undergoing cardiac surgery. CytoSorb® (Cytosorbents, NJ, USA) is a recent device designed to remove cytokine from the blood using haemoadsorption (HA). This trial aims to evaluate the potential of CytoSorb® to decrease peri-operative cytokine levels in cardiac surgery. We have conducted a single-centre pilot randomized controlled trial in 30 patients undergoing elective cardiac surgery and deemed at risk of complications. Patients were randomly allocated to either standard of care (n = 15) or CytoSorb® HA (n = 15) during cardiopulmonary bypass (CPB). Our primary outcome was the difference between the two groups in cytokines levels (IL-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ, MCP-1) measured at anaesthesia induction, at the end of CPB, as well as 6 and 24 h post-CPB initiation. In a consecutive subgroup of patients (10 in HA group, 11 in control group), we performed cross-adsorber as well as serial measurements of coagulation factors' activity (antithrombin, von Willebrand factor, factor II, V, VIII, IX, XI, and XII). Both groups were similar in terms of baseline and peri-operative characteristics. CytoSorb® HA during CPB was not associated with an increased incidence of adverse event. The procedure did not result in significant coagulation factors' adsorption but only some signs of coagulation activation. However, the intervention was associated neither with a decrease in pro- or anti-inflammatory cytokine levels nor with any improvement in relevant clinical outcomes. CytoSorb® HA during CPB was not associated with a decrease in pro- or anti-inflammatory cytokines nor with an improvement in relevant clinical outcomes. The procedure was feasible and safe. Further studies should evaluate the efficacy of CytoSorb® HA in other clinical contexts. ClinicalTrials.gov NCT02775123 . Registered 17 May 2016