141 research outputs found
Nonconservative higher-order hydrodynamic modulation instability
The modulation instability (MI) is a universal mechanism that is responsible
for the disintegration of weakly nonlinear narrow-banded wave fields and the
emergence of localized extreme events in dispersive media. The instability
dynamics is naturally triggered, when unstable energy side-bands located around
the main energy peak are excited and then follow an exponential growth law. As
a consequence of four wave mixing effect, these primary side-bands generate an
infinite number of additional side-bands, forming a triangular side-band
cascade. After saturation, it is expected that the system experiences a return
to initial conditions followed by a spectral recurrence dynamics. Much complex
nonlinear wave field motion is expected, when the secondary or successive
side-band pair that are created are also located in the finite instability gain
range around the main carrier frequency peak. This latter process is referred
to as higher-order MI. We report a numerical and experimental study that
confirm observation of higher-order MI dynamics in water waves. Furthermore, we
show that the presence of weak dissipation may counter-intuitively enhance wave
focusing in the second recurrent cycle of wave amplification. The
interdisciplinary weakly nonlinear approach in addressing the evolution of
unstable nonlinear waves dynamics may find significant resonance in other
nonlinear dispersive media in physics, such as optics, solids, superfluids and
plasma
Spectral up- and downshifting of Akhmediev breathers under wind forcing
We experimentally and numerically investigate the effect of wind forcing on
the spectral dynamics of Akhmediev breathers, a wave-type known to model the
modulation instability. We develop the wind model to the same order in
steepness as the higher order modifcation of the nonlinear Schroedinger
equation, also referred to as the Dysthe equation. This results in an
asymmetric wind term in the higher order, in addition to the leading order wind
forcing term. The derived model is in good agreement with laboratory
experiments within the range of the facility's length. We show that the leading
order forcing term amplifies all frequencies equally and therefore induces only
a broadening of the spectrum while the asymmetric higher order term in the
model enhances higher frequencies more than lower ones. Thus, the latter term
induces a permanent upshift of the spectral mean. On the other hand, in
contrast to the direct effect of wind forcing, wind can indirectly lead to
frequency downshifts, due to dissipative effects such as wave breaking, or
through amplification of the intrinsic spectral asymmetry of the Dysthe
equation. Furthermore, the definitions of the up- and downshift in terms of
peak- and mean frequencies, that are critical to relate our work to previous
results, are highlighted and discussed.Comment: 30 pages, 11 figure
Hemodynamic and anti-inflammatory effects of early esmolol use in hyperkinetic septic shock. a pilot study
Background: Several studies have shown that heart rate control with selective beta-1 blockers in septic shock is safe. In these trials, esmolol was administered 24 h after onset of septic shock in patients who remained tachycardic. While an earlier use of beta-blockers might be beneficial, such use remains challenging due to the difficulty in distinguishing between compensatory and non-compensatory tachycardia. Therefore, the Esmosepsis study was designed to study the effects of esmolol aimed at reducing the heart rate by 20% after the initial resuscitation process in hyperkinetic septic shock patients on (1) cardiac index and (2) systemic and regional hemodynamics as well as inflammatory patterns. Methods: Nine consecutive stabilized tachycardic hyperkinetic septic shock patients treated with norepinephrine for a minimum of 6 h were included. Esmolol was infused during 6 h in order to decrease the heart rate by 20%. The following data were recorded at hours H0 (before esmolol administration), H1–H6 (esmolol administration) and 1 h after esmolol cessation (H7): systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, central venous pressure, heart rate, PICCO transpulmonary thermodilution, sublingual and musculo-cutaneous microcirculation, indocyanine green clearance and echocardiographic parameters, diuresis, lactate, and arterial and venous blood gases. Results: Esmolol was infused 9 (6.4–11.6) hours after norepinephrine introduction. Esmolol was ceased early in 3 out of 9 patients due to a marked increase in norepinephrine requirement associated with a picture of persistent cardiac failure at the lowest esmolol dose. For the global group, during esmolol infusion, norepinephrine infusion increased from 0.49 (0.34–0.83) to 0.78 (0.3–1.11) µg/min/kg. The use of esmolol was associated with a significant decrease in heart rate from 115 (110–125) to 100 (92–103) beats/min and a decrease in cardiac index from 4.2 (3.1–4.4) to 2.9 (2.5–3.7) l/min/m−2. Indexed stroke volume remained unchanged. Cardiac function index and global ejection fraction also markedly decreased. Using echocardiography, systolic, diastolic as well as left and right ventricular function parameters worsened. After esmolol cessation, all parameters returned to baseline values. Lactate and microcirculatory parameters did not change while the majority of pro-inflammatory proteins decreased in all patients. Conclusion: In the very early phase of septic shock, heart rate reduction using fast esmolol titration is associated with an increased risk of hypotension and decreased cardiac index despite maintained adequate tissue perfusion (NCT02068287)
Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside
PurposeTo delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Methods Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. Results Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2–ERK1/2 pathway, H2S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression. Conclusions Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension
Compared effects of inhibition and exogenous administration of hydrogen sulphide in ischaemia-reperfusion injury
INTRODUCTION: Haemorrhagic shock is associated with an inflammatory response consecutive to ischaemia-reperfusion (I/R) that leads to cardiovascular failure and organ injury. The role of and the timing of administration of hydrogen sulphide (H2S) remain uncertain. Vascular effects of H2S are mainly mediated through K+ATP-channel activation. Herein, we compared the effects of D,L-propargylglycine (PAG), an inhibitor of H2S production, as well as sodium hydrosulphide (NaHS), an H2S donor, on haemodynamics, vascular reactivity and cellular pathways in a rat model of I/R. We also compared the haemodynamic effects of NaHS administered before and 10 minutes after reperfusion. METHODS: Mechanically ventilated and instrumented rats were bled during 60 minutes in order to maintain mean arterial pressure at 40 +/- 2 mmHg. Ten minutes prior to retransfusion, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl) or PAG (50 mg/kg). PNU, a pore-forming receptor inhibitor of K+ATP channels, was used to assess the role of K+ATP channels. RESULTS: Shock and I/R induced a decrease in mean arterial pressure, lactic acidosis and ex vivo vascular hyporeactivity, which were attenuated by NaHS administered before reperfusion and PNU but not by PAG and NaHS administered 10 minutes after reperfusion. NaHS also prevented aortic inducible nitric oxide synthase expression and nitric oxide production while increasing Akt and endothelial nitric oxide synthase phosphorylation. NaHS reduced JNK activity and p-P38/P38 activation, suggesting a decrease in endothelial cell activation without variation in ERK phosphorylation. PNU + NaHS increased mean arterial pressure when compared with NaHS or PNU alone, suggesting a dual effect of NaHS on vascular reactivity. CONCLUSION: NaHS when given before reperfusion protects against the effects of haemorrhage-induced I/R by acting primarily through a decrease in both proinflammatory cytokines and inducible nitric oxide synthase expression and an upregulation of the Akt/endothelial nitric oxide synthase pathway
Numerical instability of the Akhmediev breather and a finite-gap model of it
In this paper we study the numerical instabilities of the NLS Akhmediev
breather, the simplest space periodic, one-mode perturbation of the unstable
background, limiting our considerations to the simplest case of one unstable
mode. In agreement with recent theoretical findings of the authors, in the
situation in which the round-off errors are negligible with respect to the
perturbations due to the discrete scheme used in the numerical experiments, the
split-step Fourier method (SSFM), the numerical output is well-described by a
suitable genus 2 finite-gap solution of NLS. This solution can be written in
terms of different elementary functions in different time regions and,
ultimately, it shows an exact recurrence of rogue waves described, at each
appearance, by the Akhmediev breather. We discover a remarkable empirical
formula connecting the recurrence time with the number of time steps used in
the SSFM and, via our recent theoretical findings, we establish that the SSFM
opens up a vertical unstable gap whose length can be computed with high
accuracy, and is proportional to the inverse of the square of the number of
time steps used in the SSFM. This neat picture essentially changes when the
round-off error is sufficiently large. Indeed experiments in standard double
precision show serious instabilities in both the periods and phases of the
recurrence. In contrast with it, as predicted by the theory, replacing the
exact Akhmediev Cauchy datum by its first harmonic approximation, we only
slightly modify the numerical output. Let us also remark, that the first rogue
wave appearance is completely stable in all experiments and is in perfect
agreement with the Akhmediev formula and with the theoretical prediction in
terms of the Cauchy data.Comment: 27 pages, 8 figures, Formula (30) at page 11 was corrected, arXiv
admin note: text overlap with arXiv:1707.0565
Mega-trials in heart failure:effects of dilution in examination of new therapies
International audienceAims: Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power.Methods and results: Using simulations, we examined the probability that a positive finding in a Phase 2 trial would result in the study of a truly effective medicine in a Phase 3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta-analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase 3 trials should have yielded ∼35% positive results. Patient populations in Phase 3 trials are similar to those in Phase 2 trials but both differ substantially from the populations of 'real-life' registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients.Conclusions: The selection of more positive Phase 2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase 3 trials
Anti-Tuberculosis Therapy-Induced Hepatotoxicity among Ethiopian HIV-Positive and Negative Patients
Background: To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH) in HIV positive and HIV negative tuberculosis (TB) patients in Ethiopia. Methodology/Principal Findings: In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3 % of the patients and 8 out of the 197 (4.1%) developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg. Conclusions/Significance: Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002), concomitant drug intake (p = 0.008), and decrease in CD4 count (p = 0.001). Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk
Definitions and pathophysiology of vasoplegic shock.
Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition
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