A mixed anti-inflammatory and pro-inflammatory response associated with a high dose of corticosteroids.

OBJECTIVE: Hydrocortisone, at a low dose (100 mg), induces an anti-inflammatory response including inducing IkBα and suppressing intranuclear NFκB and AP-1 binding and the expression of pro-inflammatory mediators like MMPs. We have now investigated the effect of a high dose of hydrocortisone (300mg=60 mg prednisolone) on NFκB binding and the expression of TLRs, the mediators of TLR signal transduction, MyD88 and TRIF and HMG-B1. DESIGN AND SUBJECTS: A 300mg of hydrocortisone or saline was injected intravenously in ten normal subjects during 2 separate visits, in a randomized crossover study. Blood samples were obtained at 0, 1, 4, 6 and 24h after the injection and mononuclear cells (MNC) were prepared. RESULTS: There was a significant increase in glucose (from 92±4 to 116±6 mg/dl), insulin (from 4.5±0.7 to 5.3±0.8 mU/ml) and FFA concentrations (from 0.38±0.1 to 0.80±0.15mM) following the administration of hydrocortisone compared to placebo treatment. While NFκB binding and the mRNA expression of MyD88, TRIF, chemokines and chemokine receptors were suppressed significantly in MNC, there was a paradoxical increase in the mRNA expression of TLR 2, 5 and 9 and HMG-B1 was increased by 103±24%, 107±19%, 56±13% and 58±12% above the baseline, respectively in the MNC. Plasma concentrations of HMG-B1 and MMP-9 increased by 37±12% and 125±22%, respectively, while TNF-α concentrations fell by 27±9%. CONCLUSION: While this high dose of hydrocortisone exerts a powerful anti-inflammatory effect, it also exerts certain proinflammatory effects mainly on TLRs expression. The known pro-inflammatory effects of glucose and FFAs may have contributed to these effects. These paradoxical pro-inflammatory effects may account for the inability of these drugs to show benefit in clinical trials of septicemia and other severe pro-inflammatory states and might contribute to some of the side effects of corticosteroids use.

Phase and light shift determination in an optically pumped cesium beam frequency standard.

The determination of the phase shift and the light shift in our optically pumped Cs beam is reported here. We show that an error on the phase difference value determined by our fit method, without beam reversal, can be induced if the light shift is not taken into account. If the experimental data are corrected for the light shift, the results of the fit method are in very good agreement with the beam reversal results. This allows us to reduce the related uncertainty in the accuracy budget of our standard. The resulting overall accuracy of the standard is now estimated to be 6.3x10(-15).

Frequency stability degradation of an oscillator slaved to a periodically interrogated atomic resonator.

Atomic frequency standards using trapped ions or cold atoms work intrinsically in a pulsed mode. Theoretically and experimentally, this mode of operation has been shown to lead to a degradation of the frequency stability due to the frequency noise of the interrogation oscillator. In this paper a physical analysis of this effect has been made by evaluating the response of a two-level atom to the interrogation oscillator phase noise in Ramsey and multi-Rabi interrogation schemes using a standard quantum mechanical approach. This response is then used to calculate the degradation of the frequency stability of a pulsed atomic frequency standard such as an atomic fountain or an ion trap standard. Comparison is made to an experimental evaluation of this effect in the LPTF Cs fountain frequency standard, showing excellent agreement.

Properties of an oscillator slaved to a periodically interrogated atomic resonator.

In advanced atomic resonators, such as those using a fountain of cold cesium atoms or an ensemble of stored ions, the atomic medium is interrogated periodically, and the control signal of the slaved oscillator is updated at equally spaced time intervals. We analyze the properties of the output frequency of these frequency standards. We establish the equations that describe the time behavior of this frequency. We give the stability condition and the transient response of the frequency feedback loop, the response to systematic frequency changes of the free running oscillator, the frequency stability for given free-running oscillator noise and given optical detection noise, and the limitation of the frequency stability by down-conversion of the intrinsic oscillator frequency noise (Dick effect). We point out that a second integration in the feedback loop may not improve significantly the rejection of slow perturbations, unless a condition relative to the timing of the atom-field interaction is verified.