Neutrophil Heterogeneity as Therapeutic Opportunity in Immune-Mediated Disease

Neutrophils are versatile innate effector cells essential for immune defense but also responsible for pathologic inflammation. This dual role complicates therapeutic targeting. However, neither neutrophils themselves nor the mechanisms they employ in different forms of immune responses are homogeneous, offering possibilities for selective intervention. Here we review heterogeneity within the neutrophil population as well as in the pathways mediating neutrophil recruitment to inflamed tissues with a view to outlining opportunities for therapeutic manipulation in inflammatory disease

The relationship between twitch depression and twitch fade during neuromuscular block produced by vecuronium: correlation with the release of acetylcholine

<p>Abstract</p> <p>Background</p> <p>Train-of-four stimulation pattern following the administration of non-depolarizing neuromuscular blocking drugs reveals fade on successive contractions. Fade is caused by the release of fewer acetylcholine molecules by the fourth (A₄) than by the first stimulus (A₁). The current study was conducted to define the relationship between the clinically observed fade and the simulated decline in acetylcholine release (A₄/A₁) that would be necessary to produce it.</p> <p>Methods</p> <p>The T₄/T₁ratios produced by different doses of vecuronium (15–80 μg·kg^-1) were plotted as a function of the concomitant T₁. Separately in a model of neuromuscular transmission, T₁, T₄, and T₄/T₁were estimated using simulations in the presence and in the absence of a neuromuscular blocking drug and a stepwise decrease in A₄, but constant A₁.</p> <p>Results</p> <p>Vecuronium induced neuromuscular block was associated with larger T₄/T₁ratios (less fade) during the onset than during the offset of the block. All doses caused similar fade during offset. Simulations revealed that the smallest T₄/T₁was associated with the nadir of A₄/A₁and occurred at the beginning of T₁recovery. The nadir of A₄/A₁was only marginally affected by the dose of vecuronium: 15 μg·kg^-1producing the minimum A₄/A₁of 0.8 and 80 μg·kg^-1the minimum A₄/A₁of 0.7.</p> <p>Conclusion</p> <p>The hysteresis in the fade between onset and offset appears to be caused by a delayed decrease of A₄/A₁as compared with the decrease in T₁. Tentative estimates of the decrease in A₄/A₁during fade produced by vecuronium are offered. However, the validity of these estimates is dependent on the validity of the assumptions made in simulations.</p

Volume of the effect compartment in simulations of neuromuscular block

BACKGROUND: The study examines the role of the volume of the effect compartment in simulations of neuromuscular block (NMB) produced by nondepolarizing muscle relaxants. METHODS: The molar amount of the postsynaptic receptors at the motor end plates in muscle was assumed constant; the apparent receptor concentration in the effect compartment is the ratio of this amount and the volume arbitrarily assigned to the effect compartment. The muscle relaxants were postulated to diffuse between the central and the effect compartment and to bind to the postsynaptic receptors. NMB was calculated from the free concentration of the muscle relaxant in the effect compartment. RESULTS: The simulations suggest that the time profiles of NMB and the derived pharmacokinetic and pharmacodynamic variables are dependent on the apparent receptor concentration in the effect compartment. For small, but not for large, volumes, times to peak submaximal NMB are projected to depend on the magnitude of NMB and on the binding affinities. CONCLUSION: An experimental design to estimate the volume of the effect compartment is suggested