National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, and NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula.
Nitric oxide (NO) and ornithine, products of NO synthase or arginase, respectively, have opposing biological activities. The effect of mediators of leukocyte activation and inhibition on arginine metabolism of resident mouse peritoneal exudate cells (MPEC) was determined. Factors that increased basal NO synthase activity, interferon (IFN)-gamma and lipopolysaccharide (LPS), decreased arginase activity in intact cells. Transforming growth factor (TGF)-beta1 decreased IFN-gamma-stimulated NO synthase activity and produced a reciprocal increase in urea and ornithine release. TGF-beta1 had no effect on the activity of these enzymes in LPS-stimulated MPEC. Corticosterone (Cort, 100 ng/ml) decreased the basal activity of both enzymes. However, Cort inhibited NO synthase activity and increased ornithine release in MPEC exposed to IFN-gamma or LPS. The difference between arginase activity in intact cells vs. that of cell lysates suggested intracellular inhibition of arginase activity. Products of NO synthase, NO and citrulline, were shown to inhibit MPEC arginase activity under maximal assay conditions. Intracellular pH was not altered by exposure of MPEC to LPS, IFN-gamma, TGF-beta, and Cort. This reciprocal change in arginine metabolism is proposed to be an important component of wound healing. Expression of NO synthase creates a cytotoxic environment that may be important to the early phase of wound healing. As wound healing progresses, increased arginase activity produces an environment favorable for fibroblast replication and collagen production.
The pulsed-laser polymerization (PLP) technique for determination of free radical propagation rate coefficients (kp) by gel permeation chromatography analysis has been extended to systems with rapid chain growth. A mathematical model is developed to gain a better understanding of the relative importance of propagation, termination, and transfer events on the laser-generated molecular weight distributions. Insights from the model are used to define appropriate PLP experimental conditions for vinyl acetate (VAc), for which measured kp values are an order of magnitude higher than values measured for styrene and methyl methacrylate at the same temperature. The behavior of VAc is contrasted with methyl methacrylate, both by experimental means and through simulation. Results suggest that VAc radicals not only propagate quickly but also have a higher rate of termination than methacrylate or styrene monomer systems, explaining the formation of broad, featureless molecular weight distributions under typical PLP experimental conditions. This work demonstrates the value of mathematical modeling to aid in the design of optimal PLP experiments.
In patients with normal intracranial pressure, PEEP at 5 cm H2O did not significantly alter intracranial pressure. The clinical relevance of the intracranial pressure increase at PEEP levels of 10 and 15 cm H2O is questionable because cerebral perfusion pressure did not change and remained > 60 mm Hg. In patients with increased intracranial pressure, higher levels of PEEP did not significantly change intracranial pressure or cerebral perfusion pressure.
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