Uric acid, the naturally occurring product of purine metabolism, is a strong peroxynitrite scavenger, as demonstrated by the capacity to bind peroxynitrite but not nitric oxide (NO) produced by lipopolysaccharide-stimulated cells of a mouse monocyte line. In this study, we used uric acid to treat experimental allergic encephalomyelitis (EAE) in the PLSJL strain of mice, which develop a chronic form of the disease with remissions and exacerbations. Uric acid administration was found to have strong therapeutic effects in a dose-dependent fashion. A regimen of four daily doses of 500 mg͞kg uric acid was required to promote long-term survival regardless of whether treatment was initiated before or after the clinical symptoms of EAE had appeared. The requirement for multiple doses is likely to be caused by the rapid clearance of uric acid in mice which, unlike humans, metabolize uric acid a step further to allantoin. Uric acid treatment also was found to diminish clinical signs of a disease resembling EAE in interferon-␥ receptor knockout mice. A possible association between multiple sclerosis (MS), the disease on which EAE is modeled, and uric acid is supported by the finding that patients with MS have significantly lower levels of serum uric acid than controls. In addition, statistical evaluation of more than 20 million patient records for the incidence of MS and gout (hyperuricemic) revealed that the two diseases are almost mutually exclusive, raising the possibility that hyperuricemia may protect against MS.The induction of the nitric oxide synthase isoform (NOS-2) in the central nervous system (CNS) commonly associated with cells of the macrophage͞monocyte lineage is a characteristic feature of experimental allergic encephalomyelitis (EAE) (see refs. 1-7 for examples). Moreover, production of the free radical nitric oxide (NO) in CNS tissue of mice has been correlated with the development of clinical signs of the disease (2, 7). The contribution of NO in the etiology of EAE has been confirmed in mice that were immunized with proteolipid protein peptide but failed to develop EAE when treated with a compound that inactivates NO (8).It remains unproven whether NO, which has a short half-life in vivo, exerts a toxic effect on CNS cells directly or through the formation of a more toxic compound, the production of which is directly related to the induction of elevated NO levels in brain tissue. Peroxynitrite (ONOO Ϫ ), a potent oxidant that is formed by the rapid combination of NO with superoxide (O2 Ϫ ), can be formed in an inflammatory response (9) and can cause a variety of toxic effects, including lipid peroxidation (10) and tyrosine nitration (11,12). It therefore has been suggested that peroxynitrite is responsible for a significant proportion of the inflammatory damage attributed to NO (12).We have shown that treatment with uric acid, a naturally occurring compound that selectively binds and inactivates peroxynitrite (13), inhibits the onset of clinical disease in an acute, aggressive form of mouse EAE,...

We compared the contributions of impaired neuromuscular transmission (transmission fatigue) and impaired muscle contractility (contractile fatigue) to fatigue of the isolated rat diaphragm. To make this comparison, we measured the differences in active tension elicited by direct muscle stimulation and by indirect (phrenic nerve) stimulation before and after fatigue induced by indirect supramaximal stimulation at varying frequencies and durations. Transmission fatigue was observed after all experimental protocols. Although significant contractile fatigue was not demonstrated after brief periods of low-frequency stimulation (6 min, 15 Hz, 25% duty cycle), it was present after longer or higher frequency stimulation. We repeated the direct stimulation in the presence of neuromuscular blockade with 6 microM d-tubocurarine to demonstrate that a reduced response to stimulation of intramuscular branches of the phrenic nerve during direct stimulation was not responsible for the apparent contractile fatigue. Since we found significant decreases in the response to direct stimulation even after neuromuscular blockade, we could verify the presence of contractile fatigue. We conclude that both contractile and transmission fatigue can occur in the isolated rat diaphragm and that transmission fatigue is a much more important factor after brief periods of fatiguing contractions.

The diaphragm is a skeletal muscle of mixed fiber type that is unique in its requirement to maintain contractile function and fatigue resistance across a wide range of temperatures to sustain alveolar ventilation under conditions of hypo- or hyperthermia. The direct effect of temperature (15-41 degrees C) on rat diaphragm isometric contractility and fatigue was determined in vitro. As temperature decreased from 37 to 15 degrees C, contraction and relaxation times increased, and there was a left shift of the diaphragm's force-frequency curve, with decreased contractility at 41 and 15 degrees C. Fatigue was induced by 10 min of stimulation with 30 trains/min of 5 Hz at a train duration of 900 ms. Compared with 37 degrees C, fatigue resistance was enhanced at 25 degrees C, but no difference in fatigue indexes was evident at extreme hypothermia (15 degrees C) or hyperthermia (41 degrees C). Only when the fatigue program was adjusted to account for hypothermia-induced increases in tension-time indexes was fatigue resistance evident at 15 degrees C. These findings indicate that despite the diaphragm's unique location as a core structure, necessitating exposure to in vivo temperatures higher than found in limb muscle, the temperature dependence of rat diaphragm muscle contractility and fatigue is similar to that reported for limb muscle of mixed fiber type.

The emissions from coal power plants have serious implication on the environment protection, and there is an increasing effort around the globe to control these emissions by the flue gas cleaning technologies. This research was carried out on the limestone forced oxidation (LSFO) flue gas desulfurization (FGD) system installed at the 2*660 MW supercritical coal-fired power plant. Nine input variables of the FGD system: pH, inlet sulfur dioxide (SO2), inlet temperature, inlet nitrogen oxide (NOx), inlet O2, oxidation air, absorber slurry density, inlet humidity, and inlet dust were used for the development of effective neural network process models for a comprehensive emission analysis constituting outlet SO2, outlet Hg, outlet NOx, and outlet dust emissions from the LSFO FGD system. Monte Carlo experiments were conducted on the artificial neural network process models to investigate the relationships between the input control variables and output variables. Accordingly, optimum operating ranges of all input control variables were recommended. Operating the LSFO FGD system under optimum conditions, nearly 35% and 24% reduction in SO2 emissions are possible at inlet SO2 values of 1500 mg/m3 and 1800 mg/m3, respectively, as compared to general operating conditions. Similarly, nearly 42% and 28% reduction in Hg emissions are possible at inlet SO2 values of 1500 mg/m3 and 1800 mg/m3, respectively, as compared to general operating conditions. The findings are useful for minimizing the emissions from coal power plants and the development of optimum operating strategies for the LSFO FGD system.