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Chemical weapons have given the human experience of warfare a uniquely terrifying quality that has inspired a general repugnance and led to periodic attempts to ban their use. Nevertheless, since ancient times, toxic agents have been consistently employed to kill and terrorize target populations. The evolution of these weapons is examined here in ways that may allow military, law enforcement, and scientific professionals to gain a perspective on conditions that, in the past, have motivated their use - both criminally and as a matter of national policy during military campaigns. Special emphasis is placed on the genocidal use of chemical weapons by the regime of Saddam Hussein, both against Iranians and on Kurdish citizens of his own country, during the Iran-Iraq War of 1980-88. The historical development of chemical weapons use is summarized to show how progressively better insight into biochemistry and physiology was adapted to this form of warfare. Major attributes of the most frequently used chemical agents and a description of how they affected military campaigns are explained. Portions of this review describing chemical-casualty care devote particular focus to Iranian management of neurotoxic (nerve) agent casualties due to the unique nature of this experience. Both nerve and blistering "mustard" agents were used extensively against Iranian forces. However, Iran is the only nation in history to have sustained large-scale attacks with neurotoxic weapons. For this reason, an understanding of the successes and failures of countermeasures to nerve-agent use developed by the Iranian military are particularly valuable for future civil defense and military planning. A detailed consideration of these strategies is therefore considered. Finally, the outcomes of clinical research into severe chronic disease triggered by mustard-agent exposure are examined in the context of the potential of these outcomes to determine the etiology of illness among US and Allied veterans of the 1991 Persian Gulf War.

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The present review examines the role of the cytoprotective enzyme haeme oxygenase-1 (HO-1) in adaptive responses to inflammatory disease and explores strategies for its clinical use, with particular emphasis on use of therapeutic use of the enzyme using phytochemical inducers of HO-1 such as extracts of Ginkgo biloba, curcumin, and flavonoids extracted from seeds of the sour cherry (Prunus cerasus). This laboratory has identified strategies by which combinations of dietary phytochemicals may be configured to synergistically strengthen immunoregulatory mechanisms that normally prevent inflammation from leading to disease. A major focus of this research initiative has been HO-1, which is capable of substantially reducing oxidative stress by several mechanisms. HO-1 metabolizes haeme that accumulates in tissues because of red blood cell turnover. Two products of this degradation - carbon monoxide (CO) and bilirubin - have potent capacity for reducing oxidative stress and for counteracting its effects. A description will be provided of how HO-1 products maintain healthy tissue function and remediate oxidative tissue damage. This will be explored in four major organ systems, including the cardiovascular system, the lungs, the central nervous system and the kidneys. Particular focus will be given to the physiological coordination of cardiovascular functions mediated by CO produced by HO-1 and to nitric oxide (NO), a gaseous second messenger expressed by nitric oxide synthetase. A major unifying theme of the present review is an exploration of the potential use of dietary phytochemical formulations as tools for the clinical application of HO-1 in therapeutic reduction of oxidative stressors, with resultant improved treatment of inflammatory pathologies.

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This study has evaluated the hypothesis that activity of the detoxifying enzyme butyrylcholinesterase (BuChE) correlates with levels of serum anti-cardiolipin antibodies (ACA) and T lymphocytes in peripheral blood of women experiencing recurrent spontaneous abortion (RSA). Peripheral venous blood from 16 non-pregnant, RSA-afflicted women and 8 healthy non-pregnant women was analyzed for frequency of T lymphocyte subpopulations by two-color flow cytometry and for serum BuChE using butyrylthiocholine iodide/spectrophotometry. RSA-afflicted women with high serum ACA, but not those with normal ACA levels, exhibited significantly increased percentages of CD4+CD25+ cells (p<0.01) and CD4+HLA-DR+ cells (p<0.05) relative to healthy women. CD4+CD25+(high) cells were significantly lower (p<0.05), while CD4+CD25+(low) cells were significantly higher (p<0.01), in women with elevated ACA compared to healthy women and to RSA women with normal ACA. Relative to healthy, non-pregnant subjects, serum BuChE activity in RSA patients was elevated, both for those with normal ACA (p<0.001) and elevated ACA levels (p<0.01). Among healthy controls, a significant positive correlation was observed between frequency of CD3+NK cells and BuChE activity (p<0.01), but not for RSA-afflicted subjects. A positive correlation between BuChE activity and frequency of CD4+CD25+ cells, as well as CD4+CD25+(high) cells, was observed in the RSA-afflicted subject group with elevated ACA (p<0.05), which may be related to induction of BuChE by toxic metabolites resulting from pathogenic T cell activity. It is concluded that, among RSA patients, high serum ACA correlates with elevated levels of activated T cells and reduced CD4+CD25+(high)/CD4+CD25+(low) cells in comparison to healthy women or those afflicted with RSA but with normal ACA. BuChE activity is observed to be elevated in RSA patients irrespective of serum ACA status.

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Recent studies in our laboratory have demonstrated that Actinobacillus actinomycetemcomitans has a potent T cell stimulatory effect, activating more than half of all T cells. However, since the fate of these activated T cells was not known, the present study sought to determine whether all of these T cells differentiate into effector cells. To that end, the intracellular expression of T cell cytokines (IL-2, IFN-gamma, IL-4 and IL-10) in response to A. actinomycetemcomitans was determined by flow cytometry. Results demonstrated a time-dependent increase in the expression of the cytokines, most reaching peak levels at 24-48 h. At 48 h, the proportion of T cells expressing each of the cytokines were as follows: IL-2 (1.7%+/-0.3), IFN-gamma (1.8%+/-0.5), IL-4 (1.0%+/-0.2) and IL-10 (1.5%+/-0.5). These data indicated that only 2-5% of all T cells stimulated with A. actinomycetemcomitans expressed any T cell cytokines. The finding of large-scale T cell activation in the absence of cytokine expression suggests that the activation of T cells in response to A. actinomycetemcomitans is incomplete. To investigate this phenomenon, peripheral blood mononuclear cells (PBMC) were cultured with A. actinomycetemcomitans for 24 h followed by sorting of the activated (CD69+) cells by immunomagnetic separation and restimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. Results demonstrated that nearly 90% of the T cells were unresponsive to further restimulation. A possible explanation for this unresponsiveness is the induction of clonal anergy among the responding T cells. To determine possible preferential effects of the stimulation on specific cytokines, the expression of each cytokine among T cells responding to A. actinomycetemcomitans was compared to the maximum levels achieved by PMA + ionomycin stimulation. Results showed that number of IL-2+ and IFN-gamma+ T cells observed in response to A. actinomycetemcomitans were between 2% and 7% of those seen in response to PMA + ionomycin. Conversely, the proportions of T cells expressing IL-4 or IL-10 were between 35% and 90% of those following stimulation with PMA + ionomycin. Hence, A. actinomycetemcomitans appears to more preferentially induce T cells expressing IL-4 and IL-10. Collectively, these data suggest that the in vitro stimulation of T cells with A. actinomycetemcomitans leads to partial activation, i.e. only a minor subset of T cells responding to A. actinomycetemcomitans differentiate into effector cells, while a significant proportion become unresponsive to restimulation, suggesting clonal anergy.

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Effects of the calcineurin inhibitor FK506, the platelet-activating factor (PAF) antagonist, and free radical scavenger Ginkgo biloba extract, EGb 761, and their combination on reperfusion-induced ventricular fibrillation (VF), ventricular tachycardia (VT), and recovery of cardiac function were studied after 30 min of global ischemia followed by 2 h of reperfusion in isolated rat hearts. In the first series of studies, rats received a daily (oral) dose of 0, 1, 5, 10, 20, or 40 mg/kg/day FK506 for 10 days. FK506 dose-dependently reduced the incidence of reperfusion-induced total (irreversible plus reversible) VF from a value of 92% for untreated animals to 92% (NS), 83% (NS), 67% (NS), 33% (p<0.05), and 25% (p<0.05), for doses of 1-40 mg/kg/day, respectively, with effects on incidence of VT showing the same pattern. FK506, between 20 and 40 mg/kg/day, also resulted in significant recovery of postischemic cardiac function. In the second series of studies, rats were treated with EGb 761 alone or in combination with FK506. Whereas no significant reduction in arrhythmias or improvement in cardiac function resulted from a single intervention of EGb 761 at 25 mg/kg/day, combined treatment of rats with 25 mg/kg/day of EGb 761 and 1 or 5 mg/kg/day of FK506 resulted in a reduction in total and irreversible VF of 92% and 92% to 42% (p<0.05) and 33% (p<0.05), 25% (p<0.05) and 8% (p<0.05), respectively, versus untreated control animals, paralleled by similar effects on the incidence of VT and accompanied by significant improvements in postischemic cardiac function. Our results demonstrate a novel cardioprotective characteristic of FK506 and suggest that combination therapy by using FK506 plus EGb 761 synergistically improves postischemic cardiac function, while reducing the incidence of reperfusion-induced VF and VT, which may expand the clinical utility of FK506 and allow therapy with FK506 at lower doses than are currently useful.

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