**5.4. Others**

Very little knowledge is available with regard to the contribution of apoptosis to the neurotoxicity of other drugs and poisons at present; however, drug-related hyperthermia may induce neuronal apoptosis in a similar manner to that in heatstroke, described below. Various chemicals that trigger oxidative stress can induce neuronal apoptosis. Animal experiments showed that organophosphorus compounds caused acute necrosis of neurons in the brain at toxic doses, but induced apoptotic neuronal death at sublethal doses (Abou-Donia, 2003).

Immunohistochemistry of Neuronal Apoptosis in Fatal Traumas: The Contribution of Forensic Molecular Pathology in Medical Science 261

however, the pathophysiological process leading to death is still unclear. In particular, the influences of toxic gases usually do not leave significant pathology that is detectable after death, except that bilateral pallidum necrosis is occasionally seen in CO intoxication. With respect to this, previous studies detected specific neuronal damage in the pallidum due to CO intoxication by immunohistochemistry (Michiue et al., 2008; Piantadosi et al., 1997); immunohistochemical markers in the brain may be used to differentiate pathological conditions of the neurons and glial cells due to ischemic, metabolic, toxic and traumatic

In acute fire fatality, immunohistochemistry demonstrated higher neuronal ssDNA immunopositivity in the parietal cortex than in acute cardiac and asphyxial deaths, suggesting the induction of neuronal apoptosis, irrespective of the blood COHb level; however, such findings were not seen in cases of postmortem burns (Wang et al., 2011a). These suggest that brain damage due to a fire is not simply caused by ischemia or hypoxia, but also involves cytotoxic factors, including massive thermal tissue injury and hemolysis, which can induce systemic oxidative stress involving the brain (Gatson et al., 2009). However, neuronal ssDNA immunopositivity in the pallidum was lower in cases of a low level of blood COHb saturation than in those with a fatal level of blood COHb saturation (>60%). Therefore, increased neuronal ssDNA immunopositivity in the parietal cortex and pallidum can be used as a vitality finding in acute fire deaths, with consideration of other pathological findings; these findings can be used to interpret death due to burns or CO intoxication in a fire. Furthermore, the topographical distribution of neuronal ssDNA immunopositivity in the brain may be helpful for determining the immediate cause of death in cases of other potentially fatal traumas or diseases, e.g. strangulation, drug abuse and acute cardiac attack. However, higher neuronal ssDNA immunopositivity was sporadically detected in other cases, suggesting the partial contribution of unspecific neuronal damage due to reperfusion, possibly involved with cardiopulmonary resuscitation measures (Li et al., 2010); this should be carefully considered when determining the cause of death,

In prolonged deaths, the macro- and microscopic signs of vitality in fire death, described above, may become obscure, making the pathological diagnosis quite difficult. In immunohistochemical study of the brain, however, there were significant differences between fatal burns and CO intoxication in prolonged fire deaths under critical clinical care (Fig. 2). Neuronal loss was seen in those with burns and CO intoxication as well as in patients with a fatal ischemic heart attack and prolonged asphyxial deaths, while glial cells were increased in burns and heart attack; the glial cell number was larger in fatality due to burns than in CO intoxication and asphyxiation, regardless of temporary cardiopulmonary arrest (CPA) after insult, suggesting glial activation. The increase in glial cells in cases of fatal burns was accompanied by higher glial bFGF immunopositivity in the parietal cortex and white matter, and higher and lower glial GFAP immunopositivity in the cortex and white matter, respectively, showing low neuronal ssDNA immunopositivity. The abovementioned findings differed from those in prolonged death due to heart attack or mechanical asphyxiation involving simple cerebral ischemia or hypoxia, regardless of

brain injury (Chen et al., 1997; Piantadosi et al., 1997; Zhang et al., 2010).

especially in cases where the vitality findings are sparse.
