**8. Limitations and outlook**

266 Apoptosis and Medicine

available.

predominates (Bouchama & Knochel, 2002).

loses the capacity for a compensatory response.

the underlying mechanisms.

systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulation (DIC), and ultimately MODS. Clinical diagnosis of heatstroke and related syndromes is usually not difficult, considering hyperpyrexia and laboratory findings, and excluding other causes of hyperpyrexia; however, postmortem diagnosis is obstructed by a lack of specific findings. The diagnosis should be established by collecting pathological findings compatible with heatstroke, related to the predisposition, drug abuse, and physical abuse or neglect, and to differentiate other insults, in combination with toxicology and biochemistry (Maeda et al., 2011). Circumstantial evidence may also be considered when

In immunohistochemcal investigation of the brain, characteristic findings in hyperthermia cases were lower glial GFAP and S100β immunopositivity in the white matter, and higher neuronal ssDNA immunopositivity in the cerebral cortex and hippocampus, accompanied by high glial bFGF and S100β immunopositivity in the cerebral cortex, without glial or neuronal loss (Fig. 3 and Table 3) (Wang et al., 2012a). Survival in hospital for days under a clinical diagnosis of heatstroke showed similar findings. Increased cortical glial bFGF and S100β may indicate self-protective responses of the brain, as described above for hypothermia; however, these findings were milder in hyperthermia than in hypothermia, involving neuronal and glial damage described below, and may also be related to the initiation of inflammatory processes involved in the systemic inflammatory response leading to MODS, in which encephalopathy

Hyperthermia can exert direct damage on tissue cells by inducing apoptosis (Basile et al., 2008; Vogel et al., 1997); increased neuronal ssDNA expression can be used as evidence of brain dysfunction involving apoptosis as part of MODS from hyperthermia. These observations suggest diffuse neuronal apoptosis despite initiation of neuroprotective cortical astrocyte reactions in hyperthermia. Furthermore, the BBB, composed of endothelial tight junctions, basal lamina and perivascular astrocytes, may be damaged by hyperthermia, characterized by vasogenic brain edema (Sharma, 2006; Sharma & Hoopes, 2003). Low glial GFAP and S100β immunopositivity in the white matter in hyperthermia cases suggests that astrocyte damage may be involved in BBB dysfunction. In addition, low bFGF immunopositivity in the white matter in hyperthermia cases indicates that white matter

These observations suggest characteristic brain responses in the death process due to an extreme environmental temperature; hyperthermia as well as hypothermia involved higher glial bFGF positivity in the cerebral cortex, indicating activation of neuroprotective processes. To summarize, fatal hyperthermia cases showed diffuse neuronal apoptosis despite the initiation of neuroprotective cortical astrocyte responses, accompanied by glial damage in the white matter; diffuse neuronal and glial deterioration in the brain may lead to a fatal outcome even under critical medical care. Further investigation is needed to clarify Different from animal experimentation, forensic and clinical materials are not homogenous owing to the complexity of insults and the consequent brain damage, varied susceptibility of subjects, and intensive clinical intervention. In addition, forensic autopsy materials partly include cases where the estimated survival time and/or postmortem interval depend on obscure circumstantial evidence. Therefore, it is difficult to elucidate the time course of cellular responses after individual specified insults in detail. It is important, however, to collect postmortem human data involving the whole brain pathology, which are not clinically or experimentally available. Further investigation is needed, including other markers involved in apoptotic pathways as well as in water homeostasis, BBB integrity and inflammatory responses, combined with the systematic analysis of related gene expressions.
