Sudden death of a preschool child diagnosed by postmortem examination.

An autopsy case of sudden death due to pulmonary arterial hypertension (PAH) in a 5-year-old boy whose cause of death was not determined during autopsy, but was later determined by postmortem examination, is presented. The boy developed convulsions that subsequently stopped, but remained unconscious. He was transported to hospital by ambulance, but died soon after. The boy had been found to have right ventricular overload on ECG 2 weeks earlier. A plan had been made to consult a doctor for a specialist visit 2 months later. During autopsy, significant abnormalities or injuries were not observed on the body's external surface. Internal examination showed congested organs, and the blood remaining in the body was dark red with fluidity. The heart was significantly enlarged (146 g), with nearly equivalent thickness of the left and right ventricles, showing right ventricular hypertrophy. Obvious macroscopic abnormalities were not observed at the origin and main trunk of the pulmonary artery. The lungs were slightly swollen (right lung 100 g, left lung 95 g), severely congested, and edematous. A postmortem CT scan displayed some patchy shadows in both lungs; however, no significant abnormalities were detected. Histopathological examination suggested a diagnosis of PAH. Three genes (BMPR2, ALK1, and ENG) were tested, revealing a heterozygous insertion of five nucleotides, TTTCC, between nucleotides 2677 and 2678 within exon 12 of the BMPR2 gene. Therefore, the subject was considered to have had heritable PAH due to a BMPR2 gene mutation.

Autopsy findings for a case of acute gastric volvulus in a child.

Acute gastric volvulus resulting in abdominal compartment syndrome was determined to be the cause of death in a 4-year-old girl who presented with abdominal distension. At about 1AM on the day of her death, she was brought to our emergency medical center. Physical examination and plain abdominal X-ray revealed pronounced gastric dilatation. A decompression procedure was performed, followed by observation. She went into cardiopulmonary arrest around 1PM on the same day and died. Postmortem investigation, including an autopsy and computed tomography (CT), was performed to determine the cause of death. The findings included that the stomach was severely distended. Evidence was seen of mucosal hemorrhage in the gastric mucosa on the greater curvature side, which was thinned in places but without perforation. No necrosis of the gastric mucosa was observed; reversible changes were evident on histopathological examination. The postmortem CT images suggested that the pyloric region was positioned cranioventrally to the cardiac region. None of the findings indicated sudden blockage, and the cause of death was determined to be acute gastric volvulus resulting in abdominal compartment syndrome. The abnormal placement of the organs was difficult to determine based on physical examination alone; postmortem CT and careful examination were helpful in conducting the autopsy in this case.

Does methamphetamine affect bone metabolism?

There is a close relationship between the central nervous system activity and bone metabolism. Therefore, methamphetamine (METH), which stimulates the central nervous system, is expected to affect bone turnover. The aim of this study was to investigate the role of METH in bone metabolism. Mice were divided into 3 groups, the control group receiving saline injections, and the 5 and 10mg/kg METH groups (n=6 in each group). All groups received an injection of saline or METH every other day for 8 weeks. Bone mineral density (BMD) was assessed by X-ray computed tomography. We examined biochemical markers and histomorphometric changes in the second cancellous bone of the left femoral distal end. The animals that were administered 5mg/kg METH showed an increased locomotor activity, whereas those receiving 10mg/kg displayed an abnormal and stereotyped behavior. Serum calcium and phosphorus concentrations were normal compared to the controls, whereas the serum protein concentration was lower in the METH groups. BMD was unchanged in all groups. Bone formation markers such as alkaline phosphatase and osteocalcin significantly increased in the 5mg/kg METH group, but not in the 10mg/kg METH group. In contrast, bone resorption markers such as C-terminal telopeptides of type I collagen and tartrate-resistant acid phosphatase 5b did not change in any of the METH groups. Histomorphometric analyses were consistent with the biochemical markers data. A significant increase in osteoblasts, especially in type III osteoblasts, was observed in the 5mg/kg METH group, whereas other parameters of bone resorption and mineralization remained unchanged. These results indicate that bone remodeling in this group was unbalanced. In contrast, in the 10mg/kg METH group, some parameters of bone formation were significantly or slightly decreased, suggesting a low turnover metabolism. Taken together, our results suggest that METH had distinct dose-dependent effects on bone turnover and that METH might induce adverse effects, leading to osteoporosis.

Cardiotoxicity of methamphetamine under stress conditions: comparison of single dose and long-term use.

Methamphetamine (METH) abuse continues to be a worldwide problem, damaging the myocardial tissues, as well as the brains of individual users. In addition, stressors that increase drug cravings also contribute to cardiovascular diseases. The aim of the present study was to examine the myocardial effects of METH, including METH­stress interactions and particularly, the effect of METH RNA expression in the heart. The study also aimed to compare single dose (acute) and long-term (chronic) treatments. Mice were divided into the control (C), METH injection (M), stress exposure (S) and METH plus stress (MS) groups and subjected to an acute water­immersion restraint stress or a mixed chronic stress composed of restraint, electric foot­shock and temperature change. METH was injected at 30 mg/kg (the acute study) or 10 mg/kg intraperitoneally (i.p.) three times per week (the chronic study). The results demonstrated that METH induced more deleterious effects in the myocardial tissues during acute and chronic administrations when under stress conditions. Heat shock proteins (Hsps) played a critical role in the acute phase, while numerous genes, including anti­oxidant, anti­apoptotic and physiological function genes, played significant roles in the chronic phase. These results indicate that METH abuse, ranging from episodes of binge abuse to chronic abuse over several years, may cause severe myocardial damage in human users under stress.

Acute brainstem compression by intratumoral hemorrhages in an intracranial hypoglossal schwannoma.

A 77-year-old female in the hospital was found tachycardic and hypothermic by a nurse, and the patient's respiration subsequently ceased. Forensic autopsy revealed an intracranial cystic tumor that would have compressed the brainstem. On microscopic examination, the tumor was diagnosed as an Antoni A schwannoma growth, and recent multiple intratumoral hemorrhages in the intracranial schwannoma were observed, suggesting the sudden enlargement of the intracranial schwannoma due to intratumoral hemorrhaging. Accordingly, we diagnosed the cause of death as brainstem compression induced by the intratumoral hemorrhaging in the intracranial schwannoma. Meanwhile, a rhinopharyngeal tumor was also detected by the autopsy, which was compatible with an antemortem diagnosis of a dumbbell-shaped hypoglossal schwannoma.

Molecular-biological analysis of acute lung injury (ALI) induced by heat exposure and/or intravenous administration of oleic acid.

The aim of this study was to molecular-biologically investigate the interaction between heat exposure and pulmonary fat embolization in regards to the development of acute lung injury (ALI). Ten-week-old Wistar male rats were divided into four groups: (1) oleic acid injected into caudal vein after heat exposure, (2) oleic acid injected without heat exposure, (3) soybean oil injected after heat exposure, and (4) soybean oil injected without heat exposure, and then mRNA expression of eight inflammatory mediators related to ALI/acute respiratory distress syndrome (ARDS) and heat shock protein 70 (Hsp70) in lung was determined 1h after the injection. mRNA expression of interleukin 1 beta (Il1b), tumor necrosis factor alpha (Tnfa), vascular endothelial growth factor A (Vegfa), transforming growth factor beta 1 (Tgfb1) and Hsp70 was significantly increased by heat exposure, while that of Il1b, interleukin 6 (Il6), Tnfa, macrophage inflammatory protein 2 (Mip2) and granulocyte macrophage-colony stimulating factor (Gm-csf) was significantly elevated by the injection of oleic acid. Moreover, the expressions of inflammatory cytokines and chemokines in lung almost paralleled their mRNA expressions. In particular, IL-1ß expression was synergistically elevated by heat exposure followed by injection of oleic acid. Additionally, IL-6 expression tended to increase under the same conditions as well. It is likely that heat exposure itself injures lung tissue within a short time, and that more than two conditions which induce ALI/ARDS interact with each other synergistically, exacerbating the development of ALI/ARDS.

The blood concentration and organ distribution of haloperidol at therapeutic and toxic doses in severe fatty liver disease.

The aim of this study was to investigate the difference between the pharmacokinetics of haloperidol in normal rats and in rats with fatty liver disease. A therapeutic dosage (0.1 mg/kg) and a toxic dose (15 mg/kg) of haloperidol were administrated to normal 9-week-old male rats or those with severe fatty liver disease, and the blood concentration of haloperidol was determined 15 min, 1, 2, and 3 h following haloperidol administration. The concentration of haloperidol in the organs was determined 1, 2, and 3 h after the haloperidol administration. Additionally, the volume of the portal vein blood flow was measured 3 h after haloperidol administration. When given at the therapeutic dosage, the concentrations of haloperidol in both the blood and organs of the rats with fatty liver disease were significantly higher than those in the normal rats. However, when given at the toxic level, the blood and organ haloperidol concentrations 1 h after administration tended to be lower in the rats with fatty liver disease than those in the normal rats; these lower haloperidol levels returned to be the levels in the normal rats 3 h after the administration of haloperidol. The volume of the portal vein blood flow significantly increased following the toxic haloperidol dose as compared with the volume pre-administration and following the therapeutic haloperidol dose in the normal rats. However, the volume did not change after the toxic or the therapeutic dose of haloperidol compared with pre-administration in rats with severe fatty liver disease, although it was significantly higher than in the normal rats. The pathway for haloperidol metabolism might have been saturated before the administration of haloperidol in rats with fatty liver disease; thus, it is possible that the blood concentration of haloperidol tends to be much higher in individuals with severe fatty liver disease than in those with normal livers in an inverse proportion to the dosage of haloperidol.

Molecular biological analysis of cardiac effect of high temperature in rats.

The aim of this study was to investigate direct effects of heat exposure on the heart molecular-biologically and pathohistologically, using rats exposed to high temperatures. The mRNA expression of natriuretic peptide type A (Nppa), natriuretic peptide type B (Nppb), actin alpha 1 skeletal muscle (Acta1), myosin heavy polypeptide 6 cardiac muscle alpha (Myh6) and myosin heavy polypeptide 7 cardiac muscle alpha (Myh7) was determined in the hearts of the rats. Whereas the expression of Nppa and Nppb rapidly increased immediately after the heat exposure, the expression of Acta1 was gradually reduced, which indicated cardiac overload. Moreover, the expression of Myh6 and Myh7 in the heart increased 4h after the heat exposure, which suggested the involvement of a compensatory mechanism. Immunohistochemical staining with anti-fibronectin antibody showed that positive cardiomyocytes could be detected sparsely 4h after the heat exposure, and they could be clearly observed 8h after the heat exposure. Our results showed that hyperthermia causes myocardial damage shortly after the exposure to heat and that the ventricle was more vulnerable to hyperthermia-induced damage than the atrium. Cardiac dysfunction may be induced not only by hypercytokinemia but also by the direct effect of heat exposure at the early period of heat stroke, which may be one of the mechanisms by which heat causes death. Elucidating the mechanism of death from heat stroke could lead to not only diagnostic improvement but also the prevention of death from heat stroke.

A subacute epidural haematoma extending over the occipital region and posterior cranial fossa due to a laceration in the transverse sinus.

A 6-year-old male was found dead on his stomach with massive reddish vomiting from his mouth and nose. Postmortem cranial CT revealed an epidural haematoma in the left occipital region, but the cause and origin of the haematoma were unclear. An autopsy revealed that the epidural haematoma expanded over the left temporal region and the left side of the occipital region and posterior cranial fossa, and its origin was a laceration in the left transverse sinus induced by diastases in the left lambdoidal and occipitomastoid sutures. A pathohistological examination revealed that one portion of the haematoma was an early-stage hemorrhage, while the other portion extended approximately 1 week after the hemorrhage. Moreover, approximately 1 week elapsed after the laceration of the transverse sinus. Thus, we believe that the primary haematoma was induced by the laceration in the transverse sinus approximately 1 week before death, but the haematoma ceased to enlarge due to hemostasis. However, later, the size of the haematoma rapidly increased again due to rebleeding from the laceration, which led to intracranial hypertension. Consequently, we diagnosed the direct cause of death as choking due to vomit aspiration that resulted from intracranial hypertension induced by a subacute epidural haematoma.

Water-restraint stress enhances methamphetamine-induced cardiotoxicity.

Methamphetamine (MAP) and stress both cause a variety of cardiovascular problems. Stress also increases stimulant drug-seeking or drug-taking behavior by both humans and animals. In addition to the physiological effects on circulation, metabolism, and excretion, stress affects subject's responses to stimulant drugs such as MAP. However, the mechanisms underlying the drug-stress interactions remain unknown. In the present study, we assessed the effects of stress on myocardial responses to MAP in mice. Mice were injected with MAP (30mg/kg) immediately before exposure to water-restraint stress (WRS), which has often been used as a stressor in animal experiments. The combination of MAP with WRS produced a significant increase (p<0.01) in the leakage of proteins specific to myocardial damage and the levels of cytokines IL-6, TNF-α, and IL-10. The histological findings indicated the possibility that a combination of MAP with WRS induced cardiac myocytolysis. We also examined the expression of heat shock proteins (Hsps), which have cardioprotective effects. Administration of MAP alone significantly stimulated the RNA expressions of Hsp32, 60, 70, and 90 and the protein Hsp70 in cardiac muscles, whereas the expressions due to WRS or MAP plus WRS were not increased. These results reveal the fact that exposure to WRS depresses the induction of Hsps, in particular Hsp70, due to MAP injection, following to enhance MAP-induced myocardial damage. We believe that interactions between MAP and severe stress, including environmental temperature, affect the induction of Hsps, following to susceptibility of hosts to cardiotoxicity due to the stimulant drug.

[Drug dependency and drug-related sudden death].

Abuse of many substances is one of the serious problems in Japan, and we often encounter an autopsy case where the individual died in association with the administration of them. Although their intoxication is mainly diagnosed on the basis of their serum concentrations, it is difficult to diagnose as their poisoning when their concentrations are less than lethal level. Moreover, the mechanism of death induced by them is still unclear. Therefore, forensic autopsy should be performed in the case where drug-related death is suspicious not only so as to make a precise diagnosis but also so as to elucidate the mechanism of the drug-related deaths, leading to the efficient therapy for drug intoxication.

Relationships between suicide and three economic factors in South Korea.

The number of suicides in South Korea totaled 4840 in 1995 and 8569 in 1998; in Japan, suicides totaled 21,420 in 1995 and 31,755 in 1998. Suicide prevention is an important issue for both South Korea and Japan. In South Korea, factors related to the increase in suicides must be clarified, and specific suicide prevention measures must be promptly discussed in order to decrease the number of suicides. Therefore, this report examined suicide and unemployment rates and increased rates of mining and industrial production and of money supply in South Korea from 1990 to 2002. This report also discusses the relationships between suicide and unemployment rates and increased rates of mining and industrial production and increased rates of money supply during the same period. During the period studied, annual suicide rates ranged from 7.1 to 18.3 per 100,000 populations. Multiple regression analysis indicated that the suicide rate was clearly related to the unemployment rate, but the suicide rate was not related to increased rates of mining and industrial production and increased rates of money supply. Thus, when unemployment rates increase, relevant organizations and the community should pay close attention to the increase in suicide rates.

Molecular-biological analysis of the effect of methamphetamine on the heart in restrained mice.

In order to investigate the interaction in the heart between the administration of methamphetamine (MAP) and restraint of the body following it, we administrated MAP intraperitoneally to mice and restrained them, and then determined the level of mRNA expression of 22 genes in the heart using quantitative RT-PCR method. The mRNA expressions of Nfkbiz, Nr4a1 and Dusp1 changed significantly after the administration of MAP, suggesting the induction of an inflammatory condition such as damage to the myocardium. Moreover, the serum concentrations of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1 beta and IL-6 were significantly increased by the administration of MAP. On the other hand, the mRNA expressions of Rgs2 and Rasd1 were changed by both the administration of MAP and body restraint without interaction, which indicated that these insults affected the circulatory system additively or synergistically. From these results, it is likely that the administration of MAP, followed by body restraint, might cause acute myocardial damage due to the direct myocardial toxic effect of MAP, myocardial hypoxia and/or severe hypertension, which is one of the mechanisms for sudden death in MAP abusers who were restrained due to their excited state.

The effect of CAG repeat polymorphism in the glucocorticoid receptor on stress responses of mice exposed to water-immersion restraint stress.

Exposure to stress activates the hypothalamus-pituitary-adrenal (HPA) axis, which is followed by an increase in production of its end product, corticosterone, considered to be the most important glucocorticoid (GC) in rodents. Glucocorticoid receptor (GR) signaling has been suggested as a potential mechanism responsible for the pathogenesis of many clinical disorders. Here, we investigated the involvement of the GR polymorphism in stress response. ICR mice were screened by genomic PCR, bred, and divided into 3 groups according to the GR polymorphism, GRwt/wt, GRwt/Qn, and GRQn/Qn. Mice were exposed to water-immersion restraint stress (WRS), and then examined for gastric mucosal lesions, serum corticosterone, serum cytokines and serum Hsp70 levels. Male mice with GRQn/Qn exhibited a significantly greater gastric lesion index than those with GRwt/wt at 6 h of WRS. Stress-induced corticosterone output achieved peak levels at 3 h, after which it was downregulated. The serum level in the control group was GRwt/wt >GRwt/Qn >GRQn/Qn, whereas the order at 6 h of WRS was reversed, GRQn/Qn >GRwt/Qn >GRwt/wt, suggesting that the GRwt allele responded rapidly to stress. The IL-6 levels of each polymorphic line increased at 3 h and particularly at 6 h. On the contrary, the IL-10 levels in GRwt/wt and GRwt/Qn increased following exposure to WRS, whereas that in GRQn/Qn showed no change. The Hsp70 levels in mice with GRQn allele particularly increased at 6 h of WRS, and the concentration in GRQn/Qn significantly increased as compared to that in GRwt/wt. These results suggest that the GR gene polymorphism has a significant impact on the stress-induced output, including the gastric lesion index, corticosterone, cytokines, and Hsp70 levels in serum. The present study provides insights into the role of GR in individual responses to stress.

Methamphetamine protects against stress-induced gastric mucosal lesions in mice.

Stress-induced gastric mucosal injury is a common clinical entity. On the other hand, abuse of methamphetamine (MA) represents a growing social problem. MA users are frequently in stressful situations. In this study, we examined the effects of MA on gastric injury, corticosterone level and immunomodulation using a water-immersion restraint stress (WRS) mouse model that is well known to induce gastric lesions. Mice were randomly divided into five groups: (1) the normal group, (2) the 3 hour (3 h)-WRS group, (3) the 6 hour (6 h)-WRS group, (4) the MA (3 mg/kg) plus 6 h-WRS group and (5) the MA (30 mg/kg) plus 6h-WRS group. As expected, most animals examined (above 90%) showed gastric injury after the WRS exposure. However, administration of MA at both 3 and 30 mg/kg resulted in significant suppression of the injury. The corticosterone levels were increased by exposure to the stress and/or MA, but there was no difference between these groups. The levels of the serum cytokines IL-6, IL-10 and TNF were increased by WRS, and were markedly increased by MA plus WRS; in particular, the level of IL-6 was synergistically increased. On the contrary, the level of IL-1beta was significantly decreased by WRS and MA plus WRS. This is the first report showing the protective effect of MA on stress-induced gastric injury, although further study is necessary to resolve the mechanism of MA-driven suppression of the injury.