Masayuki Nata

Gene expression on liver toxicity induced by administration of haloperidol in rats with severe fatty liver

Sudden deaths are often encountered in schizophrenic patients prescribed with antipsychotic drugs, and fatty liver may be more prevalent among patients with schizophrenia. The aim of this study is to investigate the adverse effects of antipsychotic drugs on fatty liver. We administered haloperidol intraperitoneally to fatty liver rats and examined the mRNA expression in the liver. Basic expressions of cytochrome P450 (CYP)1A2, CYP2C11 and CYP3A2 decreased, and response of these CYPs to haloperidol was reduced in the fatty liver. Metabolism of haloperidol was also suppressed in the fatty liver rats. Moreover, hepatic injury by administration of haloperidol was shown pathohistologically and molecular-biologically in severe fatty liver. These results suggest that fatty liver increases susceptibility to adverse effects of haloperidol, possibly leading to life-threatening events. It should be noted by clinicians that excessive dose of antipsychotic drugs may be more harmful in patients with fatty liver.

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-1β 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.

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.

Diatom numbers around the continental shelf break.

Diatom concentrations in seawater were examined monthly at four aquatic areas. Diatom concentrations inside a bay showed a monthly variation, but these were detectable. On the other hand, in the open sea around the continental shelf break, there were few diatoms in any season. When a person drowns in the open sea, the diatom test cannot be expected to function reliably.

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 subjects 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.

Causative factors as cues for addressing the rapid increase in suicide in Mie Prefecture, Japan: comparison of trends between 1996-2002 and 1989-1995.

Abstract  The number of suicides in Japan has increased from approximately 22 000 per year from 1988 to 1997 to >30 000 per year since 1998. Likewise, the number of suicides has been increasing in Mie Prefecture. The purpose of the present study was to examine the incidence of and circumstances surrounding all suicide cases during 1996–2002 in Mie Prefecture and to compare the data with those from 1989 to 1995. In Mie Prefecture, the age‐specific suicide rate during the second 7‐year period included marked increases among men aged 50–59 and 60–69 years. Among women, the age‐specific suicide rate increased with age during both 7‐year periods. During the second period, psychiatric disorders as causative factors increased in all generations. They were especially important for women of the younger generation, whereas economic problems were the most common causative factor among men aged 40–64. Physical illness as a causative factor in suicide was high among the elderly, but among the other age groups this factor trailed behind economic difficulties for men and psychiatric disorders for women. To prevent suicide, social cooperation as well as a plenitude of visiting nurses and psychiatric care is required, and early detection and treatment are also important.

Dental identification using digital images via computer network.

Dental identification is a useful scientific method. In Japan, however, there are only a few forensic odontologists; moreover, until now, forensic dental services have only been offered by general dentists. These dentists may not be able to offer such forensic services during office time. For a quick comparison, the authors tried sending digital photos, taken with a 2-million-pixel digital camera, to dental offices via the Internet. If a dental office has Internet access, it is possible for dental charting to be sent directly to the autopsy room. Of course, digital images only provide the first outline. However, when antemortem dental records of the person in question are available at autopsy, a quick comparison can be made.

The report in the correlation between the factor of unemployment and suicide in Japan.

To the Editor: The number of suicides in Japan has increased from approximately 22,000 per year in 1988–1997 to over 30,000 per year since then, and this increase in numbers is one of the most important problems in Japan. Among Japanese, the 34,427 recorded suicides in 2003 was the highest ever. The unemployment rates in Japan have increased rapidly since 1998. In Japan, Yoshioka has reported a large-scale study of suicide covering the 7 years from 1989 to 1995. According to his report, economic difficulties, which include suffering from unemployment, are an important factor in increased suicide rates. The present study provides a more detailed correlation between rates of unemployment and the suicide rate than other related studies in Japan. In the present report, we examined all the suicide numbers and rates throughout Japan between 1985 and 2004 in cooperation with the national police agency (Tables 1 and 2), and we investigated the unemployment rates throughout Japan between 1985 and 2004 in cooperation with the Department of Work (Table 3). We focused on the correlation of annual suicide rates in Japan from 1985 to 2004 (Table 2) with the annual unemployment rates in Japan from 1985 to 2004 (Table 3). The statistical analysis was performed using single regression analysis. During the test period, the number of suicides was 355,737 males and 169,833 females (Table 1). The annual suicide rates by sex were 29.0 males and 13.3 females per 100,000 population (Table 2). Annual suicide rates in total correlated significantly with the unemployment rates in Japan: r 0.91, r 0.83, F(1, 18) 86.18, P 0.001 (y 2.87x 11.13); the rates in males correlated significantly with the unemployment rates in Japan: r 0.95, r 0.90, F(1, 18) 168.92, P 0.001 (y 5.00x 11.57); while the rates in females did not correlate with unemployment rates: r 0.45, r 0.20, F(1,18) 4.49, P 0.05 (y 0.52x 11.54). We therefore conclude that the rate of unemployment is an important factor in suicide that is significantly relevant to the increase in suicide rates in total and in males. It is considered that when unemployment rates become high, people experience more stress. It should be noted that suicide seems to be less related to the level of unemployment, but rather to the change in an individual’s situation from employment to unemployment. The risk of suicide increases when people lose their jobs. Effective preventive intervention of suicide as related to first-time job loss has not yet been reported in Japan. It is clear, however, that psychosocial health care should be a part of occupational affairs administered by industrial physicians, primary care physicians, and psychiatrists in an attempt to prevent suicide. According to the report of Voss et al, an increased risk of death from external causes implies a need for support for those experiencing unemployment, and particularly for susceptible individuals. When the patient is in a bad situation because of unemployment, the family and the medical staff should pay close attention to the patient. TABLE 1. The No. Suicides in Japan for the Years 1985–2004: (Population)

Significant correlation of yearly suicide rates with the rate of unemployment among men results in a rapid increase of suicide in Mie Prefecture, Japan.

The number of suicides in Japan has increased from approximately 22 000 per year in 1988‐1997 to >30 000 per year since then. Likewise, the number of suicides has been increasing in Mie Prefecture. Many researchers consider that a major factor related to the number of suicides is an increase of unemployment in men; 1,2 but it has not been described clearly in Mie Prefecture so far. According to Yoshioka, Mie Prefecture had intermediate suicide rates similar to the rates for Japan as a whole. 3 It is possible to analyze enough suicide data for this prefecture to investigate the causes of suicide in detail. In the present study, we investigated the incidence and the circumstances of all suicide cases between 1989 and 2002 in cooperation with the First Department of Criminal Investigation of the Mie Prefectural Police Headquarters, and we investigated the unemployment rate from 1989 to 2002 in cooperation with the Department of Work in Mie Prefecture. In Japan, the annual rate of unemployment among the whole Japanese population and the current rate of unemployment are available for each Prefecture every 5 years, but the annual rate of unemployment is not available in each Prefecture. Therefore we calculated the correlation between the rate of unemployment every 5 years in the total Japanese population and that in Mie Prefecture for each sex. The correlations were r = 0.80 and r = 0.97 for men and women, respectively. Accordingly we considered that the rate of unemployment in the Japanese total reflected the rate of unemployment in Mie Prefecture. We focused on the correlation of yearly suicide rates in Mie Prefecture from 1989 to 2002, with the rate of unemployment in Japan from 1989 to 2002. The statistical analysis was performed using single regression analysis and Fisher’s exact test. During the test period, 3276 male and 1772 female suicides were reported to Mie Prefectural Police Headquarters. The suicide rates by sex were 26.2 (male) and 13.4 (female) per 100 000 (P < 0.05). Among the causative factors, ‘economic difficulties (including suffering from unemployment)’ was the second most prevalent in men (20.0%), and the least prevalent in women (5.0%). The yearly suicide rates for men correlated significantly with the unemployment rate in Japan: r(14) = 0.92, P < 0.001; the yearly sucidie rates for women also showed some correlation with the unemployment rate in Japan: r(14) = 0.56, P = 0.04. The factor of ‘economic difficulties’ is particularly relevant for the increase in suicide in men. When economic conditions become worse, people are exposed to more stress in the workplace. 3‐6 It should be noted that suicide rates were less related to the level of unemployment than to the change in situation from employment to unemployment. One typical case was the significant increase in suicide rates in the year 1997‐1998 when such worsened changes of working conditions were observed. In 1997 and 1998, yearly suicide rates were 17.19 and 26.91, and the unemployment rates were 3.5 and 4.3, respectively. We conclude that psychosocial health care should be considered to be part of occupational affairs by industry physicians, primary care physicians and psychiatrists in order to prevent suicide, which is now a national increasing trend in Japan. When the patient is in a bad situation because of unemployment, the family and medical staff should be aware of the correspondence between suicide rates and unemployment. REFERENCES

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.