Multi-level analysis of symptoms of poison exposure reported to the Japanese Poison Information Center.

Two types of analytical multi-level approach to analyse symptoms after exposure to poisons were performed using numerical data extracted from reports received by the JAPAN POISON INFORMATION CENTER on the number "Poisoning 110" during 1998-2017. In the first approach, data collected in 2017, 2012, 2007 and 2002 were used, while in the second approach, all data collected during 1999-2017 were used. In the first approach, according to the odds ratio, the order of causative agents was industrial drugs>home drugs>general drugs and in the second approach, it was industrial drugs>foods/natural poisoning>agricultural drugs. However, in the first approach, the order based on the 95% confidence interval (CI) and profile likelihood was general drugs>home drugs>industrial drugs and in the second approach, the order based on 95% CI, profile likelihood and Wald value was agricultural drugs>foods/natural poisoning>industrial drugs. These multi-prospects were developed using a multilevel approach and the most optimized model was selected from the number of numerical data and the adaptability of fit of the multi-level logistic regression models in this report.

[Underlying Mechanisms of Methamphetamine-Induced Self-Injurious Behavior and Lethal Effects in Mice].

Relatively high doses of psychostimulants induce neurotoxicity on the dopaminergic system and self-injurious behavior (SIB) in rodents. However the underlying neuronal mechanisms of SIB remains unclear. Dopamine receptor antagonists, N-methyl-D-aspartic acid (NMDA) receptor antagonists, Nitric Oxide Synthase (NOS) inhibitors and free radical scavengers significantly attenuate methamphetamine-induced SIB. These findings indicate that activation of dopamine as well as NMDA receptors followed by radical formation and oxidative stress, especially when mediated by NOS activation, is associated with methamphetamine-induced SIB. On the other hand, an increase in the incidence of polydrug abuse is a major problem worldwide. Coadministered methamphetamine and morphine induced lethality in more than 80% in mice, accompanied by an increase in the number of poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine were significantly attenuated by pretreatment with a phospholipase A2 inhibitor or a radical scavenger, or by cooling of body from 30 to 90 min after drug administration. These results suggest that free radicals play an important role in the increased lethality induced by the coadministration of methamphetamine and morphine. Therefore, free radical scavengers and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine. These findings may help us better understand for masochistic behavior, which is a clinical phenomenon on SIB, as well as polydrug-abuse-induced acute toxicity.

[Some Attentional Points in the Clinical Aspects of Trauma Care].

Almost all patients requiring care for a combination of sexual, physiological, and psychological trauma, suffer from psychological or mental illness. Mental symptoms are well known to be associated with the violence very well and assailants have a violence dependency but it is not a well known mental disease. Changing of roles between being an assailant and being a victim is observed in half of the patients. In patients with trauma, hyperarousal and apathy appears simultaneously, and avoidance symptoms, intrusion symptoms, and crashed sleep, dissociation are also recognized. In addition, symptoms of orality are observed in patients requiring trauma care. However, hyperarousal, disturbance of sleep, and suicidal ideation improve quickly and the symptoms of a pair of a mother-child pair are well correlated. In organic non-temporary hyper psychogenic diseases (physiological diseases and surgery, and so on), non-organic psychogenic diseases (psychiatric diseases), and diseases on the border line between organic and non-organic diseases (psychosomatic diseases and may be unknown to non-medical professionals knowledge of such characteristic symptoms) is important information for health and medical care in the regional comprehensive care setting.

[Approach to the Development of Mind and Persona].

OBJECTIVES: To access medical specialists by health specialists working in the regional health field, the possibility of utilizing the voice approach for dissociative identity disorder (DID) patients as a health assessment for medical access (HAMA) was investigated. The first step is to investigate whether the plural personae in a single DID patient can be discriminated by voice analysis. METHODS: Voices of DID patients including these with different personae were extracted from YouTube and were analysed using the software PRAAT with basic frequency, oral factors, chin factors and tongue factors. In addition, RAKUGO story teller voices made artificially and dramatically were analysed in the same manner. Quantitive and qualitative analysis method were carried out and nested logistic regression and a nested generalized linear model was developed. RESULTS: The voice from different personae in one DID patient could be visually and easily distinquished using basic frequency curve, cluster analysis and factor analysis. In the canonical analysis, only Roy's maximum root was <0.01. In the nested generalized linear model, the model using a standard deviation (SD) indicator fit best and some other possibilities are shown here. CONCLUSIONS: In DID patients, the short transition time among plural personae could guide to the risky situation such as suicide. So if the voice approach can show the time threshold of changes between the different personae, it would be useful as an Access Assessment in the form of a simple HAMA.

Estimation of the postmortem duration of mouse tissue by electron spin resonance spectroscopy.

Electron spin resonance (ESR) method is a simple method for detecting various free radicals simultaneously and directly. However, ESR spin trap method is unsuited to analyze weak ESR signals in organs because of water-induced dielectric loss (WIDL). To minimize WIDL occurring in biotissues and to improve detection sensitivity to free radicals in tissues, ESR cuvette was modified and used with 5,5-dimethtyl-1-pyrroline N-oxide (DMPO). The tissue samples were mouse brain, hart, lung, liver, kidney, pancreas, muscle, skin, and whole blood, where various ESR spin adduct signals including DMPO-ascorbyl radical (AsA(∗)), DMPO-superoxide anion radical (OOH), and DMPO-hydrogen radical (H) signal were detected. Postmortem changes in DMPO-AsA(∗) and DMPO-OOH were observed in various tissues of mouse. The signal peak of spin adduct was monitored until the 205th day postmortem. DMPO-AsA(∗) in liver (y = 113.8-40.7 log (day), R1 = -0.779, R2 = 0.6, P < .001) was found to linearly decrease with the logarithm of postmortem duration days. Therefore, DMPO-AsA(∗) signal may be suitable for detecting an oxidation stress tracer from tissue in comparison with other spin adduct signal on ESR spin trap method.

Monoaminergic neuronal changes in orexin deficient mice.

Orexin knockout (KO) mice and orexin/ataxin-3 mice (which have a different pathophysiological background in orexin deficiency) exhibit a phenotype that is similar to human narcolepsy. Although the interactions between the monoaminergic and orexinergic systems are not entirely clear, indirect monoamine-receptor agonists (especially psychostimulants) may contribute to the treatment of narcolepsy. The present study was designed to investigate the interaction between brain orexinergic and monoaminergic neurons as measured by the status of monoaminergic systems and monoamine-related behaviors using orexin-deficient mice. Previous studies have shown that a reduction of monoaminergic tone is related to wakefulness. In the present study, locomotor activity in a novel environment and dopamine turnover was significantly decreased in orexin-deficient mice compared to WT mice, which suggests that psychostimulants may be useful for maintaining wakefulness in orexin deficiency. We also examined the effects of orexin deficiency on psychostimulant-induced hyperlocomotion. The hyperlocomotion induced by methamphetamine and methylphenidate was lower, whereas that induced by MDMA was higher in orexin KO mice compared to WT mice. The sensitivities against psychostimulants in orexin/ataxin-3 mice differed from those in orexin KO mice. These results indicate that the effectiveness of each psychostimulant, which is closely related to its monoaminergic function, was influenced by orexin deficiency itself as well as by the different pathophysiological background in orexin deficiency.

Dopamine-independent psychostimulant activity of a delta-agonist.

The effects of dopamine receptor agonists and antagonists on hyperlocomotion in mice induced by the nonpeptide delta-opioid receptor agonist (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide) (SNC80) were investigated. SNC80 significantly increased locomotion (maximally at 2 mg/kg). In antagonism tests, naltrindole and naltriben completely attenuated this SNC80-induced hyperlocomotion, which suggests that SNC80-induced hyperlocomotion may be mainly mediated through delta-opioid receptors. Although haloperidol (dopamine D2-receptor antagonist) did not affect SNC80-induced hyperactivity, it inhibited morphine-induced hyperlocomotion. In combination tests, SNC80, at a dose that did not affect spontaneous activity, significantly potentiated hyperlocomotion induced by methamphetamine and the dopamine D1-receptor agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepin hydrobromide (SKF81297), whereas the combination of SNC80 and the D2-like receptor agonist 7-OH-N,N-di-n-propyl-2-aminotetralin did not affect locomotor activity. An earlier study demonstrated that the combination of the D1-receptor agonist SKF81297 and the D2-like receptor agonist 7-OH-N,N-di-n-propyl-2-aminotetralin synergistically induced hyperactivity in mice. Therefore, the present findings suggest that stimulation of either D2-like receptors or delta-opioid receptors can enhance the hyperlocomotion induced by stimulation of D1 receptors by methamphetamine and SKF81297, and the mechanism that underlies the hyperactivity caused by SNC80 may be different from that which underlies the effects of morphine.

Complicated interaction between psychostimulants and morphine in expression of phenotype of behavior in the dopaminergic system of BALB/c mice.

It is believed that BALB/c mice appear to be less sensitive to the locomotor effects of abused drugs compared to other strains, and several behaviors induced by abused drugs depend on genetic factors. The present study was designed to investigate the effects of the interaction between psychostimulants and morphine on behavior in BALB/c mice. Morphine and cocaine induced hyperlocomotion and hypolocomotion, respectively, while methamphetamine did not affect locomotor activity and high doses of methamphetamine significantly increased self-injurious behavior. Cocaine or methamphetamine increased the effects of morphine on locomotor behavior. Haloperidol (a dopamine-receptor antagonist) attenuated the hyperlocomotion induced by the combination of cocaine or methamphetamine plus morphine. These results indicate that the synergistic effects of methamphetamine or cocaine and morphine on locomotor activity are mediated through enhancement of the dopaminergic system and that combinations of psychostimulants and morphine enhance the locomotor activity in BALB/c mice. On the other hand, morphine completely attenuated methamphetamine-induced self-injurious behavior. Furthermore, a low dose (0.01 mg/kg) of haloperidol significantly increased the effects of methamphetamine and morphine on the locomotor activity. Hyperlocomotion induced by psychostimulants is mediated by the mesolimbic dopaminergic system, whereas stereotyped behaviors is mediated by the nigrostriatal dopaminergic system. Our findings suggest that balances of the activation of dopaminergic neurons (between mesolimbic and nigrostriatal systems) may play an important role to engender corresponding behavioral outcomes in BALB/c mice.

Comparison of nitric oxide synthase inhibitors, phospholipase A2 inhibitor and free radical scavengers as attenuators of opioid withdrawal syndrome.

Chronic morphine-induced withdrawal syndrome after morphine cessation remains a severe obstacle in the clinical treatment of morphine. Previous studies have shown that nitric oxide synthetase (NOS) inhibitors may have therapeutic potential in morphine withdrawal in humans. The mechanisms that underlie expression of morphine-induced withdrawal syndrome are, however, not yet fully understood. Therefore, this study was designed to determine the mechanism of the expression of morphine-induced withdrawal syndrome in mice. Morphine-dependent mice showed marked body weight loss and several withdrawal signs after naloxone challenge. Pretreatment with a NOS inhibitor, such as N-nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole, but not aminoguanidine, significantly attenuated the expression of morphine-induced withdrawal syndrome. Furthermore, mepacrine (a phospholipase A2 inhibitor) significantly attenuated the morphine-induced withdrawal syndrome in a manner that was different than that with a NOS inhibitor. These results suggest that nNOS and phospholipase A2, which might increase free radicals, play an important role in the expression of morphine-induced withdrawal syndrome. On the contrary, free radical scavengers (including fullerenes, ascorbate-2-phosphate, and DL-alpha-tocopheryl phosphate) attenuated the expression of the morphine-induced withdrawal syndrome. These results indicate that free radicals play an important role in the expression of physical dependence on morphine, and fullerenes could be a potential clinical tool in the relief of morphine withdrawal syndrome.

Differential effects of the ascorbyl and tocopheryl derivative on the methamphetamine-induced toxic behavior and toxicity.

A previous study showed that high doses of methamphetamine induce self-injurious behavior (SIB) in rodents. Furthermore, the combination of methamphetamine and morphine increased lethality in mice. We recently surmised that the rise in SIB and mortality induced by methamphetamine and/or morphine may be related to oxidative stress. The present study was designed to determine whether an antioxidant could inhibit SIB or mortality directly induced by methamphetamine and/or morphine. The SIB induced by 20mg/kg of methamphetamine was abolished by the administration of Na L-ascorbyl-2-phosphate (APS: 300 mg/kg), but not Na DL-alpha-tocopheryl phosphate (TPNa: 200mg/kg). In contrast, APS (300 mg/kg) and TPNa (200mg/kg) each significantly attenuated the lethality induced by methamphetamine and morphine. The present study showed that the signal intensity of superoxide adduct was increased by 20mg/kg of methamphetamine in the heart and lungs, and methamphetamine plus morphine tended to increase superoxide adduct in all of the tissues measured by ESR spin trap methods. Adduct signal induced in brain by methamphetamine administration increased in significance, but in mouse administrated methamphetamine plus morphine. There are differential effects of administration of methamphetamine and coadministration of methamphetamine plus morphine on adduct signal. These results suggest that APS and TPNa are effective for reducing methamphetamine-induced toxicity and/or toxicological behavior. While APS and TPNa each affected methamphetamine- and/or morphine-induced toxicology and/or toxicological behavior, indicating that both drugs have antioxidative effects, their effects differed.

Involvement of free radicals followed by the activation of phospholipase A2 in the mechanism that underlies the combined effects of methamphetamine and morphine on subacute toxicity or lethality in mice: comparison of the therapeutic potential of fullerene, mepacrine, and cooling.

An increase in polydrug abuse is a major problem worldwide. The coadministration of methamphetamine and morphine increased subacute toxicity or lethality in rodents. However, the underlying mechanisms by which lethality is increased by the coadministration of methamphetamine and morphine are not yet fully understood. Coadministered methamphetamine and morphine induced lethality by more than 80% in BALB/c mice, accompanied by the rupture of cells in the kidney and liver, and an increase in poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine was significantly attenuated by pretreatment with mepacrine (phospholipase A(2) inhibitor) or fullerene (a radical scavenger), or by cooling from 30 to 90 min after drug administration. Furthermore, based on the results of the electron spin resonance spin-trapping technique, hydroxyl radicals were increased by the administration of methamphetamine and morphine, and these increased hydroxyl radicals were potently attenuated by fullerene and cooling. These results suggest that hydroxyl radicals plays an important role in the increased lethality induced by the coadministration of methamphetamine plus morphine. The potency of cooling or drugs for decreasing the subacute toxicity or lethality induced by the coadministration of methamphetamine and morphine was in the order fullerene=cooling>mepacrine. These results indicate that fullerene and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine.

Oxidative stress in methamphetamine-induced self-injurious behavior in mice.

Previous studies have shown that N-methyl-D-aspartate, the formation of free radicals and poly(ADP-ribose) polymerase are related to methamphetamine-induced neurotoxicity. This study was designed to investigate the involvement of oxidative stress in methamphetamine-induced self-injurious behavior in mice. In this study, methamphetamine (20 mg/kg) induced continuous self-injurious behavior in six of seven mice. N-methyl-D-aspartate-receptor antagonists (MK801 and 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid) significantly attenuated this methamphetamine-induced self-injurious behavior. These results suggest that the activation of N-methyl-D-aspartate receptors is involved in methamphetamine-induced self-injurious behavior. Furthermore, we found that the nonselective nitric oxide synthase inhibitor l-N-nitro-L-arginine methyl ester hydrochloride and the neuronal nitric oxide synthase inhibitor 7-nitroindazole, but not the inducible nitric oxide synthase inhibitor aminoguanidine, the free-radical inhibitors fullerene and 3-methyl-1-phenyl-2-pyrazolin-5-one-186, or the poly(ADP-ribose) polymerase inhibitor benzamide, significantly attenuated methamphetamine-induced self-injurious behavior. The present results show that oxidative stress, which is mediated by the activation of neuronal nitric oxide synthase, is associated with methamphetamine-induced self-injurious behavior. These findings may help us to better understand the clinical phenomenon of self-injurious behavior.

Differential effects of micro-opioid, delta-opioid and kappa-opioid receptor agonists on dopamine receptor agonist-induced climbing behavior in mice.

Interactions between the dopaminergic system and opioids have not been adequately clarified. The present study was designed to investigate the effects of micro-opioid (morphine), delta-opioid (SNC80) and kappa-opioid (U50 488H) receptor agonists on dopamine receptor agonist-induced climbing behavior in mice. Apomorphine (dopamine-receptor agonist) increased stereotyped climbing behavior, unlike methamphetamine, morphine, U-50 488H and (+/-)7-hydroxy-N,N-di-n-propyl-2-aminotetralin hydrobromide (D2-like receptor agonist). Furthermore, SKF81297 (D1 receptor agonist) and SNC80 caused climbing behavior. In addition, while morphine (20 mg/kg), but not U50 488H or SNC80, significantly attenuated high-dose apomorphine (2.0 mg/kg)-induced climbing behavior, it significantly potentiated low-dose apomorphine (0.5 mg/kg)-induced climbing behavior. These results suggest that morphine may have dual effects on the behavioral effects induced by apomorphine. Furthermore, we interestingly showed that the combination of apomorphine or SKF81297 and SNC80 enhanced frequent nonstereotypic climbing behavior, suggesting that delta/D1 interactions may play a prominent role in the expression of certain types of behavior in mice. Thus, micro-opioid, delta-opioid and kappa-opioid receptor agonists induce possible differential effects on the dopaminergic system in mice.

Preclinical studies on safety of fullerene upon acute oral administration and evaluation for no mutagenesis.

Fullerenes characterized as an antioxidant are believed to reduce various reactive chemical species, such as free radicals, and their characteristic features have been disclosed to furnish many useful medical technologies. Despite the numerous applications for the biological efficacy of fullerenes, less is known about the toxicity of fullerenes in mammals. Hence, the protocol was designed to determine the acute oral median lethal dose and evaluate the acute toxicity of fullerenes when administrated as a single dose to Sprague-Dawley rats. In an acute toxicity test, fullerenes were administered once orally to a single group of male and female at a dose level of 2000 mg/kg. No deaths were observed and the body weights in both sexes of 2000 mg/kg group increased in a similar pattern to the control group. Genotoxicity of fullerenes was also assessed in a bacterial reverse mutation assay (Ames test) and the chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells. Although structural chromosomal aberrations were induced at up to 5000 microg/mL, there was no significant increase in the frequency of chromosomal aberrations at any dose level regardless of presence of S9. Fullerenes did not cause genetic damage in Salmonella typhimurium TA100, TA1535, TA98 and TA1537 and Escherichia coli WP2uvrA/pKM101. These results indicate that fullerenes are not of high toxicological significance.

Effects of mu-, delta- and kappa-opioid receptor agonists on methamphetamine-induced self-injurious behavior in mice.

Opioid receptor agonists can differentially modify the behavioral effects of direct/indirect dopamine receptor agonists, such as methamphetamine, cocaine and apomorphine. However, the effects of opioid receptor agonists on high-dose methamphetamine-induced behavior have not yet been clarified. Therefore, the present study was undertaken to investigate the effects of mu (morphine)-, delta (SNC80)- and kappa (U50,488H)-opioid receptor agonists on methamphetamine-induced self-injurious behavior and locomotor activity in mice. Methamphetamine (20 mg/kg) induced severe self-injurious behavior. In a combination test, some opioid receptor agonists significantly attenuated methamphetamine-induced self-injurious behavior, with potencies in the order morphine>buprenorphine (mu-opioid and kappa-opioid receptor agonist/antagonist) >U50,488H, as maximum effects. These results suggest that the stimulation of mu- and kappa-opioid receptors plays an inhibitory role in high-dose methamphetamine-induced stereotypic self-injurious behavior in mice, without affecting locomotor activity.

Generalization of NMDA-receptor antagonists to the discriminative stimulus effects of kappa-opioid receptor agonists U-50,488H, but not TRK-820 in rats.

Generalizations of NMDA-receptor antagonists to the discriminative stimulus effects of kappa-opioid receptor agonists in rats were examined. Phencyclidine, MK-801, and ketamine, non-competitive NMDA-receptor antagonists, generalized to the discriminative stimulus effects of U-50,488H, but not those of TRK-820, whereas (+/-)-3-(2-carbaxypiperazine-4-yl) propyl-1-phosphonic acid (CPP), a competitive NMDA-receptor antagonist, and ifenprodil, an NR1/NR2B NMDA-receptor antagonist, did not, suggesting that non-competitive NMDA-receptor antagonists possess U-50,488H-like discriminative stimulus effects in rats. Since U-50,488H and phencyclidine both induce aversive effects, our findings indicate that the cue of the discriminative stimulus effects of U-50,488H and non-competitive NMDA-receptor antagonists may be associated with their aversive effects.

Microsatellite polymorphism in Japanese mongrel dogs.

The genetic variability of 182 unrelated mongrel dogs living in various areas of Japan (from Hokkaido to Okinawa) was studied by collecting their blood. Ten microsatellite loci were chosen from different autosomal chromosomes. After combining a few rare adjoining alleles to allelic classes, it was confirmed that the Hardy-Weinberg equilibrium was attained in each locus. The polymorphic information contents (PICs) of the loci, Ren37A11, Ren48E01, AHTk253, ZuBeCa30, Ren277K09, Ren42N13, AHT130, PEZ03, PEZ12, and AHT121, were 0.58, 0.63, 0.67, 0.67, 0.68, 0.71, 0.79, 0.80, 0.80, and 0.80, and the power of discriminations (PDs) were 0.80, 0.85, 0.87, 0.88, 0.88, 0.89, 0.94, 0.94, 0.94, and 0.94, respectively. The combined mean exclusion chance (MEC) was 0.9995, indicating that these microsatellite loci are useful for kinship testing of Japanese dogs.

Underlying mechanism of combined effect of methamphetamine and morphine on lethality in mice and therapeutic potential of cooling.

An increase in polydrug abuse is a major problem worldwide. A previous study showed that coadministration of methamphetamine and morphine induced lethality in rodents and humans. However, the underlying mechanisms by which the lethality is increased by the coadministration of methamphetamine and morphine have not been fully understood. Therefore, the present study was designed to determine the mechanism of increased lethality induced by methamphetamine and morphine. Coadministered methamphetamine and morphine increased the lethality by more than 70% in BALB/c mice. Pretreatment with NMDA-receptor antagonists, such as MK-801 and 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP), and benzamide [poly(ADP-ribose) polymerase (PARP) inhibitor] significantly attenuated the increased lethality induced by methamphetamine and morphine. Furthermore, the lethal effect induced by methamphetamine and morphine was completely attenuated by immediate cooling after the coadministration of methamphetamine and morphine. It has been reported that methamphetamine-induced neurotoxicity can be blocked by lowering the temperature, and this effect might be mediated by a reduction of release of free radicals. These results suggest that activation of NMDA receptors and PARP play an important role in the increased lethality induced by methamphetamine and morphine.

[Sudden infant death syndrome].

The Disability-SIDS Research Committee, Ministry of Health and Welfare defines sudden infant death syndrome (SIDS) as "a syndrome that causes sudden death of an infant in which the demise of the victim cannot be anticipated by his prior health status or medical history and the cause of death cannot be determined from the circumstances surrounding the final moment or from the results of an autopsy". A diagnostic autopsy is obligatory. SIDS brings a profound psychological shock to the victim's family. If the incidence takes place at a nursery or a certain medical facility (such as that involved in delivery), it may develop into a civil or criminal case related to professional responsibility for placing the infant in a prone position or a possible fault in nursing care. The current study describes the epidemiology, pathogenesis, and physiopathology of SIDS, as well as prospects for its prevention and related social problems.