TACR1 gene polymorphism and sex differences in postoperative nausea and vomiting.

We hypothesised that the genetic effect of single nucleotide polymorphisms in the TACR1 gene, which encodes NK1 receptors, could influence the sex difference in postoperative nausea and vomiting. Thirty-two selected single nucleotide polymorphisms were genotyped by the Sanger sequencing method in 200 patients who underwent lower abdominal surgery. The incidence and severity of postoperative nausea and vomiting were evaluated after surgery. The rs3755468-SNP showed significant association with the incidence and severity of postoperative nausea and vomiting (p = 0.016). The TT haplotype defined by two single nucleotide polymorphisms, including the rs3755468-SNP, was associated with reduced incidence and severity of postoperative nausea and vomiting in female patients (p = 0.03). The rs3755468-SNP is located within the predicted oestrogen response element and a DNase I hypersensitive site. The single nucleotide polymorphisms in the TACR1 gene are associated with sex differences in postoperative nausea and vomiting and may help to elucidate the mechanisms underlying these differences.

[Acute left ventricular rupture and cardiac tamponade caused by blunt trauma; report of a case].

It is difficult to save patients with acute left ventricular rupture and cardiac tamponade caused by blunt trauma. A 67-year-old man hospitalized due to sustained multiple blunt trauma. The systolic blood pressure was 40 mmHg. Chest computed tomography (CT) and ultrasonic echocardiography revealed cardiac tamponade. Abdominal CT indicated left renal contusion. Pericardial drainage via the subxiphoid approach drew about 1,000 ml of blood from the pericardial sac, which only transiently increased blood pressure. Median sternotomy and subsequent pericardiotomy revealed pulsatile bleeding jet through a laceration of about 2.0 cm long in the left ventricle near the first diagonal branch. After complete digital compression, the portion was covered by a biological tissue adhesive/sealant sheet (TachoComb), which completely suppressed bleeding. The postoperative course was uneventful. He was discharged from the hospital on the 20th day after the operation.

Persistent anxiogenic effects of a single or repeated doses of cocaine and methamphetamine: interactions with endogenous cannabinoid receptor ligands.

As persistent behavioural changes, such as increased anxiety-related behaviours, can be predicted based on the phenomenon of psychostimulant-induced neuronal plasticity, the time course (3-, 5- and 10-day time points) of the effects of both a single and repeated (daily for 7 days) i.p. administrations of cocaine (COC) and methamphetamine (MA) on anxiety-related behavioural symptoms in the elevated plus-maze test were examined in mice. Furthermore, based on the reported interactions between brain dopamine versus cannabinoid (CB) receptors and the contribution of CB receptors to the occurrence of persistent anxiety-related behavioural symptoms, the interactions of the agonist CP 55940 (CP) and the endogenous ligands anandamide (arachidonylethanolamide: AEA), 2-arachidonylglycerol (ARA), N-arachidonyldopamine (NADA), noladin ether (NL), and virodhamine (VA) with the COC- or MA-induced anxiety-related behaviours were also studied. In both an acute experiment using a single COC (30 mg/kg) or MA (4 mg/kg) dose and a chronic experiment using repeated COC (15 mg/kg) or MA (2 mg/kg) doses, anxiety-related behavioural symptoms were observed similarly at 3- and 5-day time points, but disappeared at the 10-day time point. Among the CB ligands, the agonists CP, AEA, ARA, NADA, and NL provided strong protective effects against each parameter at 3- and 5-day time points. Therefore, it was concluded that both COC and MA caused persistent anxiety-related behavioural symptoms following both a single and repeated treatments. Since these anxiogenic effects were attenuated by the endogenous CB agonists, the involvement of brain CB receptors was suspected.

[Coronary artery bypass graftingin a patient with aortitis syndrome; report of a case].

We present a case of surgical treatment for a coronary lesion due to aortitis syndrome. A 41-year-old woman, suffering from aortitis syndrome and under prednisolone (PSL) therapy, underwent coronary artery bypass grafting (CABG). Surgical treatment was performed according to the aortic no-touch technique, but the patient showed a poor cardiac performance 5 days after the operation. This accident was resolved by increasing the PSL dose. Aortitis syndrome treated with PSL needs careful perioperative management besides an operative procedure.

[Successful management of traumatic aortic valve insufficiency; report of a case].

A case of the successful management of traumatic aortic valve insufficiency is reported. A previously healthy 48-year-old man sustained multiple injuries in a traffic accident. One month after the accident, heart failure, derived from aortic insufficiency, was noted. Three years and 5 months after the injuries, aortic valve replacement was performed, and a large tear, approximately 7 mm in length, was found in the aortic right coronary cusp. This finding corresponded to the traumatic aortic valve insufficiency. Traumatic aortic valve insufficiency is rare, and early diagnosis may be difficult. Examinations for associated intracardiac injuries should be carefully undertaken.

Similar effects of cocaine and immobilization stress on the levels of heat-shock proteins and stress-activated protein kinases in the rat hippocampus, and on swimming behaviors: the contribution of dopamine and benzodiazepine receptors.

Cocaine (COC) has been reported to cause effects similar to physiological stressors in the brain neuroendocrinal system, including heat-shock protein (HSP) expression, although these effects have not been elucidated in detail. In the present study, we examined the effects of repeated (4 days) treatments with cocaine hydrochloride (35 mg/kg, i.p.) and 10 min immobilization stress (IM) on the distribution of HSP (HSP27, HSP60, HSP70, HSC70) and stress-activated protein kinase (SAPK) (SAPKalpha, SAPKbeta, SAPKgamma) immunoreactive nerve cells (positive cells) in the rat hippocampus. The swimming behaviors of the rats in the forced swimming test were also examined. In both COC and IM groups, an early enhancement (5 h time point) of hippocampal HSP (HSP27, HSP60, HSP70, HSC70) and SAPK (SAPKbeta, SAPKgamma) positive cells was observed, whereas a recovery (SAPKs) or attenuation (HSP60 and HSC70) was observed at the 24 h time point. In both groups, a depression of the swimming behaviors (attenuation in the activity counts and time until immobility) below the control level was observed at the 5 h point, but a recovery was observed at the 24 h time point. At the 48 h time point, all parameters returned to the control level. These alterations in the levels of HSPs and SAPKs, and the swimming behaviors were similar to those observed in the stress (IM) group, and were characteristic in that all of these alterations were attenuated by the benzodiazepine inverse agonist, Ro 15-4513 (5 mg/kg, i.p.), and the dopamine D1 receptor antagonist, SCH23390 (0.5 mg/kg, i.p.), which was not observed in the groups treated with another stressor-like drug (bicuculline).

Protective effects of cannabinoid receptor agonists against cocaine and other convulsant-induced toxic behavioural symptoms.

Based on the previously reported co-localization and relationship between cannabinoid and dopamine receptors, the effects of cannabinoid receptor agonists against cocaine-induced toxic behavioural symptoms, including convulsive seizures, were examined in mice. The anticonvulsant effect of several cannabimimetics against seizures induced by other convulsants was also compared. The cannabinoid receptor agonists CP 55940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-cyclohexanol) and WIN 55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone), and the endogenous cannabinoid anandamide were co-administered intraperitoneally with cocaine (75 mg kg(-1)) or other convulsants such as bicuculline, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-carboxylate (DMCM), L-glutamic acid and N-methyl-D-aspartate (NMDA). CP 55940 (2.5 mg kg(-1)) and anandamide (15 mg kg(-1)) significantly antagonized cocaine-induced lethality, and CP 55940 and WIN 55212-2 (2.5 mg kg(-1)) significantly attenuated the severity of cocaine-induced convulsive seizures. Furthermore, ataxic hyperactivity, which was observed only in the cocaine-treated group of mice and could be evaluated by their activity counts, was also depressed in the groups of mice co-treated with each of the three cannabinoid agonists. However, none of these agonists protected against bicuculline- or DMCM-induced lethality or convulsive seizures. In contrast, all of the cannabinoid agonists, most notably anandamide, antagonized both L-glutamic acid (2 g kg(-1))- and NMDA (200 mg kg(-1))-induced convulsive seizures. These data support the previously reported close correlation between dopamine and cannabinoid receptors, and between cannabinoid agonists, especially anandamide, and glutamate (NMDA) receptors. Furthermore, these results suggest a potential therapeutic role for cannabinoid agonists against cocaine- and other-convulsant-induced toxicities.

Protective effects of cannabinoid receptor ligands analogous to anandamide against cocaine toxicity.

The effects of the endogenous cannabinoid (CB) anandamide (AEA) and its analogs on cocaine (COCA)-induced toxic symptoms such as lethality, convulsive seizures and hyperactivity were examined in mice. In addition to AEA, the effects of the AEA analogs arachidonyl-2-chloroethylamide (ACEA), arachidonylcyclopropylamide (ACPA) and R-(+)-methanandamide (METH) were compared to the selective and strong CB1 agonist CP 55940 (CP). Intraperitoneal (i.p.) coadministrations of these drugs with COCA (75 mg/kg) demonstrated that AEA (10 and 15 mg/kg), ACEA (5 mg/kg), ACPA (5 mg/kg), METH (5, 10 and 15 mg/kg) and CP (2.5 and 5 mg/kg) all antagonized the COCA-induced lethality, and that ACEA (5 and 10 mg/kg), ACPA (5 and 10 mg/kg), METH (5, 10 and 15 mg/kg) and CP (1, 2.5 and 5 mg/kg) antagonized the COCA-induced convulsive seizures. When alterations in the COCA-induced toxic behaviors were also evaluated by an activity counting instrument, antidotal effects against the COCA-induced hyperactivity were also observed using the above doses. The effects against hyperactivity were stronger in the groups of mice cotreated with CP or ACEA than in the groups of mice cotreated with AEA or METH. However, the antidotal effects against the lethality and convulsive seizures were stronger in the METH-treated group than in the AEA-, ACEA- or ACPA-treated groups, although the selectivity of METH for brain CB1 receptors was lower than for ACEA or ACPA. The correlation with other brain receptors and/or peripheral CB receptors seemed to contribute to the strong antidotal effects of METH, which were not exceeded even by CP.

Comparison of effect of ethanol and anticonvulsants on cardiovascular drug-modified cocaine toxicity.

The anticonvulsant (AC drug)- or ethanol (EtOH)-modified effects of cardiovascular (CV) drugs against cocaine (COCA)-induced toxicity were examined in male ICR mice. Nontoxic doses of the CV drugs nimodipine (NIMO), prazosin (PRA), phentolamine (PHEN), propranolol (PRO), and enalapril (ENA) were used with or without the AC drugs diazepam (DZP), phenobarbital (PHB), phenytoin (PHY), and EtOH. Each CV drug combined with or without each AC drug was administered intraperitoneally (IP) 5 min before an IP injection of COCA 75 mg/kg. Of the CV drugs examined, PRA 5 mg/kg and PHEN 5 mg/kg protected against COCA-induced seizures, but only the alpha1-adrenergic blocking agent PRA protected against COCA-induced deaths. Of the AC drugs examined, DZP 5 mg/kg and PHB 50 mg/kg, as well as EtOH 3 g/kg, attenuated the severity of the COCA-induced seizures, but only PHB protected against COCA-induced deaths. The total mortality rate was significantly, often synergistically, decreased compared to the COCA-only group when the appropriate CV drugs were combined with the AC drugs: PRA 5 mg/kg in the EtOH-cotreated groups, PRA 5 mg/kg, PHEN 5 mg/kg or ENA 10 mg/kg in the DZP-cotreated groups, and NIMO 5 mg/kg, PRA 5 mg/kg, PHEN 5 mg/kg, or PRO 10 mg/kg in the PHB-cotreated groups. The decrease in the COCA concentration in the blood and/or brain was not always accompanied by an attenuation of the mortality rate. However, the attenuation of severe seizures by a single PRA, PHEN, DZP, or PHB cotreatment was accompanied by a decrease in the brain COCA concentration.

A new sensitive determination method of estradiol in plasma using peroxyoxalate ester chemiluminescence combined with an HPLC system.

A new sensitive determination method of estradiol in a plasma sample using peroxyoxalate ester chemiluminescence was developed. Estradiol, which was extracted by liquid-liquid extraction using ethyl acetate from plasma, was derivatized with dansyl-chloride (DNS-Cl) and separated by reverse-phase HPLC. The performance of four oxalates, bis(trichlorophenyl)oxalate (TCPO), bis(2,4-dinitrophenyl)oxalate (DNPO), bis(pentafluorophenyl)oxalate (PFPO), and bis[4-nitro-2-(3,6, 9-trioxadecyloxycarbonyl)phenyl] oxalate (TDPO), were evaluated using the static system, and DNPO was found to have the most sensitive and stable chemiluminescence at a H(2)O(2) concentration of 30 mM. HPLC-chemiluminescence system using DNPO for the determination of estradiol was established. The detection limit of dansylated-estradiol (DNS-E2) was 15 fmol (4 pg) in the standard solution and 44 fmol (12 pg) in the rat plasma sample at S/N = 3.

Relationship between cocaine-induced hepatotoxic neurobehavioral & biochemical changes in mice: the antidotal effects of buprenorphine.

Cocaine (COCA)-induced neurobehavioral symptoms, which can be observed simultaneously with exacerbation in biochemical markers, were evaluated in mice, and compared with the changes observed in a representative hepatic failure model induced by thioacetamide (TAA). The effects of pretreatment with buprenorphine (BUP) (0.25, 0.5 or 1 mg/kg i.p.), a mixed opioid agonist-antagonist and an antidote against fatal COCA toxicity, were also examined. At 5 min after the COCA administration (65 mg/kg i.p.), the liver ATP levels were attenuated, and an exacerbation of the CNS-stimulating effects of COCA could be characteristically observed for hepatotoxicity-related neurobehavioral symptoms (changes in alertness, interest, body tension, head movement and walking). At 24 h, the ALT (alanine aminotransferase) activity was elevated, and hepatotoxic attenuation was observed for all of the scores on the neurobehavioral symptoms; this was almost identical to the symptoms observed in the TAA-treated group of mice. Recovery was observed by 72 h for all of the morbid changes. The hepatotoxic biochemical changes and the sum score for all five neurobehavioral symptoms were significantly ameliorated by low doses (0.25 and 0.5 mg/kg) of BUP, both at 5 min and 24 h.

Stress-related behavioral alterations accompanying cocaine toxicity: the effects of mixed opioid drugs.

The present study evaluated the effects of mixed opioid drugs on the severity of cocaine (COCA) toxicity by examining stress-related behavioral alterations in mice. In order to ascertain the strength of the stress, the continuous observation of the behavioral symptoms in the cage and the forced swimming test (Porsolt test) were performed in the COCA (75 mg/kg, i.p.)-treated groups, with or without the mixed mu-kappa receptor-related opioid drugs, buprenorphine (BUP) and pentazocine (PEN). Using the high-sensitivity activity measuring instrument Supermex, both the spontaneous behaviors in the cage and the forced swimming behaviors in the water were assessed as activity counts. The behavioral alterations in the COCA-treated groups were compared with a group of mice given a 10 min immobilization stress (IM group). In the COCA-only group, a prolonged increase in the spontaneous behaviors accompanied by convulsive seizures was observed even in the surviving mice, unlike in the IM group. However, an acceleration of behavioral despair in the Porsolt test similar to that observed in the IM group was observed in the COCA group after the disappearance of the acute toxic symptoms (5 hours after the COCA treatment). Among the opioid-treated groups, the mortality rate was attenuated only in the COCA-BUP (0.25 mg/kg, i.p.) group. In the COCA-BUP group, a prolonged suppression of the morbid hyperactivity in the cage except for the convulsive seizures, and a normalization of the swimming behavior in the Porsolt test were observed in the survivors. On the other hand, in the COCA-PEN (5 mg/kg, i.p.) group, the swimming behavior in the Porsolt test was abnormally increased in addition to the prolonged morbid hyperactivity in the cage. Therefore, the COCA-induced stress-related behaviors were normalized in the group of mice treated with BUP, a group with a good prognosis.

Effects of ethanol and/or cardiovascular drugs on cocaine- and methamphetamine-induced fatal toxicities in mice.

The antidotal effects of antihypertensive cardiovascular (CV) drugs against cocaine (COCA)- and methamphetamine (MA)-induced fatal toxicities were examined in mice. Considering the previously-reported favorable interactions, the effects of CV drugs against combined COCA-ethanol (EtOH) or MA-EtOH toxicities were also evaluated. COCA (75 mg/kg) or MA (18 mg/kg) was administered 5 min after an injection of CV drugs, with or without EtOH (3 g/kg); all drugs were injected intraperitoneally. The CV drugs used were 10 mg/kg diltiazem (DIL), 5 mg/kg nimodipine (NIMO) and 5 mg/kg nitrendipine (NITRE) as calcium channel blockers, 5 mg/kg prazosin (PRA) and 5 mg/kg phentolamine (PHEN) as alpha-adrenergic blocking agents, 10 mg/kg propranolol (PRO) as a beta-adrenergic blocking agent, and 10 mg/kg enalapril (ENA) as an angiotensin converting-enzyme inhibitor. In both the COCA (n = 10) and MA (n = 6) groups, regardless of EtOH or CV drug cotreatment, the fatalities could be divided into the early and late deaths, depending on the survival times, the presence of a temporary recovery from acute toxic symptoms such as observable respiratory and locomotive symptoms, and the presence of the drugs (COCA or MA) in blood samples. The acute toxic symptoms included seizures in both the COCA and MA groups, but they were generally suppressed by EtOH regardless of the mortality rate. Some of the CV drugs, such as PRA and PHEN in the COCA groups and DIL, NIMO, NITRE, PRA and PHEN in the MA groups, also suppressed the seizures. The mortality rate was attenuated by PRA in the COCA groups, and by NIMO, NITRE, PRA and PHEN in the MA groups. In the groups cotreated with EtOH, which has been reported to exacerbate the COCA- and MA-induced cardiotoxicity, the frequency of late deaths was increased. Nevertheless, antidotal effects due to NIMO, NITRE, PRA and ENA in the COCA-EtOH groups, and NIMO, NITRE and PRA in the MA-EtOH groups were observed.

Effect of methamphetamine on male mice fertility.

The effect of methamphetamine (MAMP) on the ability of males to mate with females and to impregnate them was examined in 8-week-old ICR mice. Male mice that had been administered an intraperitoneal injection of MAMP (15 mg/kg, 7.5 mg/kg, or 3.75 mg/kg) or saline were housed with females 24 or 48 hours later. The vaginal plugs were checked, and the number of births was counted. The effect of MAMP on sperm motility and the serum testosterone (TS) concentration was also examined. Methamphetamine was observed to have harmful effects only at the highest dose level. In the mice housed 24 hours after the injection of 15 mg/kg MAMP, the increase in the cumulative number of vaginal plugs lagged, and the total number of vaginal plugs decreased significantly. A significant decrease was also observed in the total number of births. Methamphetamine, at a dose of 15 mg/kg, decreased sperm motility. The TS concentration decreased initially, then increased.

Role of cocaethylene in toxic symptoms due to repeated subcutaneous cocaine administration modified by oral doses of ethanol.

The present study investigated the toxicity of repeated subcutaneous cocaine administrations combined with oral doses of ethanol, and discussed the role of the toxic metabolite cocaethylene. Subcutaneous cocaine (70 mg/kg) was given to male ICR mice at 45 min after an oral administration of either ethanol (maximum 3 g/kg) (cocaine-ethanol group; n = 50) or saline control (cocaine group; n = 30), once per day, for up to 5 days. In the combined cocaine-ethanol group, the total frequency of death was significantly increased (86%) as compared to the cocaine group (40%). In both administration groups, regardless of the day of death, "late" deaths characterized by the late and unexpected onset of fatal symptoms could be differentiated from "early" deaths on the basis of the survival time after the last cocaine injection, the drug concentrations in the tissues at the time of death, and/or the observed physical disorders. In the combined cocaine-ethanol group, a late death group with survival times exceeding 12 hr and two early death groups could be differentiated, based on the presence or absence of cocaethylene and the different types of clinical symptoms. In the early death group in which cocaethylene could be detected, the volume of ethanol ingested was not significantly different from the late death group with large ethanol consumption and slow exacerbation of the respiratory and locomotive symptoms. Furthermore, the severity of the cocaine-induced seizures was also similarly decreased by ethanol. In the other early death group in which cocaethylene could not be detected, the volume of ethanol ingested was significantly lower than in the late death group, and seizures as severe as in the cocaine-only group were observed.

Effects of buprenorphine and Ro 15-4513 on delayed death and brain beta-endorphin levels in rats treated with cocaine or cocaine-ethanol.

The present study was aimed at elucidating the relationship between brain beta-endorphin, which was estimated by the immunofluorescence method, and fatal drug toxicities due to cocaine and combined cocaine-ethanol administration, including the late fatal toxicities clinically noted. beta-endorphin is an endogenous opioid peptide, and its secretion has been suggested to be influenced by physiological stresses. Furthermore, since protection against these fatal toxicities has been previously reported to be provided by buprenorphine (a ligand for opioid receptors) and Ro 15-4513 (a ligand for benzodiazepine receptors), this study also focused on the relationship between the effects of these two ligands and the changes in brain beta-endorphin immunoreactivity. In the fatal toxicity study, a toxic dose (75 mg/kg, i.p.) of cocaine combined with and without ethanol (3 g/kg, i.p.) was administered to the rats, with and without buprenorphine (0.25, 0.5, 1 mg/kg, i.p.) or Ro 15-4513 (5, 10, 15 mg/kg, i.p.). All of the deaths that occurred in these animals were divided into two groups: early deaths with early toxic symptoms in which the drugs were detected in the tissue samples, and late deaths with late toxic symptoms in which no drugs were detected in the samples. Without the administration of buprenorphine or Ro 15-4513, the frequency of late deaths was higher in the cocaine group as compared to the cocaine-ethanol group. The total mortality rate was effectively attenuated by treatment with 0.25 mg/kg buprenorphine or 10 mg/kg Ro 15-4513. Following treatment with 1 mg/kg buprenorphine or 15 mg/kg Ro 15-4513, the frequency of late deaths was significantly enhanced in the cocaine group. The brain and liver cocaethylene concentrations were also attenuated in those groups in which the total mortality rates were attenuated. In the brain beta-endorphin immunoreactivity study, the number of beta-endorphin immunoreactive nerve cells at the arcuate nucleus was counted at 3 minutes or 24 hours after the drug treatment. At 3 minutes after the drug treatment, the number of weakly immunoreactive cells with photographic light absorption values greater than 50% was enhanced in the groups in which the frequency of late deaths had been increased. In the cocaine-ethanol groups treated with buprenorphine or Ro 15-4513, this enhancement of weakly immunoreactive cells was observed when the total mortality rate was increased, regardless of the type of death. At 24 hours after the drug treatment (50 mg/kg cocaine), an enhancement of the weakly immunoreactive cells only was observed in all of the groups in which the occurrence of toxicities had been enhanced, regardless of the type of toxicity. Therefore, it can be concluded that the enhancement of total brain beta-endorphin immunoreactivity was closely correlated with the increase in the frequency of total fatal toxicities, and that the enhancement of weakly immunoreactive cells was closely correlated with the increase in the frequency of delayed fatal toxicities.

Brain beta-endorphin immunoreactivity as an index of cocaine and combined cocaine-ethanol toxicities.

The present study examines alterations in the cytoplasmic immunoreactivity of brain beta-endorphin, an endogenous opioid peptide regarded as the mediator of both euphoria and antinociceptive systems, in relation to toxicities due to cocaine and combined cocaine-ethanol. Beta-endorphin-immunoreactive cells were visualized and counted in adjacent sections from male rat brains at the level of the arcuate nucleus. In this region, cytoplasmic beta-endorphin immunoreactivity is prevalent. An intraperitoneal injection of cocaine (75 or 15 mg/kg) was given 15 min after an intraperitoneal injection of 3 g/kg ethanol or vehicle. With a fatally toxic dose (75 mg/kg) of cocaine, the number of neurons exhibiting cytoplasmic beta-endorphin immunoreactivity (immunoreactive nerve cells) was significantly increased immediately after the drug administration. Ethanol further enhanced the effects of both 15 and 75 mg/kg of cocaine. When the immunoreactivity was visually estimated by computer imaging analysis, lightly stained, weakly immunoreactive cells with photographic light absorption values greater than 50% were enhanced in the cocaine-ethanol groups compared to the cocaine only groups. Fatal toxicities were only observed in the groups treated with the high cocaine doses (75 mg/kg), with or without ethanol. In these groups, the number of strongly immunoreactive cells had increased significantly compared to the other groups. In the group treated with the high cocaine dose (75 mg/kg) plus ethanol, an increased frequency of late deaths that occurred over 1 h after the drug administration was observed, together with a decreased severity of cocaine-induced seizures and an early enhancement of weakly immunoreactive cells. Unlike the strongly immunoreactive cells, the weakly immunoreactive cells appeared to be continuously enhanced, based on an experiment examining beta-endorphin immunoreactivity at 24 h after an injection of 50 mg/kg cocaine.

[Suicidal hanging or simulated suicide? Once again a case of Kobue: a spectacular case in the history of Japanese legal medicine]. / Suizidales Erhängen oder vorgetäuschter Suizid? Noch einmal der Fall Kobue: einer der spektakulärsten Fälle in der Geschichte der japanischen Gerichtsmedizin.

The cause of death of a 45-year-old woman named Kobue Hiramatsu became an issue in a notable criminal trial called the Kobue-case. The woman and three young girls were found dead in Kobue's house at the end of June 1926. The bodies were decomposed. The three girls had been strangled, while Kobue was found suspended by a waist band tied to a lintel. An open noose had been arranged by winding the band twice around the lintel and tying the both ends. The ligature lay immediately under the chin. Her feet touched the tatami mat and between feet, there were a charcoal brazier and a cutting board. There were two abrasions, not parallel with each other, ont he front of her neck. One abrasion was under the ligature. The other was about 2 cm below the first and was accompanied by bruise. An expert diagnosed that the upper mark without the bruise was produced after death, while the lower abrsion was a ligature mark from strangulation, and that she was suspended for simulation of suicide after being strangled. A former lodger at her house was arrested, but he denied any guilt. The main issue at the trial was the nature of the lower mark and the mechanism by which the two marks were produced. The defendant was found innocent and acquitted based on the expert opinions that the lower mark was a hanging mark and the upper one was produced by the upward movement of the ligature when asphyxia-induced convulsion occurred during hanging. There was no unanimity on how the body weight affected the neck during hanging or what the posture of the body was when convulsion occurred. In the present paper, how Kobue hanged herself and what caused the ligature to move upward is discussed.

Effects of amphetamine on rat embryos developing in vitro.

Wistar rat embryos were explanted on Day 10.5 of gestation and exposed in vitro to amphetamine (AMP) at concentrations of 0.1, 0.4, 0.8, 1.2, or 1.6 mM for 24 h, and the direct dysmorphogenic effects of the drug on the embryos were examined by comparisons with a control group. The viability of the cultured embryos was not affected by the AMP treatment. The yolk sac diameter was reduced at AMP concentrations of 1.2 and 1.6 mM. The crown-rump length, the somite number, and the protein content of the embryos were decreased significantly at these two doses, as was the developmental score. The frequency of malformed embryos was increased significantly at the two highest concentrations. The malformations induced in treated embryos included microcephaly, neural tube defects, incomplete rotation of the body axis, and tortuous spinal cord. Abnormal histologic changes, such as derangement and necrosis of the neuroepithelial tissue, were observed in the embryos exposed to the two highest concentrations of the drug. The observed embryotoxic effects appeared to depend on the AMP concentration. Our results demonstrated the direct embryotoxic effects of AMP on rats. The direct dysmorphogenic effect of AMP might be weaker than that of methamphetamine.