Deaths Associated With Brotizolam Poisoning From a Single Drug Overdose: Four Reported Cases.

Brotizolam is a short-acting hypnotic in the benzodiazepine family, and fatal poisonings by an overdose of brotizolam are rare. This report describes 4 cases of deaths associated with brotizolam poisoning from a single drug overdose. The ages ranged from 51 to 90 years, and the postmortem interval between death and tissue sampling was 1.5 to 2.5 days. These deaths were classified as 1 homicide and 3 suicides. The concentration of the brotizolam ranged from 0.05 to 0.21 mg/L in the blood samples. Ethanol, which could cause mild alcohol intoxication, was detected in the blood samples from 2 cases. Postmortem examinations did not find any significant pathologic conditions, except for a case of death by drowning in a bathtub due to brotizolam poisoning. These 4 cases suggest that a brotizolam overdose should not be underestimated in terms of its fatal effects, particularly when situations involve alcohol intoxication, injury subsequent to the poisoning, or underlying medical conditions including aging.

Bath-related deaths: Preventive strategies and suggestions for general physicians.

Bath-related deaths occur frequently in Japan, particularly in the elderly population; however, this fact is not sufficiently well known by the public. The advent of a super-aging society will expose general physicians to more cases of fatal and nonfatal bath-related accidents. As many of the victims have one or more lifestyle-related diseases, general physicians will play a more important role in preventing these fatalities in the future. In addition, general physicians may have to perform postmortem examinations in these cases. This review article addresses the latest studies on bath-related deaths from various medical departments, including forensic medicine, emergency medicine, and physiology. We also discuss preventive strategies based on the assumed mechanisms, and because Japan does not have a well-developed system of medical examiners, we also provide suggestions for physicians who will encounter bath-related deaths in the future.

Characteristics of cancer patients who died by suicide in the Tokyo metropolitan area.

The purpose of this study was to investigate the sociodemographic characteristics of cancer patients who died by suicide in comparison with cancer-free cases. Suicide data from the Tokyo Medical Examiner's Office from 2009 to 2013 were extracted retrospectively. A total of 503 (5.1%) out of 9841 people who committed suicide had cancer; age ranged from 26 to 97 years. The cancer patients were significantly older than the cancer-free cases. There were significantly more cancer patients with cohabiters than cancer-free cases with cohabiters. Only half of young to middle-aged subjects had a job in both groups. There were significantly more cancer patients who lived on pensions and welfare assistance, and less cancer patients who drink or smoke than those without cancer. Given the high incidence of suicide in elderly cancer patients, healthcare professionals should pay attention for risk even in cancer patients who have cohabiters, benefit from a pension, and do not drink or smoke.

[Identification of Psychotropic Drugs Attributed to Fatal Overdose--A Case-control Study by Data from the Tokyo Medical Examiner's Office and Prescriptions].

Drug overdose is a serious public health issue and fatal cases have been reported from various fields of medicine. This case-control analysis assessed the comparison between fatal overdose cases in the special wards of Tokyo Metropolitan area and prescribed psychotropic drugs in Tokyo in 2009-2010. It was suggested that the prescribed drugs serve as a direct cause of death in overdose cases. Furthermore, pentobarbital calcium, chlorpromazine-promethazine-phenobarbital, levomepromazine and flunitrazepam were identified as drugs with a high risk of fatal overdose. It is encouraged to prudently verify the intended application and usage of such psychotropic drugs in each case upon their prescription. This is the first study in Japan to identify psychotropic drugs with a high risk of fatal overdose by case-control study.

Postmortem Computed Tomography Findings Associated with Sudden Death in Alcoholics.

Forensic pathologists.frequently encounter sudden natural.death of alcoholic in which fatty liver is the only pathological finding detected at autopsy, however, characteristics of postmortem CT (PMCT) of sudden death of alcoholic have not been reported so far. In this study, we investigated radiographic measurements of PMCT of the cases diagnosed as sudden death of alcoholic (ALC), and compared them with those of other causes of death (IHD; ischemic heart disease, SV; starvation), with reference to autopsy findings. The cardio-thoracic ratio, the cross-sectional area of the inferior vena cava and the radio density of the lungs of ALC on PMCT were significantly lower than those of IHD, and tended to be midway between IHD and SV. These findings were in parallel with the total heart blood volume at autopsy and the extent of lung edema on histopathological findings. In addition, the radiodensity of the liver of ALC was significantly lower than the other groups, which was in parallel with the extent of fatty deposit in the hepatocytes on histopathology. More than 60% of ALC cases showed BMI < 18.0, and acetone was detected in blood in 87.5% of ALC cases. The lower radiodensity of the liver, and lack of signs suggestive of significant pulmonary edema and congestion in the great vessels, on PMCT, are considered to mirror terminal pathophysiology of sudden death of alcoholic, such as severe fatty liver- disease and metabolic disturbance (e.g., concomitant volume depletion with alcoholic ketoacidosis). Utilization of these findings on PMCT may serve to discern sudden death of alcoholic from other causes of death, in combination with detailed scene investigation, pathological, toxicological and biochemical analysis.

Epidemiology of Alcohol-related Death while Bathing in a Bathtub.

OBJECTIVES: Alcohol consumption before bathing is listed as a risk factor for sudden death in a bathtub, which occurs relatively frequently in Japan. This study aimed to clarify the epidemiology of alcohol-related deaths in bathtubs. SUBJECTS: Among all autopsy cases that were performed at the Tokyo Medical Examiner's Office between 2009 and 2010 (N = 5635), 357 cases of death in a bathtub were evaluated. Data regarding age, sex, blood ethanol level, manner and. cause .of death, alcohol consumption, and alcohol-related gastrointestinal diseases were extracted. The cases were divided into three groups according to their blood ethanol levels (no blood ethanol, low ethanol, and high ethanol), and their data were compared. RESULTS: A large majority of the cases in all groups involved persons who were 50-89 years old. The mean age of the high ethanol group (61.7 years) was significantly lower than.that of the control group (71.1 years; P < 0.01). In addition, the proportion of men was significantly higher in the low and high ethanol groups (70.1% and 75.5%, respectively), compared to that in the control group (55.9%; P < 0.05). Daily alcohol consumption was significantly more common in the low and high ethanol groups (49.5% and 87.8%, respectively), compared to that in the control group (23.2%; P < 0.01). Furthermore, alcohol-related gastrointestinal diseases were more common in the low and high ethanol groups (26.8% and 63.3%, respectively), compared to that in the control group (4.3%; P < 0.01). CONCLUSIONS: Preventive strategies for reducing alcohol-related deaths in bathtubs should target male habitual drinkers (middle-aged to seniors), especially patients who have been diagnosed with alcohol-related diseases.

Characteristics of sudden bath-related death investigated by medical examiners in Tokyo, Japan.

BACKGROUND: Sudden bath-related deaths occur frequently in Japan, particularly among elderly people. However, the precise mechanism of bath-related death remains uncertain, and effective prevention strategies have not been established. METHODS: Cases of bath-related deaths (n = 3289) were selected from all cases handled by the Tokyo Medical Examiner's Office from 2009 to 2011 (N = 41 336). The ages and occurrence dates were examined, and major autopsy findings, including toxicological analysis, were evaluated for the autopsied cases (n = 550). RESULTS: Most cases occurred in individuals older than 60 years of age during winter. Analysis of autopsy findings revealed water inhalation signs in many cases (n = 435, 79.1%). Circulatory system diseases constituted more than half of the pathological findings regarding factors that may have contributed significantly to death (n = 300, 54.5%), and cardiac lesions were the most common pathological finding (n = 250, 45.5%). However, approximately one-third of the cases exhibited no remarkable pathological findings (n = 198, 36.0%). A quarter of all cases involved blood ethanol levels that exceeded 0.5 mg/mL (n = 140). CONCLUSIONS: The results suggested that drowning plays an important role in the final process of bath-related death. Circulatory system diseases may be the primary underlying pathology; however, there were variations in the medical histories and pathologies of cases of bath-related death. From a preventive perspective, family members should pay attention to elderly people with circulatory system diseases during bathing, particularly in winter. Additionally, the notion that ill or inebriated individuals should not take baths should be reinforced.

Sudden death of a middle aged woman with a series of undiagnosed gynaecologic diseases.

Gynaecologic diseases unrelated to pregnancy are not generally associated with sudden death, which limits the number of case reports published in the field of forensic medicine. Presented in this paper is a fatal case in a middle aged woman with an early stage endometrial cancer and a series of gynaecologic diseases, in whom such typical features of sudden death were not applicable. Forensic autopsy revealed the hypoplasia of left circumflex coronary artery, Stage 1B endometrial cancer, endometriosis, polycystic ovary syndrome (PCOS) and micro pituitary adenoma, whereas histochemical analyses confirmed hyperprolactinemia and hyperestradiolemia. It was considered that the hypoplasia of coronary artery, chronic anaemia and electrolyte imbalance due to endometrial cancer all collaborated to induce acute cardiac failure. The association between prolactinoma, PCOS and endometrial cancer was also suggested, though they are rarely observed synchronously. It was speculated that the deceased had been anaemic for a substantial period of time and lacked clear subjective symptoms, which made the antemortem diagnosis of her underlying diseases difficult. Forensic pathologists must always consider the possibility of gynaecologic diseases taking significant part in a fatal cause of reproductive-aged women.

Child deaths from injury in the special wards of Tokyo, Japan (2006-2010): a descriptive study.

BACKGROUND: There has been increasing interest in the formal review of child deaths in Japan. In this study we examined the causes and scene information regarding child deaths from injury in Tokyo, the capital of Japan, as preparation for implementation of a full-scale review of child deaths. METHODS: Documents on deaths from injury (excluding homicides) investigated by the Tokyo Medical Examiner's Office during the period from 2006 through 2010 were reviewed. Deaths of children younger than 18 years (N = 217) were selected as the study sample. We examined the cause of and information on the death and were particularly interested in whether a case had preventable factors. RESULTS: Overall, 67% of the cases were deaths from unintentional injury. The main cause of death among children younger than 1 year was asphyxia, and the proportions of deaths from traffic accidents were higher in older age groups. Thirty percent of deaths from injury were due to suicide, and all cases of suicide were among children older than 10 years. Although analysis of preventable factors was difficult in some cases, owing to limited information on the death scene, 87% of deaths from unintentional injury, excluding those involving traffic accidents, had preventable factors. CONCLUSIONS: Most unintentional child deaths from injury appear to be preventable. Development of a system to collect detailed information on the scene at the time of death will help decrease child deaths in Japan.

Fatal broncho-pneumonia of an infant with arthrogryposis multiplex congenita (AMC).

Arthrogryposis multiplex congenita (AMC) is a heterogenous group of disorders characterized by multiple joint contractures with an estimated frequency of 1 in 3000-5100 livebirths. The authors present a case of an 11-month-old infant with AMC who died due to severe pneumonia. The deceased had no significant anomaly except for the stated orthpaediatric deformities, and the long-term outcome was expected to be positive. The only remarkable past medical history was respiratory syncytial virus (RS) infection at 6-months old which had taken a few days for a complete recovery. Onset of high fever was observed 3 days prior to her death and she was found in a state of cardiopulmonary arrest in bed by her father in an early morning. Forensic autopsy confirmed the pathohistological diagnosis of severe broncho-pneumonia. The presence of scoliosis and funnel chest was considered to be attributable to the disability to turn herself over and excrete sputum sufficiently, leading to a fatal respiratory complication. This paper stresses the possibility of distal arthrogryposis type of AMC becoming contributory to death despite the initial optimistic prognosis, as well as the importance of postmortem investigation in unexpected fatal cases.

Suicide of physicians in the special wards of Tokyo Metropolitan area.

Numerous studies on physician suicide in various countries have been reported but no data from Japan on the issue can be found to date. In this study, physician suicides in the special wards of Tokyo Metropolitan area in 1996-2010 were investigated retrospectively. A total of 87 cases were enrolled. The results suggested that physician suicide has been linked to pre-existing psychiatric illnesses and occupational problems, and that psychiatrists have a relatively higher suicide risk compared to those majoring in other specialities of medicine. A distinctive feature was that 19 cases had used either drugs or devices which were accessible due to their profession some time during the process of committing suicide. Another notable feature was that 4 out of 5 anaesthesiologists enrolled in the study had chosen poisoning for their suicide method, with the drugs frequently used in their speciality. The findings advocate strongly for efficient suicide prevention measures for physicians including an early detection and treatment of psychiatric illnesses, as well as an urgent need for a more effective pharmacy management in applicable institutions together with the implementation of self discipline on each physician. This is the first broad academic study on physician suicide in Japan.

Acute fatal poisoning with Tolfenpyrad.

The authors present a fatal case of poisoning with Tolfenpyrad (TFP), a pesticide first approved in Japan in 2002. A man in his fifties was found dead in the supine position at his son's home and the small towel with a smell of naphthalene was found nearby. Forensic autopsy was unremarkable, except for a very small amount of light pink fluid in the stomach, with naphthalene odour. The toxicological analyses revealed the presence of TFP and its major metabolite PTCA (4-[4-[(4-chloro-3-ethyl-1-methylpyrazol-5-yl)carbonylaminomethyl]phenoxy]benzoic acid), together with naphthalene and methyl naphthalenes in the post-mortem sample, with liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) respectively. The plasma concentrations of each substance were quantified as 1.97 µg/ml (TFP), 2.88 µg/ml (PTCA), 1.70 µg/ml (naphthalene), 0.67 µg/ml (1-methyl naphthalene) and 1.44 µg/ml (2-methyl naphthalene). According to these results together with autopsy findings, the cause of his death was determined to be acute Tolfenpyrad poisoning. This is the first case report of fatal poisoning attributable to an intake of TFP product.

An autopsy case of a homeless person with unilateral lower extremity edema.

We present an autopsy case of a homeless person showing remarkable unilateral lower extremity edema, which was strongly associated with the cause of death. A 55-year-old homeless man without any past medical history was found dead in a flophouse. External examination showed evidence of malnourishment and remarkable swelling of the right, lower extremity. Putrefactive discoloration in the same area was evident at the time of autopsy (approximately 30h post-mortem). The autopsy revealed focal pneumonia in the right lower lobe, dehydration and chronic pancreatitis. Dissection of the edematous extremity revealed massive abscess formation in the subcutaneous tissue and superficial fascia around the right knee joint. Histopathological findings were compatible with necrotizing fasciitis and blood chemistry results showed an elevation of HbA1c (6.3%). The cause of death is considered to be necrotizing fasciitis and secondary pneumonia/dehydration. This case suggests that necrotizing fasciitis should be differentiated during postmortem diagnosis, especially in cases showing lower extremity edema with early putrefactive changes. In addition, forensic pathologists should closely examine a lower extremity of such cases to detect a true cause of death, even if other pathological findings which can be a cause of death, such as pneumonia and dehydration, are observed in major internal organs.

Fatal amniotic fluid embolism with typical pathohistological, histochemical and clinical features.

Despite the decrease in maternal mortality rate, amniotic fluid embolism (AFE) is still one of the most feared complications of pregnancy due to the high rate of mortality in Japan. The authors present a fatal case of a healthy 39-year-old woman who died during delivery after a normal 40-week second pregnancy. Shortly after the arrival at hospital, an abrupt drop of foetal heart rate was observed, followed by deterioration of consciousness and cardiac arrest of the patient. Prompt cardiopulmonary resuscitation (CPR) was performed but the patient died about an hour and a half after her arrival at hospital. Forensic autopsy confirmed the pathohistological diagnosis of amniotic fluid embolism supported by histochemical analysis results and excluded other possible causes of death. This paper stresses the fundamental importance of autopsy in an unexpected maternal death in conjunction with the significance of data accumulation on maternal death.

Medicolegal death of homeless persons in Tokyo Metropolis over 12 years (1999-2010).

BACKGROUND: Recently, the number of homeless persons in Japan has steadily decreased. However, it is not certain whether unexpected death of the homeless have actually decreased in proportion to decrease in total number of cases. METHODS: The documentation of medicolegal deaths among homeless persons handled in the Tokyo Medical Examiner's Office during 1999-2010 were reviewed, and we compared the number and manner/cause of death between cases occurring before 2004 and those occurring after 2004. In addition, we compared manner/cause of death between homeless and non-homeless persons. RESULTS: The number of medicolegal deaths of homeless persons remained almost the same during the study period in spite of a marked decrease in the total number of homeless persons after 2004. Age distribution shifted to older after 2004, and a higher proportion of the deceased had longer postmortem periods after 2004. Comparison between the manners/causes of death of the cases occurring before 2004 and those occurring after 2004 showed little difference. Disease constituted about 70% of all cases, and causes of death from disease were more various than those of non-homeless persons. Certain specific patterns included a higher proportion of death from circulatory disease in elderly homeless persons and a higher proportion of death from alcohol-related digestive disease and tuberculosis among younger homeless persons. Regarding accidental death, hypothermia was a leading cause of death irrespective of age group. CONCLUSION: Aging and isolation among homeless persons might contribute to an unchanged number of medicolegal death of them. In addition to measures to address frequent causes of death in each age group, better intervention for isolated homeless persons might be a key factor to prevent unexpected deaths of homeless persons in the future.

Analysis of tolfenpyrad and its metabolites in plasma in a tolfenpyrad poisoning case.

Tolfenpyrad (TFP) is a pesticide that was first approved in 2002 in Japan under the trade name of Hachi-hachi. Analyses of TFP and its major metabolite, 4-[4-[(4-chloro-3-ethyl-1-methylpyrazol-5-yl)carbonylaminomethyl]phenoxy]benzoic acid (PTCA), in plasma obtained from a cadaver suspected to have died of TFP poisoning, were conducted by liquid chromatography-mass spectrometry. The existence of TFP and PTCA was confirmed by scan mode and quantitative analysis was performed by selected ion monitoring mode. Calibration curves showed good linearity over the range of 0.1-4 and 0.25-4 µg/mL, and concentrations were estimated to be 1.97 ± 0.02 and 2.88 ± 0.04 µg/mL for TFP and PTCA, respectively. The plasma extract was further examined to find other metabolites using quadrupole time-of-flight MS, and the results revealed three more metabolites, which were suggested to be hydroxy-TFP, dehydro-TFP and hydroxy-PTCA. Plausible metabolic pathways of TFP in humans are: (i) oxidation of the methyl group on the benzene ring, and (ii) hydroxylation followed by dehydration at the ethyl group on the pyrazole ring.

An autopsy case of misdiagnosis based on postmortem computed tomography findings.

A middle-aged man was found lying beside his bicycle on an early winter morning. The cause of death was diagnosed by clinicians as traumatic intracerebral hemorrhage and cerebral contusion with frontal bone fracture based on the findings of Computed Tomography (CT) of the head. However, forensic autopsy revealed that there were no evidences of intracerebral hemorrhage and left frontal bone fracture but the defect of golf ball size on the frontal lobe which was considered to be a complication from the old cerebral contusion and old bone fracture. The bleeding and pooling blood from subarachnoid hemorrhage (SAH) to the frontal lobe defect had the appearance of an intracerebral hemorrhage. Disruption of left renal artery was found and the cause of death was diagnosed as massive hemorrhage due to this rupture. Although postmortem CT is a useful tool for obtaining information on the body prior to conducting an autopsy, it should be used with extreme caution.

A simple and sensitive method for the determination of propofol in human solid tissues by gas chromatography-mass spectrometry.

Propofol is a widely used intravenous agent for induction and maintenance of anesthesia and for sedation in intensive care patients, but it is also associated with abuse and dependency. A simple and sensitive method for the determination of propofol in human whole blood, brain, liver, and adipose tissue by gas chromatography-mass spectrometry using selected-ion monitoring mode is described. Propofol was extracted from 0.2-mL or 0.2-g sample size by a single-step basic extraction procedure using 100 microL heptane with thymol (50 ng) as an internal standard. The calibration curves of the specimens were linear in the concentration range of 10-5000 ng/mL or ng/g, and the limit of detection was 2.5 ng/mL in blood, 5.0 ng/g in brain and liver, and 10 ng/g in adipose tissue. Absolute recovery of propofol was determined in three samples and averaged over 95% for blood and brain, 66% for liver, and 51% for adipose tissue. Within-day and between-day precision was measured in five samples each at 50 and 500 ng/mL or ng/g in all specimens and was determined to be less than 10%. The developed propofol method was applied to a forensic autopsy case where a suspected propofol misinjection occurred eight days prior to death, and the tissue analysis was vital to the case.

A silent allele in the locus D19S433 contained within the AmpFlSTR Identifiler PCR Amplification Kit.

We present two cases where a single locus mismatch was found in the locus D19S433 using the AmpFlSTR Identifiler PCR Amplification Kit (Applied Biosystems) (Identifiler Kit) during paternity and maternity tests. This mismatch differed from the mismatch pattern where there is usually a one repeat difference. We designed forward and reverse primers so that they were positioned further away from the primer set contained in the Identifiler Kit. The results showed the existence of a silent allele 13 in both families, due to a point mutation that changed guanine to adenine at 32 nucleotides downstream from the 3' end of the AAGG repeat sequences in all four members. A single locus mismatch due to a silent allele may occur in any locus using any kit. Accordingly, we should pay attention to this silent allele when carrying out human identification and parentage analysis.