Microdialysis perfusion of COA-Cl enhances dopamine metabolism in the dorsal striatum of freely moving mice.

We performed a microdialysis study to examine the effects of local perfusion of COA­Cl on the extracellular levels of dopamine (DA) and its metabolites in the dorsal striatum of mice in vivo. The mice were perfused with Ringer's solution (control) and COA­Cl (0.05, 0.1, or 0.5 mM) into the dorsal striatum. Dialysate samples were collected every 30 min and then analyzed using high­performance liquid chromatography coupled with an electrochemical detector. We found that local perfusion of COA­Cl (0.1 or 0.5 mM) into the dorsal striatum of living mice produced a significant and dose­dependent increase in extracellular levels of DA, 3­methoxytyramine (3­MT), and homovanillic acid (HVA), where only 0.5 mM COA­Cl increased dihydroxyphenylacetic acid (DOPAC) levels. However, 0.05 mM of COA­Cl did not significantly affect either DA levels or its metabolites. Then, we administered the monoamine oxidase (MAO) inhibitor clorgyline alone or in combination with COA­Cl (0.1 mM) to test whether COA­Cl­induced increases in DOPAC and HVA are mediated by increased MAO activity. Clorgyline alone increased 3­MT levels and decreased DOPAC and HVA levels but not DA levels. When combined with COA­Cl, clorgyline increased 3­MT levels and reversed the decrease in DOPAC and HVA levels caused by clorgyline. The increase in DA metabolism induced by COA­Cl suggests that some DA was further metabolized into DOPAC, 3­MT, and HVA. This indicates that COA­Cl plays a role in DA metabolism via increased DA release and/or activation of MAO, offering new insights into the effects of COA­Cl on DA metabolism in the brain.

An autopsy case of intoxication caused by drug interaction with multiple psychotropic drugs, fluvoxamine, levomepromazine, and trihexyphenidyl.

A case of death due to combined use of multiple drugs is reported, and the pharmacokinetic interactions are discussed. A woman in her thirties was found dead in her home. A medico-legal autopsy found no findings suggestive of injury or natural disease. Toxicological analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS) identified a toxic level of fluvoxamine (0.947 µg/mL), and concentrations greater than the therapeutic levels of levomepromazine (0.238 µg/mL) and trihexyphenidyl (0.225 µg/mL) were present, while bromazepam, haloperidol, sulpiride, and 7-aminoflunitrazepam were within or below their therapeutic ranges. Fluvoxamine is mainly metabolized by cytochrome P450 2D6 (CYP2D6), and levomepromazine is a potent CYP2D6 inhibitor. A high concentration of levomepromazine may increase the blood fluvoxamine level. Since the combined use of levomepromazine and fluvoxamine induces seizures, it may have been involved in causing the subject's death. In addition, combined use of trihexyphenidyl may potentiate anticholinergic effects of fluvoxamine overdose, including convulsions and coma. It was concluded that the cause of the subject's death was the interaction of multiple drugs.

Active use of local exercise facilities can improve physical performance of community-dwelling older adults.

[Purpose] In this study, we investigated the effects of local exercise facility use on physical function of Japanese community-dwelling older adults. [Participants and Methods] We analyzed data obtained from a cohort project initiated in 1991. The study included approximately 4,800 individuals from suburban areas of central Japan; we investigated 322 older individuals residing in Municipality A, who underwent physical fitness assessments in 2018 and 2019. We recorded participants' exercise facility use frequency and physical performance, based on handgrip strength, open-eye single-leg standing, timed up-and-go, and walking speed tests. [Results] Baseline values in the open-eye single-leg standing test were significantly higher in the no-use than in the low- and high-use groups. Follow-up assessments revealed that grip strength was significantly higher in the high-use than in the no- and low-use groups. [Conclusion] Active use of exercise facilities was positively correlated with maintenance and improvement in physical fitness among participants, which highlights the benefits of easily accessible exercise facilities in maintaining long-term physical function. Future studies should focus on functions that extend beyond physical fitness to develop effective support programs that address the evolving health needs of the aging population.

Senility deaths in aged societies: The case of Japan.

Senility is now the third largest cause of death in Japan, comprising 11.4% of the total number of deaths in 2022. Although senility deaths were common in the period before the Second World War, they declined sharply from 1950 to 2000 and then increased up to the present. The recent increase is more than what we could expect from an increasing number of very old persons or the increasing number of deaths at facilities. The senility death description in the death certificate is becoming poorer, with 93.8% of them only with a single entry of "senility". If other diseases are mentioned, those are again vague diseases or conditions. Senility, dementia and Alzheimer's disease, sequelae of cerebrovascular disease, and heart failure are the largest causes of death in which senility is mentioned in the death certificate. The period from senility onset to death is often described within a few months, but it varies. In some cases, the deceased's age was written out of a conviction that the ageing process starts from birth. As senility is perceived differently among the certifying doctors, a standardised protocol to certify the senility death is needed. On the other hand, senility death is the preferred cause of death and many people do not wish to receive invasive medical examinations before dying peacefully. Together with other causes of death related to frailty, there would be a need to capture senility as a proper cause of death, not just as a garbage code, in the aged, low-mortality population.

Kerosene condenses in the trachea following inhalation.

PURPOSE: We have investigated the absorption dynamics of petroleum fuel components from the analytical results of autopsy samples. METHODS: Post-mortem samples of the severely burned case, including femoral blood, intratracheal contents (mucus) and intratracheal gas-phase samples were collected, and analysed by gas chromatography-mass spectrometer with head-space solid-phase microextraction. RESULTS: The composition of flammable substances in the tracheal gas phase differed slightly from that in mucus. CONCLUSION: High-boiling point components are retained in the trachea, whereas relatively lower-boiling point components are detected predominantly in the tracheal gas phase and blood.

An autopsy case of BRONTM overdose with multiple drug ingestion.

A man in his forties was found dead in his friend's home, with moderate putrefaction. Quantitative toxicological analysis showed that concentrations of caffeine, chlorpheniramine, dihydrocodeine, and methylephedrine were 183.3 µg/mL, 0.533 µg/mL, 2.469 µg/mL and 8.336 µg/mL, respectively. Ephedrine, amitriptyline, nortriptyline, etizolam, fluvoxamine and 7-aminoflunitrazepam were detected in an aortic blood sample. Caffeine, chlorpheniramine, dihydrocodeine and methylephedrine are the main components of BRONTM, an over-the-counter antitussive sold in Japan. Those concentrations in blood were within fatal ranges. Caffeine is classified as a methylxanthine and is mainly metabolized by cytochrome P450 (CYP)1A2. Fluvoxamine is a potent CYP1A2 inhibitor. Blood fluvoxamine concentration was within the therapeutic range, but would have increased blood caffeine level by the inhibition of caffeine metabolism. The conclusion was that his death was caused by BRONTM overdose. Inhibition of caffeine metabolism may increase blood caffeine concentrations. This suggests that more attention should be paid to potential interactions between multiple drugs.

Case report: Fatal poisoning caused by additive effects of two barbiturates.

A case of fatal poisoning involving multiple psychotropic drugs is presented. Quantitative toxicological analysis showed femoral blood concentrations of pentobarbital, phenobarbital, duloxetine, acetaminophen and tramadol were 10.39, 22.57, 0.22, 0.61 and 0.22 µg/ml, respectively. We concluded that the death was due to the additive effects of two barbiturates. As both pentobarbital and phenobarbital act on gamma-aminobutyric acid (GABA) receptors, central nervous system activity was suppressed, causing respiratory depression. Additive pharmacological effects should be considered in cases of massive ingestion of multiple drugs.

Case report: An autopsy case of pilsicainide poisoning.

We present a fatal case of pilsicainide poisoning. Quantitative toxicological analysis revealed that the concentrations of pilsicainide in femoral blood and urine samples were 17.5 µg/mL and 136.9 µg/mL, respectively. No morphological changes due to poisoning were observed. Based on the autopsy findings, results of the toxicological examination, and investigation by the authorities, we concluded that the cause of death was due to pilsicainide poisoning.

COA-Cl Evokes Protective Responses Against H2O2-and 6-OHDA-Induced Toxic Injury in PC12 Cells.

COA-Cl, a novel adenosine-like nucleic acid analog, has recently been shown to exert neuroprotective effects and to increase dopamine levels both in vivo and in vitro. Therefore, we hypothesized that COA-Cl could protect dopaminergic neurons against toxic insults. Thus, the present study aimed to investigate the protective effects of COA-Cl against hydrogen peroxide (H2O2)- and 6-hydroxydopamine (6-OHDA)-induced toxicity in PC12 cells and to elucidate the possible mechanisms. PC12 cells were incubated with COA-Cl (100 µM) with or without H2O2 or 6-OHDA (200 µM) for 24 h. Treatment with COA-Cl attenuated the decrease in cell viability, SOD activity and the Bcl-2/Bax ratio caused by H2O2. In addition, COA-Cl attenuated the increase in LDH release, ROS production, caspase-3 activity, and apoptosis induced by H2O2. Further, COA-Cl enhanced the protection of PC12 cells against the toxicity caused by 6-OHDA, as evidenced by an increase in cell viability and the Bcl-2/Bax ratio, and a decrease in LDH release. Our results are the first to demonstrate that COA-Cl potentially protects PC12 cells against toxicity induced by H2O2 and 6-OHDA, implying that COA-Cl could be a promising neuroprotective agent for the treatment of Parkinson's disease.

Low Friction of Graphene Oxide Aggregates in Lubricant Oil between a Steel Ball and Glass Disk under Boundary Lubrication.

Previously, isolated nanocarbons in lubricating oils were considered essential for good lubrication. However, we observed that graphene oxide (GO) aggregates in lubricating oil have lower frictional properties than isolated dispersed GO. The GO was dispersed in polyα-olefin (PAO) using alkylamine at different ratios of GO and alkylamine, or it was heated at different temperatures to synthesize high- and low-dispersible GO-dispersed PAO. X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), and Raman spectroscopy measurements showed that low-dispersible modified GOs retained many of the original GO chemical and structural features. Macrotribological tests between a steel ball and glass disk in GO-dispersed oil were conducted with a load of 5 N under boundary lubrication. The friction interface was observed in situ using an optical microscope. In the low-dispersible GO-dispersed PAO, many GO aggregates were observed through optical microscopy. Surprisingly, the friction coefficients decreased when the GO aggregates entered the friction interface and covered the contact area. The low-dispersible GO-dispersed PAO using alkylamine had the lowest friction coefficient of 0.05, as the GO aggregates covered the contact area. From microtribological tests with a load of 0.8 mN as well, it is assumed that the low friction of the GO aggregates originates due to the sliding between the weakest shear layers in the aligned multiple GO layers.

Finger friction with leather and seam of new and used softballs with and without rosin powder.

The purpose of this study was to investigate the friction of finger against polyurethane-coated leather and seam surfaces of new and used softballs. The effects of seam alignment (across and along the seam) and chalk/rosin powder application were also investigated. The coefficient of static friction (COF) was evaluated on 14 college female softball players who rubbed the pad of their index finger on a test surface fixed on a biaxial force plate. The mean COF of the new leather was 1.04, and those of the seam were 1.16 for the across condition, and 1.07 for the along condition. The leather-seam difference in COF was significant. The used ball's leather and seam had lower COF than those of the new ball. The seam alignment difference did not reach the level of significance. For both new and used balls, the application of chalk/rosin powder to the finger reduced COF, and the reduction was greater on the leather than on the seam. It was concluded that the outer cover of softballs, and especially the seam portions, is equipped with reasonably high friction under natural finger condition. The friction is reduced in used balls and with the use of chalk/rosin powder.

Biodiversity risk assessment of genetically modified Chaetoceros gracilis for outdoor cultivation.

A genetically modified (GM) strain of the diatom Chaetoceros gracilis expressing the phosphite dehydrogenase gene (ptxD), which is a useful gene both for the biological containment and the avoidance of microbial contamination, was characterized to estimate the risk against the biodiversity by laboratory experiments. GM strain could grow in the medium containing phosphite as a sole source of phosphorus, while its general characteristics such as growth, salt tolerance, heat and dehydration resistance in the normal phosphate-containing medium were equivalent to those of wild type (WT) strain. The increase in potential toxicity of GM strain against plant, crustacean, fish and mammal was also disproved. The dispersal ability of WT strain cultured in an outdoor raceway pond was investigated for 28 days by detecting the psb31 gene in vessels, settled at variable distances (between 5 and 60 m) from the pond. The diatom was detected only in one vessel placed 5 m apart. To estimate the influence on the environment, WT and GM strains were inoculated into freshwater, seawater and soil. The influence on the microbiome in those samples was assessed by 16S rRNA gene amplicon sequencing, in addition to the analysis of the survivability of those strains in the freshwater and the seawater. The results indicated that the effect to the microbiome and the survivability were comparable between WT and GM strains. All results showed that the introduction of the ptxD gene into the diatom had a low risk on biodiversity.

Ethanol concentration induces production of 3,4-dihydroxyphenylacetic acid and homovanillic acid in mouse brain through activation of monoamine oxidase pathway.

First, we aimed to investigate ex vivo the effects of ethanol (EtOH) on levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their metabolites in the frontal cortex, hippocampus, and striatum of Aldh2-knockout (Aldh2-KO) and wild-type (WT) mice. Animals were treated intraperitoneally with saline (control) or EtOH (1.0, 2.0, or 3.0 g/kg). Brain samples were collected 60 and 120 min after EtOH injection, and monoamines and their metabolites were measured by HPLC-ECD. We found in both WT and Aldh2-KO mice that 3.0 g/kg EtOH increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and decreased the level of 3-methoxytyramine (3-MT). A 2.0 g/kg dose of EtOH also increased HVA, but there was not a consistent effect within the brain regions of Aldh2-KO and WT mice. There were inconsistent findings of genotype differences in the levels of DA, 5-HT, and their metabolites in the brain regions tested. None of the EtOH doses altered NE, DA, 5-HT, or 5-hydroxyindoleacetic acid contents in any of the brain regions studied. Second, we tested whether EtOH-induced increases in DOPAC and HVA are mediated by increased monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT) activity. To test this, we used the MAO blocker clorgyline (2.0 and 4.0 mg/kg) and the COMT blocker tolcapone (15 and 30 mg/kg) alone or in combination with EtOH (3.0 g/kg). Clorgyline alone increased 3-MT and decreased DOPAC and HVA levels, whereas tolcapone alone increased DOPAC and decreased 3-MT and HVA levels. Surprisingly, the combination of EtOH with clorgyline (4.0 mg/kg) or tolcapone (30 mg/kg) further decreased 3-MT and increased DOPAC and HVA levels, an effect that reversed the inhibitor-induced decreases in HVA. These results suggest that a high concentration of EtOH can accelerate DA metabolism, as evidenced by the increase in DOPAC and HVA, and this effect is likely a consequence of increased degradation of DA by MAO.

Physiological role of anticipatory cardiorespiratory responses to exercise.

This study aimed to investigate whether anticipatory cardiorespiratory responses vary depending on the intensity of the subsequent exercise bout, and whether anticipatory cardiorespiratory adjustments contribute importantly to enhancing exercise performance during high-intensity exercise. Eleven healthy men were provided advance notice of the exercise intensity and a countdown to generate anticipation during 10 min prior to exercise at 0, 50, 80 or 95% maximal work-rate (Experiment 1). A different group of subjects (n = 15) performed a time to exhaustion trial with or without anticipatory countdown (Experiment 2). In Experiment 1, heart rate (HR), oxygen uptake (VO2 ) and minute ventilation (VE ) during pre-exercise resting period increased over time and depended on the subsequent exercise intensity. Specifically, there was already a 7.4% increase in HR from more than 5 min prior to the start of exercise at 95% maximal work-rate, followed by progressively augmented increases of 12.5% between 2 and 3 min before exercise, 24.4% between 0 and 1 min before exercise. In Experiment 2, the initial HR for the first 10 s of exercise in the task with anticipation was 11.4% larger compared to without anticipation (p < 0.01), and the difference in HR between the two conditions decreased in a time-dependent manner. In contrast, the initial increases in VO2 and VE were significantly lower in the task with anticipation than that without anticipation. The time to exhaustion during high-intensity exercise was 14.6% longer under anticipation condition compared to no anticipation (135 ± 26 s vs. 119 ± 26 s, p = 0.003). In addition, the enhanced exercise performance correlated positively with increased HR response just before and immediately after exercise onset (p < 0.01). These results showed that anticipatory cardiorespiratory adjustments (feedforward control) via the higher brain that operate before starting exercise may play an important role in minimizing the time delay of circulatory response and enhancing performance after onset of high-intensity exercise in man.

Dietary iso-α-acids prevent acetaldehyde-induced liver injury through Nrf2-mediated gene expression.

Acetaldehyde is the major toxic metabolite of alcohol (ethanol) and enhances fibrosis of the liver through hepatic stellate cells. Additionally, alcohol administration causes the accumulation of reactive oxygen species (ROS), which induce hepatocyte injury-mediated lipid peroxidation. Iso-α-acids, called isohumulones, are bitter acids in beer. The purpose of this study was to investigate the protective effects of iso-α-acids against alcoholic liver injury in hepatocytes in mice. C57BL/6N mice were fed diets containing isomerized hop extract, which mainly consists of iso-α-acids. After 7 days of feeding, acetaldehyde was administered by a single intraperitoneal injection. The acetaldehyde-induced increases in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were suppressed by iso-α-acids intake. Hepatic gene expression analyses showed the upregulation of detoxifying enzyme genes, glutathione-S-transferase (GST) and aldehyde dehydrogenase (ALDH). In vitro, iso-α-acids upregulated the enzymatic activities of GST and ALDH and induced the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nfe2l2; Nrf2), a master regulator of antioxidant and detoxifying systems. These results suggest that iso-α-acid intake prevents acetaldehyde-induced liver injury by reducing oxidative stress via Nrf2-mediated gene expression.

Relationship between the Number of Deaths Due to Renal Failure and Air Temperature Parameters in Hokkaido and Okinawa Prefectures, Japan.

Background: The aim of the present study was to investigate the relationship between the number of deaths due to renal failure and air temperature parameters in Hokkaido (the northernmost region) and Okinawa (the southernmost region) prefectures, Japan. Methods: Monthly data on the number of deaths due to renal failure between January 2008 and December 2016 and annual population data were collected from the Hokkaido and Okinawa official prefecture websites. Air temperature parameters were obtained from the Japan Meteorological Agency. The relationship between the number of deaths due to renal failure and air temperature parameters was evaluated by an ecological study. Results: The number of deaths due to renal failure (per 100,000 people/month) in Hokkaido and Okinawa were 2.28 ± 0.30 and 1.17 ± 0.31. In Hokkaido, the number of deaths due to renal failure negatively correlated with air temperature parameters in both sexes. The number of deaths due to renal failure was significantly higher in January than from June to September in all subjects. However, in Okinawa, no significant difference was observed among months. Conclusions: The present results suggest that the relationship between the number of deaths due to renal failure and air temperature parameters differs between Hokkaido and Okinawa.

Detection of helium in a fire victim: A case report.

We report here detection of helium in specimens derived from a burn autopsy case. A male was found in a burnt bedroom. Part of a heat-denatured plastic bag, sealing tape, and flexible tubing remained on his head and neck. In addition, five helium tanks were found near him. His history in conjunction with the discovery conditions suggested a suicide attempt by inhalation of helium. The body had extensive first to fourth degree burns caused by heat. A small amount of soot was deposited in the respiratory tract. Except for the thermal burns, no other injuries were found. Toxicologically, the blood carboxyhemoglobin saturation levels were less than 6%, while combustion-derived volatile hydrocarbons such as benzene or toluene were detected in the blood. In addition, tracheal gas, gastric gas, headspace gas of lung tissue, brain, and heart blood were collected during autopsy for detection of helium. Analysis was performed using headspace gas chromatography with a thermal conductivity detector. Helium was detected in all of the samples tested. Etizolam at a low limit of therapeutic concentration or less was detected in the blood. Neither ethanol nor other drugs of abuse were detected in his blood or urine. Autopsy findings and experiments suggest that the victim inhaled helium and was still alive when a fire broke out. The cause of his death was diagnosed as death from fire and flames. The present result suggests that helium may remain in a burned body and that investigation of helium in cases of fire-related deaths is informative for determination of the cause of death or confirmation of the ante mortem involvement of helium.

Changes and Variations in Death Due to Senility in Japan.

OBJECTIVE: The proportion of elderly individuals (≥65 years old) in Japan has markedly increased. However, the definition of senility in Japan is controversial. The aim of the present study was to investigate changes and variations in the number of deaths due to senility in Japan. METHODS: Information on the number of deaths due to senility between 1995 and 2018 as well as other major causes of death was obtained from the Statistics Bureau of Japan official website. Changes and variations in the number of deaths due to senility were compared with other major causes of death in Japan. The relationships between the number of deaths due to senility and socioeconomic factors were also examined in an ecological study. RESULTS: The number of deaths due to senility was 35.7 ± 23.2/one hundred thousand people/year during the observation period and has continued to increase. A change point was identified in 2004 by a Jointpoint regression analysis. Variations in the number of deaths due to senility, which were evaluated by a coefficient of variation, were significantly greater than those due to other major causes of death, i.e., malignant neoplasm, heart diseases, cerebrovascular diseases, and pneumonia. The number of elderly individuals (≥65 years old) (%) and medical bills per elderly subject (≥75 years old) correlated with the number of deaths due to senility. CONCLUSION: The number of deaths due to senility has been increasing, particularly since 2004. However, variations in the number of deaths due to senility were observed among all prefectures in Japan.

Determination of metallization with energy-dispersive X-ray fluorescent spectrometry in experimental electric injury.

We investigated the application of energy-dispersive X-ray fluorescent spectrometry (EDX) analysis to the detection of aluminum (Al), tin (Sn) and zinc (Zn) as the electric conductor in experimental electrical injury. Experimental electrical injury was caused by exposure to alternating current at 100 V for 10 s. The peaks of Al, Sn, and Zn were detected by EDX in formalin-fixed skin samples of each current exposure group. Histological examination revealed blister formation in all samples of each current exposure group. EDX analysis technique can be applied to detect Al, Sn, and Zn as the electric conductor, and is useful in the diagnosis of electrocution.