Publications by authors named "Hiroshi Kinoshita"

160 Publications

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

PLoS One 2021 5;16(2):e0246327. Epub 2021 Feb 5.

Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246327PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864453PMC
February 2021

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

Forensic Sci Int 2021 Jan 23;318:110613. Epub 2020 Nov 23.

Department of Forensic Medicine, Kurume University School of Medicine, Kurume, Japan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.forsciint.2020.110613DOI Listing
January 2021

Changes and Variations in Death Due to Senility in Japan.

Healthcare (Basel) 2020 Oct 30;8(4). Epub 2020 Oct 30.

Faculty of Social Studies, Shikokugakuin University, Zentsuji City 765-0013, 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.
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http://dx.doi.org/10.3390/healthcare8040443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712013PMC
October 2020

Appropriate samples for helium detection in postmortem investigations.

Leg Med (Tokyo) 2020 11 12;47:101784. Epub 2020 Sep 12.

Department of Legal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan.

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http://dx.doi.org/10.1016/j.legalmed.2020.101784DOI Listing
November 2020

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

Leg Med (Tokyo) 2020 Nov 26;47:101768. Epub 2020 Jul 26.

Hygiene Faculty of Medicine, Kagawa University, Kagawa, Japan.

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.
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http://dx.doi.org/10.1016/j.legalmed.2020.101768DOI Listing
November 2020

High ethanol and acetaldehyde decrease extracellular glutamate in the frontal cortex of freely moving mice.

Neuroreport 2020 Jun 22. Epub 2020 Jun 22.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University, Kita, Kagawa, Japan.

Our recent study demonstrated that local perfusion of ethanol (EtOH) and acetaldehyde (AcH) into the hippocampus via microdialysis decreased extracellular glutamate; however, it is not clear whether this effect occurs in the frontal cortex. To address this issue, we investigated the effects of local perfusion of EtOH and AcH on extracellular glutamate in the frontal cortex of Aldh2-knockout (Aldh2-KO) and C57BL/6 N [wild-type (WT)] mice. Dialysates were collected every 20 minutes, and extracellular glutamate was measured using HPLC coupled with electrochemical detector. We found local perfusion of 200 and 500 mM EtOH into the frontal cortex of WT and Aldh2-KO mice produced significant decreases in extracellular glutamate levels (P < 0.05). A dose of 500 mM EtOH induced a greater decrease in Aldh2-KO mice (P < 0.05) than in WT mice, indicating the action of AcH. Similarly, perfusion of 200 and 500 µM AcH decreased glutamate in the frontal cortex of Aldh2-KO mice (P < 0.05), but this decrease was not seen in WT mice at any AcH dose, due to the subsequent oxidation of AcH by mitochondrial aldehyde dehydrogenase 2. A low dose of EtOH (100 mM) or AcH (100 µM) had no effect on glutamate. These results showed that high doses of EtOH and AcH induces a significant decrease in extracellular glutamate in the frontal cortex of mice, replicating previous findings and providing further evidence that reduced glutamate is likely to be involved in the depressant effects of EtOH.
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http://dx.doi.org/10.1097/WNR.0000000000001493DOI Listing
June 2020

Formation of large area closely packed carbon onions film by plasma-based ion implantation.

Sci Rep 2020 Jun 22;10(1):10037. Epub 2020 Jun 22.

Department of Mechanical Engineering, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.

A substantial quantity of carbon onions in a durable film state is indispensable for its applications. In this study, large area fabrication of closely packed homogeneous carbon onion nanoparticle film using plasma-based ion implantation was demonstrated. Ag film deposited on a Si substrate was used as the implantation target for the hydrocarbon ions accelerated at 20 kV. Nanoparticles with the mean diameter of 7.5 nm were formed at the grain boundary of the Ag film. Carbon onions with the mean diameter of 17.4 nm were synthesized and arranged to a closely packed nanoparticle film with the thickness of around 200 nm by gradual thermal vaporization of the Ag. The closely packed configuration was achieved due to the isolated growth of carbon onion nanoparticle and high uniformity of the diameter. This process can be used in principle large area formation compered to typical ion implantation technique of carbon onion nanoparticle film, which can be applicable for the practical use in mechanical and electrochemical applications.
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http://dx.doi.org/10.1038/s41598-020-67323-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308266PMC
June 2020

High Ethanol and Acetaldehyde Inhibit Glutamatergic Transmission in the Hippocampus of Aldh2-Knockout and C57BL/6N Mice: an In Vivo and Ex Vivo Analysis.

Neurotox Res 2020 Mar 15;37(3):702-713. Epub 2020 Feb 15.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan.

We aimed to investigate whether ethanol (EtOH) and acetaldehyde (AcH) can affect glutamate and its receptors GluN1 and GluA1 in the hippocampus of Aldh2-knockout (Aldh2-KO) and C57BL/6N (wild-type (WT)) mice. To do this, we first examined the effect of local administration of EtOH (100 mM, 200 mM, and 500 mM) and AcH (100 μM, 200 μM, and 500 μM) on extracellular glutamate levels in freely moving mice. Retrodialysis of 200 mM and 500 mM EtOH into the hippocampus of WT and Aldh2-KO mice produced significant decreases in extracellular glutamate levels (p < 0.05). A dose of 500 mM EtOH induced a greater decrease in Aldh2-KO mice (p < 0.05) than in WT mice, indicating the action of AcH. Similarly, perfusion of 200 μM and 500 μM AcH decreased glutamate in Aldh2-KO mice (p < 0.05), but this decrease was not seen in WT mice at any AcH dose. Second, we tested whether the EtOH- and AcH-induced decrease in glutamate was associated with decreases in GluN1 and GluA1 expression, as measured by real-time PCR and Western blot. We found a significant decrease in GluN1 (p < 0.05) and GluA1 (p < 0.05) subunits after a high dose of EtOH (4.0 g/kg) and AcH (200 mg/kg) in WT mice. However, a 2.0 g/kg dose of EtOH did not produce a consistent decrease in GluN1 or GluA1 between messenger RNA and protein. In Aldh2-KO mice, all three doses of EtOH (1.0 g/kg, 2.0 g/kg, and 4.0 g/kg) and AcH (50 mg/kg, 100 mg/kg, and 200 mg/kg) decreased GluN1 expression (p < 0.05), while moderate-to-high doses of EtOH (2.0 g/kg and 4.0 g/kg) and AcH (100 mg/kg and 200 mg/kg) decreased GluA1 expression (p < 0.05). Together, these in vivo and ex vivo data suggest that EtOH and AcH decrease extracellular glutamate in the hippocampus of mice with a concomitant decrease in GluN1 and GluA1 subunits, but these effects require relatively high concentrations and may, therefore, explain the consequences of EtOH intoxication.
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http://dx.doi.org/10.1007/s12640-020-00180-6DOI Listing
March 2020

Relationship between Air Temperature Parameters and the Number of Deaths Stratified by Cause in Gifu Prefecture, Japan.

Healthcare (Basel) 2020 Feb 7;8(1). Epub 2020 Feb 7.

Faculty of Social Studies, Shikokugakuin University, Zentsuji city, Kagawa 765-0013, Japan.

Objective: It is well known that air temperature is closely related to health outcomes. We investigated the relationship between air temperature parameters and the number of deaths stratified by cause in Gifu prefecture, Japan.

Methods: The number of deaths stratified by cause in Gifu prefecture Japan between January 2007 and December 2016 was obtained from the official homepage of Gifu prefecture, Japan. Air temperature parameters (℃), i.e., the mean air temperature, mean of the highest air temperature, mean of the lowest air temperature, the highest air temperature, and the lowest air temperature during the same period in Gifu city were also obtained from the Japan Meteorological Agency official home page. The relationship between air temperature parameters and the number of deaths was evaluated in an ecological study.

Results: The number of deaths due to heart disease, cerebrovascular disease, pneumonia, accidents, or renal failure in January (coldest winter season in Japan) was the highest among the months. Simple correlation analysis also demonstrated a significant and negative relationship between air temperature parameters and the number of deaths due to heart disease, cerebrovascular disease, senility, pneumonia, accidents, and renal failure.

Conclusion: Lower air temperature may be associated with a higher number of deaths due to diseases in Gifu prefecture, Japan.
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http://dx.doi.org/10.3390/healthcare8010035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151071PMC
February 2020

Carbon monoxide poisoning.

Toxicol Rep 2020 20;7:169-173. Epub 2020 Jan 20.

Department of Toxicology & Forensic Sciences, Medical School, University of Crete, Voutes Campus, Heraklion, 71003, Greece.

Carbon monoxide (CO) is the leading cause of poisoning deaths in many countries, including Japan. Annually, CO poisoning claims about 2000-5000 lives in Japan, which is over half of the total number of poisoning deaths. This paper discusses the physicochemical properties of CO and the toxicological evaluation of CO poisoning.
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http://dx.doi.org/10.1016/j.toxrep.2020.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992844PMC
January 2020

An autopsy case of heatstroke under the influence of psychotropic drugs.

Soud Lek 2020 ;65(4):76-78

We present here a fatal case of heatstroke, involving olanzapine and levomepromazine medications. A male in his sixties was found dead in his storage room in the middle of August, with a high rectal temperature. Autopsy revealed congestion of the lungs without any specific findings. Quantitative toxicological analysis demonstrated concentrations of olanzapine, levomepromazine, 7-aminonitrazepam, and 7-aminoflunitrazepam in a femoral blood sample of 0.433 µg/mL, 0.177 µg/mL, 0.604 µg/mL, and 0.041 µg/mL, respectively. The concentration of olanzapine exceeded toxic levels; however, levomepromazine level was within the therapeutic range. Due to the blocking mechanism of both olanzapine and levomepromazine against muscarinic receptors, they might depress sweating and impair heat dissipation. Based on autopsy findings, results of toxicological examination, and investigation by the authorities, we concluded that the cause of death was heatstroke under the influence of olanzapine and levomepromazine.
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March 2021

Medicolegal implication of an autopsy case of methidathion ingestion.

Soud Lek 2019 ;64(4):42-43

We present an autopsy case involving ingestion of methidathion, an organothiophosphate pesticide. A headspace gas chromatography mass spectrometry system was used for screening of volatile compounds. Subsequent toxicological analysis was performed using liquid chromatography tandem mass spectrometry. Xylene and ethylbenzene were detected in stomach contents. We also identified methidathion at concentrations of 3.07 and 2240 µg/ml in femoral venous blood and stomach contents, respectively. We concluded that the victim ingested methidathion insecticide, with an estimated dose of at least 9.2 g.
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December 2019

MDGA1-deficiency attenuates prepulse inhibition with alterations of dopamine and serotonin metabolism: An ex vivo HPLC-ECD analysis.

Neurosci Lett 2020 01 5;716:134677. Epub 2019 Dec 5.

Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Kagawa, Japan. Electronic address:

MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor) has recently been linked to schizophrenia and bipolar disorder. Dysregulation of dopamine (DA) and serotonin (5-HT) systems has long been associated with schizophrenia and other neuropsychiatric disorders. Here, we measured prepulse inhibition (PPI) of the startle response and ex vivo tissue content of monoamines and their metabolites in the frontal cortex, striatum and hippocampus of Mdga1 homozygous (Mdga1-KO), Mdga1 heterozygous (Mdga1-HT) and wild-type (WT) male mice. We found that Mdga1-KO mice exhibited statistically significant impairment of PPI, and had higher levels of homovanillic acid in all three brain regions studied compared with Mdga1-HT and WT mice (P < 0.05), while levels of norepinephrine, DA and its metabolites 3,4-dihydroxyphenylacetic acid and 3-methoxytyramine remained unchanged. Mdga1-KO mice also had a lower 5-hydroxyindoleacetic acid level in the striatum (P < 0.05) compared with WT mice. 5-HT levels remained unchanged with the exception of a significant increase in the level in the cortex. These data are the first evidence suggesting that MDGA1 deficiency leads to a pronounced deficit in PPI and plays an important role in perturbation of DA and 5-HT metabolism in mouse brain; such changes may contribute to a range of neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.neulet.2019.134677DOI Listing
January 2020

Detection of toluene, methanol and formic acid in the autopsy case of a solvent abuser.

Soud Lek 2019 ;64(2):20-22

A fatal case of abuse of solvent containing mixture of toluene and methanol is presented. Concentrations of toluene, methanol and formic acid in a femoral venous blood sample were 20.1 mg/L, 210 mg/L and 25.2 mg/L, respectively. From the autopsy findings and toxicological examination, we concluded that the cause of death was poisoning by toluene and methanol.
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December 2019

Temporal and Force Characteristics of Rapid Single-Finger Tapping in Healthy Older Adults.

Motor Control 2019 Apr 10:1-17. Epub 2019 Apr 10.

3 Osaka Aoyama University.

The purpose of this study was to examine finger motor function in terms of temporal and force characteristics during rapid single-finger tapping in older adults. Ten older and 10 young males performed maximum frequency tapping by the index, middle, ring, or little finger. Nontapping fingers were maintained in contact with designated keys during tasks. Key-contact force for each of the fingers was monitored using four force transducers. The older subjects had slower tapping rates of all fingers during single-finger tapping than the young subjects. The average forces exerted by the nontapping fingers were larger for the older subjects than for the young subjects during tapping with the ring and little fingers. The ranges of the nontapping finger forces were larger for the older subjects during tapping by the middle, ring, and little fingers than for the young subjects. Thus, the motor abilities of the fingers evaluated by rapid single-finger tapping decline in older adults compared with young adults in terms of both movement speed and finger independence.
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http://dx.doi.org/10.1123/mc.2018-0060DOI Listing
April 2019

COA-Cl induces dopamine release and tyrosine hydroxylase phosphorylation: In vivo reverse microdialysis and in vitro analysis.

Brain Res 2019 03 23;1706:68-74. Epub 2018 Oct 23.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki, Kita, Kagawa 761-0793, Japan.

We found that local perfusion of COA-Cl (0.1, 0.4, or 1.0 mM) into the dorsal striatum of living mice produced a significant and dose-dependent increase in extracellular DA levels, with the highest dose of 1.0 mM COA-Cl producing an approximately 5-fold increase in DA. Consistent with in vivo findings, 0.1 and 0.2 mM COA-Cl significantly and dose-dependently enhanced DA release 3.0 to 5.0-fold in PC12 cells, an in vitro model of DA-responsive neurons. Interestingly, the increase in striatal DA levels by COA-Cl in vivo was similar in magnitude to that observed in PC12 cells. Treatment with 0.1 mM COA-Cl significantly increased both Ser31 and Ser40 phosphorylation of tyrosine hydroxylase (TH) in PC12 cells, and Ser40 phosphorylation in iCell neurons, without altering total TH protein levels. Further, we examined whether COA-Cl could stimulate neurite outgrowth in PC12 cells and iCell neurons and found that COA-Cl significantly induced neurite outgrowth in both cell lines. Our results provide the first evidence that COA-Cl can stimulate dose-dependent DA release and activation of TH phosphorylation, suggesting that COA-Cl may be a promising therapeutic candidate for the treatment of neurological dysfunction associated with low DA.
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http://dx.doi.org/10.1016/j.brainres.2018.10.026DOI Listing
March 2019

Nrf2-related gene expression is impaired during a glucose challenge in type II diabetic rat hearts.

Free Radic Biol Med 2019 01 11;130:306-317. Epub 2018 Oct 11.

School of Natural Sciences, University of California, Merced, United States.

Diabetic hearts are susceptible to damage from inappropriate activation of the renin angiotensin system (RAS) and hyperglycemic events both of which contribute to increased oxidant production. Prolonged elevation of oxidants impairs mitochondrial enzyme function, further contributing to metabolic derangement. Nuclear factor erythriod-2-related factor 2 (Nrf2) induces antioxidant genes including those for glutathione (GSH) synthesis following translocation to the nucleus. We hypothesized that an acute elevation in glucose impairs Nrf2-related gene expression in diabetic hearts, while AT1 antagonism would aid in Nrf2-mediated antioxidant production and energy replenishment. We used four groups (n = 6-8/group) of 25-week-old rats: 1) LETO (lean strain-control), 2) type II diabetic OLETF, 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 wks), and 4) ARBM (4 weeks on ARB, 4 weeks off) to study the effects of acutely elevated glucose on cardiac mitochondrial function and Nrf2 signaling in the diabetic heart. Animals were gavaged with a glucose bolus (2 g/kg) and groups were dissected at T0, T180, and T360 minutes. Nrf2 mRNA was 32% lower in OLETF rats compared to LETO and remained suppressed in response to glucose. LETO Nrf2 mRNA increased 25% at T360 in response to glucose while no changes were observed in diabetic hearts. GCLC and GCLM mRNA decreased in diabetic hearts 33% and 44% respectively and remained suppressed in response to glucose while ARB treatment increased GCLM transcripts 90% at T180. These data illustrate that during T2DM and in response to glucose, cardiac Nrf2's adaptive response to environmental stressors such as glucose is impaired in diabetic hearts and that ARB treatment may aid Nrf2's impaired dynamic response.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.10.405DOI Listing
January 2019

Acetaldehyde administration induces salsolinol formation in vivo in the dorsal striatum of Aldh2-knockout and C57BL/6N mice.

Neurosci Lett 2018 10 20;685:50-54. Epub 2018 Jul 20.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki, Kita, Kagawa, Japan.

Acetaldehyde (AcH) and salsolinol play important roles in the central effects of ethanol. This study aimed to investigate the effect of administration of AcH on dopamine (DA), DA-derived salsolinol and serotonin (5-HT) levels in the dorsal striatum of Aldh2-knockout (Aldh2-KO) and C57BL/6 N (WT) mice. Animals were treated with AcH (50, 100 and 200 mg/kg) intraperitoneally and dialysate levels of DA, 5-HT and salsolinol were determined using in vivo microdialysis coupled with HPLC-ECD. Salsolinol was first detected at 20 min after AcH administration, and reached its peak concentration (WT mice: 0.29 ± 0.22 pg/μl; Aldh2-KO mice: 0.63 ± 0.17 pg/μl) at 25 min in the 200 mg/kg AcH group, before decreasing rapidly and reaching zero at approximately 55-80 min. Treatment with 100 and 200 mg/kg AcH increased levels of salsolinol in both WT and Aldh2-KO mice, with 200 mg/kg AcH inducing a higher level of salsolinol in Aldh2-KO mice than in WT mice. Treatment with 50 mg/kg AcH produced a small increase in salsolinol levels in Aldh2-KO mice, whereas no elevation of salsolinol was detected in WT mice. The increase in salsolinol formation was found to occur a dose-dependent manner in both genotypes. Administration of AcH and the subsequent changes in salsolinol concentrations did not change DA or 5-HT levels in either genotype. Our study suggests that AcH dose-dependently increases the formation of salsolinol in the dorsal striatum of mice, which provides further support for the role of AcH in salsolinol formation in the animal brain.
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http://dx.doi.org/10.1016/j.neulet.2018.07.032DOI Listing
October 2018

Effect of the volatile anesthetic agent isoflurane on lateral diffusion of cell membrane proteins.

FEBS Open Bio 2018 Jul 23;8(7):1127-1134. Epub 2018 May 23.

Department of Chemistry Graduate School of Science Osaka University Toyonaka Osaka Japan.

The volatile anesthetic isoflurane (ISO) has previously been shown to increase the fluidity of artificial lipid membranes, but very few studies have used biological cell membranes. Therefore, to investigate whether ISO affects the mobility of membrane proteins, fluorescence-labeled transferrin receptor (TfR) and glycosylphosphatidylinositol (GPI)-anchored protein were expressed in human embryonic kidney 293T cells and neural cells and lateral diffusion was examined using fluorescence recovery after photobleaching. Lateral diffusion of the TfR increased with ISO treatment. On the other hand, there was no effect on GPI-anchored protein. We also used GC/MS to confirm that there was no change in the concentration of ISO due to vaporization during measurement. These results suggest that ISO affects the mobility of transmembrane protein molecules in living cells.
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http://dx.doi.org/10.1002/2211-5463.12443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026700PMC
July 2018

Targeted cloning of a large gene cluster from Lecanicillium genome by Cre/loxP based method.

J Microbiol Methods 2018 07 23;150:47-54. Epub 2018 May 23.

International Center for Biotechnology, Osaka University, Osaka, Japan; Mahidol University-Osaka University Collaborative Research Center for Bioscience and Biotechnology, Faculty of Science, Bangkok, Thailand. Electronic address:

Functionally related genes often form a large gene cluster on fungal genomes. To analyze, by heterologous expression system, overall pathway in which a series of related genes are involved, the whole gene cluster should be introduced intact into the host strain. However, the construction of a genomic library based on cosmid or bacterial artificial chromosome, and screening of a clone harboring the target region are time consuming and usually require additional cloning of missing regions. The available PCR-based methods are convenient, but are likely to cause unexpected errors during long-range PCR. Therefore, in this study we developed a method for targeted cloning of a large gene cluster based on Cre/loxP-mediated recombination. loxP sequences were integrated at both edges of the targeted region, and the region was excised and cloned as a circular fosmid by in vitro Cre recombination. To facilitate the Cre/loxP-based method, a competent host-vector system was developed, including a double auxotrophic Lecanicillium PTk3 (ΔpyrG trp1ku80) strain and two vectors for introducing the loxP sequences, pUTlox and pCCPlox. A targeted region longer than 45 kb in length was successfully cloned by the Cre/loxP-based method.
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http://dx.doi.org/10.1016/j.mimet.2018.05.017DOI Listing
July 2018

The Role of Apolipoprotein E and Ethanol Exposure in Age-Related Changes in Choline Acetyltransferase and Brain-Derived Neurotrophic Factor Expression in the Mouse Hippocampus.

J Mol Neurosci 2018 May 1;65(1):84-92. Epub 2018 May 1.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan.

Disruption of apolipoprotein E (APOE) is responsible for age-dependent neurodegeneration and cognitive impairment. Elderly individuals are more sensitive than young individuals to the effects of ethanol (EtOH), particularly those affecting cognition. We investigated the role of APOE deficiency and EtOH exposure on age-dependent alterations in choline acetyltransferase (ChAT) and brain-derived neurotrophic factor (BDNF) mRNA and protein expression in the mouse hippocampus. Three-month-old (young) and 12-month-old (aged) ApoE-knockout (ApoE-KO) and wild-type (WT) mice were treated with saline or 2 g/kg EtOH, and the bilateral hippocampus was collected after 60 min for real-time PCR and western blotting analyses. ChAT (P < 0.01) and BDNF (P < 0.01) expression were significantly decreased in both young and aged saline- and EtOH-treated ApoE-KO mice versus young and aged saline- and EtOH-treated WT mice. Aged saline- and EtOH-treated ApoE-KO mice exhibited greater differences in ChAT and BDNF expression (P < 0.01) than young saline- and EtOH-treated ApoE-KO mice. Aged EtOH-treated WT mice also exhibited larger decreases in BDNF expression (P < 0.01)-but not in ChAT expression-than young EtOH-treated WT mice. EtOH decreased ChAT and BDNF expression in both young (P < 0.01) and aged (P < 0.01) ApoE-KO mice versus EtOH-free ApoE-KO mice of the same age. EtOH also decreased BDNF expression in aged (P < 0.01) WT mice versus EtOH-free aged WT mice. In summary, these results suggest that APOE deficiency and EtOH exposure cause age-dependent decreases in ChAT and BDNF in the hippocampus. Importantly, the decreases in ChAT and BDNF were greater in aged EtOH-treated mice, particularly those lacking APOE, raising the possibility that APOE-deficient individuals who consume alcohol may be at greater risk of memory deficit.
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http://dx.doi.org/10.1007/s12031-018-1074-6DOI Listing
May 2018

Discovery of a long-acting glucagon-like peptide-1 analog with enhanced aggregation propensity.

Peptides 2018 04 31;102:8-15. Epub 2018 Jan 31.

Mie Research Laboratories, Sanwa Kagaku Kenkyusho, Co., Ltd., 363 Shiosaki, Hokusei-cho, Inabe-city, Mie 511-0406, Japan; Licensing & Business Development, R&D Strategy Center, Sanwa Kagaku Kenkyusho, Co., Ltd.,Mitsui Building No.2 5F 1-1 Nihonbashi-Muromachi 2-Chome, Chuo-ku, Tokyo 103-0022, Japan. Electronic address:

In the course of our search for new GLP-1 analogs, we screened a number of [Ser]-GLP-1 analogs using the C-terminal helix 3 of the albumin binding domain 3 of protein G from bacterial Streptococcal G strain 148 (G148-ABD3) as appendage. Our efforts led to the discovery of [Ser]-GLP-1 (7-35)-GVKALIDEILAA-NH, peptide 6, as a long-acting GLP-1 analog with enhanced self-associated aggregation. Peptide 6 showed enhanced stability in rat and human plasma and an extended half-life of 5.4 h with good bioavailability in rats and subsequently prolonged therapeutic effects in diabetic mice. Analytical ultracentrifugation and TLC suggest that 6 remains oligomeric in the circulation, which accounts for its extended in vivo half-life. The present work shows the possible enhancement of medium-sized oligopeptides aggregation propensity and highlights the potential advantages of peptide aggregates for long-acting peptide drugs.
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http://dx.doi.org/10.1016/j.peptides.2018.01.014DOI Listing
April 2018

Comparison of histological findings and the results of energy-dispersive X-ray spectrometry analysis in experimental electrical injury.

Leg Med (Tokyo) 2018 Mar 6;31:20-23. Epub 2017 Dec 6.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.

The findings of histological examination and the results of energy-dispersive X-ray spectrometry (EDX) analysis were compared to identify skin metallization in experimental electrical injury. Rats were divided into three experimental groups (n = 5, each group): control, current exposure for five seconds, and current exposure for ten seconds. A relatively high peak of copper, which was used as an electrical conductor, was detected in formalin-fixed skin samples of the two current exposure groups by EDX. There was a significant increase of the specific X-ray intensity in the two current exposure groups compared to the control group. On histological examination, epidermal nuclear elongation was observed in all samples of the two current exposure groups. However, deposition of metal was observed in two samples of each current exposure group. Metallization is an important finding for the diagnosis of electrocution. The present results suggest that EDX analysis is useful for the proof of metallization in electrocution, even where it is not identified on morphological examination.
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http://dx.doi.org/10.1016/j.legalmed.2017.12.005DOI Listing
March 2018

An autopsy case of death by combined use of benzodiazepines and diphenidine.

Soud Lek Winter 2017;62(4):40-43

We present an autopsy case involving benzodiazepines and diphenidine. Quantitative toxicological analysis showed concentrations of 7-aminoflunitrazepam (a flunitrazepam metabolite), 7-aminonimetazepam (a nimetazepam metabolite), chlorpheniramine and diphenidine in femoral blood of 0.086 µg/ml, 0.027 µg/ml, 0.066 µg/ml, and 0.073 µg/ml, respectively. Death was attributed to combined toxicity due to the influence of multiple drug interactions.
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April 2019

Perfusion with carbon monoxide does not affect extracellular glutamate in dialysates of the hippocampus of freely moving mice.

Drug Chem Toxicol 2018 Apr 4;41(2):245-247. Epub 2017 Sep 4.

a Department of Forensic Medicine, Faculty of Medicine , Kagawa University , Kagawa , Japan.

Carbon monoxide (CO) produces several neurological effects, including cognitive, mood, and behavioral disturbance. Glutamate is thought to play a particularly important role in learning and memory. Thus, the present study was aimed at investigating the local effect of CO on the glutamate level in the hippocampus of mice using in vivo reverse microdialysis. Mice were perfused with Ringer's solution (control) or CO (60-125 μM) in Ringer's solution into the hippocampus via microdialysis probe. Dialysate samples were collected every 20 min, and then analyzed with high-performance liquid chromatography coupled to an electrochemical detector. The result revealed that the perfusion with CO had no significant effect on glutamate levels (p = 0.316) as compared to the control group. This finding does not support a local CO rise as the cause of the increased glutamate level in the hippocampus of mice.
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http://dx.doi.org/10.1080/01480545.2017.1354873DOI Listing
April 2018

Erratum to: Search and removal of radioactive seeds: another application of postmortem computed tomography prior to autopsy.

Int J Legal Med 2017 11 30;131(6):1783. Epub 2017 Aug 30.

Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

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http://dx.doi.org/10.1007/s00414-017-1660-0DOI Listing
November 2017

Finger forces in fastball baseball pitching.

Hum Mov Sci 2017 Aug 10;54:172-181. Epub 2017 May 10.

American Sports Medicine Institute, Birmingham, AL, USA.

Forces imparted by the fingers onto a baseball are the final, critical aspects for pitching, however these forces have not been quantified previously as no biomechanical technology was available. In this study, an instrumented baseball was developed for direct measurement of ball reaction force by individual fingers and used to provide fundamental information on the forces during a fastball pitch. A tri-axial force transducer with a cable having an easily-detachable connector were installed in an official baseball. Data were collected from 11 pitchers who placed the fingertip of their index, middle, ring, or thumb on the transducer, and threw four-seam fastballs to a target cage from a flat mound. For the index and middle fingers, resultant ball reaction force exhibited a bimodal pattern with initial and second peaks at 38-39ms and 6-7ms before ball release, and their amplitudes were around 97N each. The ring finger and thumb produced single-peak forces of approximately 50 and 83N, respectively. Shear forces for the index and middle fingers formed distinct peak at 4-5ms before release, and the peaks summed to 102N; a kinetic source for backspin on the ball. An additional experiment with submaximal pitching effort showed a linear relationship of peak forces with ball velocity. The peak ball reaction force for fastballs exceeded 80% of maximum finger strength measured, suggesting that strengthening of the distal muscles is important both for enhancing performance and for avoiding injuries.
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http://dx.doi.org/10.1016/j.humov.2017.04.007DOI Listing
August 2017

Distinction between entrance and exit wounds by energy dispersive X-ray fluorescence spectrometry.

Leg Med (Tokyo) 2016 Sep 8;22:5-8. Epub 2016 Jul 8.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.

We investigated gunshot wounds in two autopsy cases using energy dispersive X-ray spectrometry (EDX). Lead and copper were detected in the entrance wound of one case and lead, antimony, and copper were detected in that of the other case. In the exit wounds of both cases, lead, antimony, and copper were below detection limits. These findings indicate that the detection of metallic elements, such as lead, antimony, and copper, which are found in bullets, may be useful for differentiating entrance from exit wounds using EDX.
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http://dx.doi.org/10.1016/j.legalmed.2016.07.003DOI Listing
September 2016

Search and removal of radioactive seeds: another application of postmortem computed tomography prior to autopsy.

Int J Legal Med 2016 09 22;130(5):1329-32. Epub 2016 Jun 22.

Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

We herein introduce 3 cases illustrating a new application for pre-autopsy postmortem computed tomography (PMCT). In all 3 cases, there was insufficient background information about the victims provided to the forensic pathologists' department. PMCT showed metallic particles in the prostate gland, an indication of metallic seeds containing radioactive isotopes. In 2 of 3 cases, migrated seeds were also detected by CT imaging in the lungs and the heart. Also in 2 of 3 cases, authorities reinvestigated the victim's history before autopsy was completed, which resulted in following appropriate procedure for dealing with the seeds. Although all 3 cadavers were cremated after autopsy, the International Commission on Radiological Protection (ICRP) discourages cremation for deaths soon after radioactive seeds implantation to prevent air pollution by radioactive isotopes in the ash. Our opinion from the present cases is that pre-autopsy PMCT can be recommended for use by forensic pathologists and guidelines for investigating deaths after permanent brachytherapy should include how to deal with cadavers when medical history is limited.
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http://dx.doi.org/10.1007/s00414-016-1404-6DOI Listing
September 2016

Investigation of optimal display size for viewing T1-weighted MR images of the brain using a digital contrast-detail phantom.

J Appl Clin Med Phys 2016 01 8;17(1):353-359. Epub 2016 Jan 8.

Osaka Saiseikai Nakatsu Hospital.

We clarified the relationship between the display size of MRI images and observer performance using a digital contrast-detail (d-CD) phantom. The d-CD phantom was developed using Microsoft Visual Basic 2010 Express. It had a 512 × 512 matrix in size and a total of 100 holes, whose diameter increased stepwise from 4 to 40 pixels with a 4-pixel interval in the vertical direction; the contrast varied stepwise in the horizontal direction. The digital driving level (DDL) of the back-ground, the width of the DDL, and the contrast were adjustable. These parameters were determined on the basis of the actual T1-weighted magnetic resonance (MR) images of the brain. In this study, the DDL, width, and contrast were set to 85, 20, and 1, respectively. The observer performance study was performed for three different display sizes (30 cm × 30 cm as the enlarged size, 16 cm × 16 cm as the original size, and 10 cm × 10 cm as the reduced size) using a 2-megapixel color liquid crystal display monitor, and it was analyzed using Friedman and Wilcoxon statistical tests. The observer performances for the original display (p < 0.01) and the reduced display sizes (p < 0.01) were superior to that observed for the enlarged size, whereas there was no significant difference between the original display and reduced display sizes (p = 0.31). Evaluation with the digital phantom simulating MR imaging also revealed that the original and reduced display sizes were superior to the enlarged display size in observer performance. The d-CD phantom enables a short-term evaluation of observer performance and is useful in analyzing relation-ship between display size and observer performance.
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http://dx.doi.org/10.1120/jacmp.v17i1.5876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690225PMC
January 2016