Publications by authors named "Kanako Noritake"

31 Publications

A mixed methods study on the readiness of dental, medical, and nursing students for interprofessional learning.

PLoS One 2021 22;16(7):e0255086. Epub 2021 Jul 22.

Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Interprofessional education (IPE) is crucial in dentistry, medicine, and nursing. However, scant mixed methods studies have compared the IPE outcomes across these disciplines to develop evidence-based IPE. This study explored the differences in the readiness of dental, medical, and nursing students for interprofessional learning before and after IPE workshops and elucidated reasons for this disparity.

Methods: Data were obtained from dental, medical, and nursing students who participated in IPE workshops conducted at Tokyo Medical and Dental University in Japan in 2019 and 2020. The participants filled the validated Japanese version of the Readiness for Interprofessional Learning Scale (RIPLS) before and after attending the workshops (n = 378). Paired t-tests were performed to assess differences between the pre- and post- workshop RIPLS scores. Welch's t-tests were deployed to evaluate interdisciplinary differences in their scores. Qualitative analyses were conducted using an explanatory sequential design with focus group discussions (FGDs) held with 17 dental students to explain the quantitative results.

Results: Total RIPLS scores increased significantly for every discipline after the workshops (p < 0.001). Dental students scored significantly lower pre- and post- workshop aggregates than medical and nursing students, respectively (p < 0.001). The FGDs yielded three principal themes in the explanations tendered by dental students on their lower scores: 1) dental students rarely felt the need for interprofessional collaborations, 2) dentists often worked without the need for interprofessional collaborations, and 3) dental students believed their contribution to the workshop was insufficient.

Conclusions: The results revealed divergences in the readiness of dental, medical, and nursing students for interprofessional learning, and the study illuminated possible reasons for these disparities. These outcomes will help develop evidence-based IPE by indicating approaches to place a higher value on interprofessional collaborations in educational environments, ameliorate the awareness of educators, and enhance the workshop facilitation style.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255086PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297869PMC
July 2021

Relationship between career education experience among final-year dental hygiene students and their perspective towards work and profession: A nationwide survey in dental hygiene schools of Japan.

Int J Dent Hyg 2021 Jul 14. Epub 2021 Jul 14.

National Institute of Public Health, Wako, Japan.

Objectives: This study aimed to clarify the relationship between the experience of receiving career education among final-year dental hygiene students and their views regarding their work and profession, as part of research on the working style of dental hygienists.

Methods: An anonymous, self-administered survey was sent by post to all the 162 dental hygienist schools in Japan with dental hygiene students in their final year in November 2019. The main questions were regarding student attributes, career aspirations, their perspective on work and profession and whether or not they received career education at a dental hygienist training school. Analysis was conducted by cross-tabulation and logistic regression.

Results: Completed questionnaires were sent to us by 150 schools (response rate 92.6%), with a response from 6,270 students. The students who had received career education had significantly higher awareness and plans for the profession and a positive attitude towards the work (p < 0.01). Following adjustment for age, sex, educational attainment, length of the course of study and timing of class the results shows that there was a significant relation between the experience of the career education with having future plans (odds ratio = 2.11, 95% confidence interval = 1.88-2.38, p < 0.01).

Conclusions: It was observed that the experience of receiving career education just before graduating from dental hygienist school was related to an increased positive attitude of the students towards their work and profession. Further long-term investigations are necessary to evaluate the effects of career education among dental hygiene students and their attitude towards their profession.
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http://dx.doi.org/10.1111/idh.12535DOI Listing
July 2021

Possible roles of AMPK and macropinocytosis in the defense responses against Δ-THC toxicity on HL-1 cardiomyocytes.

Toxicol Rep 2021 30;8:980-987. Epub 2021 Apr 30.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Cannabinoids are some of the most popular recreationally used illicit drugs, and are frequently consumed along with alcoholic beverages. Although the whole body effects of cannabinoids depend largely on their effects on the central nerve system, cannabinoids could harm the heart directly, due to the presence of the endocannabinoid system including cannabinoid receptor1 and 2 (CB-R1 and CB-R2) in the heart. The aim of this study is to examine the mechanism of direct cardiotoxicity of Δ-tetrahydrocannabinol (Δ-THC), the main psychoactive ingredient of cannabis. For this purpose, HL-1 murine atrial cardiac muscle cells were treated with 10 or 30 μM Δ-THC, along with 100 mM ethanol to examine the possible synergistic effects of Δ-THC and ethanol. Transcriptome analysis showed upregulation of the genes involved in the unfolded protein response (UPR), including Bip, CHOP, ATF4 and ATF6, in cells treated with Δ-THC. Immunoblot analysis showed caspase3 activation, indicating apoptosis caused by ER stress in Δ-THC-treated cells. Microscopic analysis showed that Δ-THC enhances macropinocytosis, a process involved in the uptake of extracellular fluids including nutrients. Moreover Δ-THC seemed to activate AMPK, a sensor of intracellular energy status and an activator of macropinocytosis. Finally, we found that compound C (AMPK inhibitor) aggravated cell death by Δ-THC while AICAR (AMPK activator) ameliorated it. Collectively, these results indicate that the activation of AMPK is necessary for the survival of HL-1 cells against Δ-THC toxicity. Macropinocytosis might serve as one of the survival pathways downstream of AMPK.
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http://dx.doi.org/10.1016/j.toxrep.2021.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131391PMC
April 2021

Perceived Preparedness of Dental Academic Institutions to Cope with the COVID-19 Pandemic: A Multi-Country Survey.

Int J Environ Res Public Health 2021 02 4;18(4). Epub 2021 Feb 4.

Department of Prosthodontics, University of Dental Medicine, Mandalay 05041, Myanmar.

Dental academic institutions are affected by COVID-19. We assessed the perceived COVID-19 preparedness of these institutions and the characteristics of institutions with greater perceived preparedness. An international cross-sectional survey of dental academics was conducted from March to August 2020 to assess academics' and institutional attributes, perceived preparedness, and availability of infection prevention and control (IPC) equipment. Principal component analysis (PCA) identified perceived preparedness components. Multilevel linear regression analysis assessed the association between perceived preparedness and fixed effect factors (academics' and institutions' attributes) with countries as random effect variable. Of the 1820 dental academics from 28 countries, 78.4% worked in public institutions and 75.2% reported temporary closure. PCA showed five components: clinic apparel, measures before and after patient care, institutional policies, and availability of IPC equipment. Significantly less perceived preparedness was reported in lower-middle income (LMICs) (B = -1.31, = 0.006) and upper-middle income (UMICs) (B = -0.98, = 0.02) countries than in high-income countries (HICs), in teaching only (B = -0.55, < 0.0001) and in research only (B = -1.22, = 0.003) than teaching and research institutions and in institutions receiving ≤100 patients daily than those receiving >100 patients (B = -0.38, < 0.0001). More perceived preparedness was reported by academics with administrative roles (B = 0.59, < 0.0001). Academics from low-income countries (LICs) and LMICs reported less availability of clinic apparel, IPC equipment, measures before patient care, and institutional policies but more measures during patient care. There was greater perceived preparedness in HICs and institutions with greater involvement in teaching, research, and patient care.
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http://dx.doi.org/10.3390/ijerph18041445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913785PMC
February 2021

The Relationship between the Sense of Coherence of Dental Hygiene Students in Their Graduation Year and Their View of the Profession and Attitude to Work: A Cross-Sectional Survey in Japan.

Int J Environ Res Public Health 2020 12 21;17(24). Epub 2020 Dec 21.

National Institute of Public Health, Wako, Saitama 351-0197, Japan.

Objective: The need to make sense of coherence in placement support for student dental hygienists has been shown. On this basis, this study investigated the relationship between the sense of coherence of student dental hygienists and their view of the profession and attitude to work in order to clarify how they perceive their prospects for employment.

Methods: The subjects were graduation-year students at all of the dental hygienist training institutions in Japan, and anonymous, self-administered questionnaires were sent to the institutions by post in 2019. The results were analyzed by χ tests, as well as one-way analysis of variance and multiple comparisons using Tukey's test, with the level of significance set at 5%.

Results: Of 6270 questionnaires that were returned, 6264 were analyzed. The sense of coherence (SOC) component senses were manageability (F(26,221) = 5306.06, < 0.01), meaningfulness (F(26,222) = 4373.48, < 0.01), and comprehensibility (F(26,216) = 3986.12, < 0.01), with meaningfulness scoring significantly higher than the other two ( < 0.01). Analysis with SOC scores divided into the low, medium, and high groups showed a relationship between the SOC of student dental hygienists and their view of the profession and attitude to work ( < 0.01), such that higher SOC scores were associated with a better view of the profession and a better attitude to work (F(26,225) = 282.18, < 0.01).

Conclusions: The results suggest that education that increases SOC in dental hygienist training programs may positively affect future prospects for student dental hygienists.
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http://dx.doi.org/10.3390/ijerph17249594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767532PMC
December 2020

Pyroptotic cell death by exposure to 1-butanol in H9c2 cardiomyoblastoma cells.

Heliyon 2020 Nov 18;6(11):e05503. Epub 2020 Nov 18.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8519, Tokyo, Japan.

The aim of this study is to examine the molecular mechanism of cytotoxicity caused by direct exposure to short chain alcohol. We showed previously that exposing H9c2 cardiomyoblastoma cells to 150 mM 1-butanol results in cell death within 1 h through an intrinsic apoptotic pathway. The cell death is accompanied by plasma membrane blebbing and caspase-3 activation. Here we show that a higher concentration (200 mM) of 1-butanol, as well as prolonged exposure (3-6 h) to 150 mM 1-butanol, induces plasma membrane ballooning, a characteristic feature of pyroptosis. Although gasderminD (GSDMD) cleavage by caspase-1 was not observed, GSDME cleavage by caspase-3 was observed during exposure to 150 mM 1-butanol for 6 h. We conclude that pyroptotic cell death by 1-butanol in H9c2 cardiomyoblastoma cells should occur via the caspase-3-GSDME pathway, revealing that 1-butanol could induce not only apoptosis but also pyroptosis in the cells.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683309PMC
November 2020

A remote program for residents to solve clinical questions and improve presentation skills.

J Dent Educ 2020 Oct 22. Epub 2020 Oct 22.

Oral Diagnosis and General Dentistry, Dental Hospital, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

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http://dx.doi.org/10.1002/jdd.12473DOI Listing
October 2020

Behavior change due to COVID-19 among dental academics-The theory of planned behavior: Stresses, worries, training, and pandemic severity.

PLoS One 2020 29;15(9):e0239961. Epub 2020 Sep 29.

Orthodontics and Pediatric Dentistry Department, Faculty of Dentistry, Arab American University, Jenin, Palestine.

Objective: COVID-19 pandemic led to major life changes. We assessed the psychological impact of COVID-19 on dental academics globally and on changes in their behaviors.

Methods: We invited dental academics to complete a cross-sectional, online survey from March to May 2020. The survey was based on the Theory of Planned Behavior (TPB). The survey collected data on participants' stress levels (using the Impact of Event Scale), attitude (fears, and worries because of COVID-19 extracted by Principal Component Analysis (PCA), perceived control (resulting from training on public health emergencies), norms (country-level COVID-19 fatality rate), and personal and professional backgrounds. We used multilevel regression models to assess the association between the study outcome variables (frequent handwashing and avoidance of crowded places) and explanatory variables (stress, attitude, perceived control and norms).

Results: 1862 academics from 28 countries participated in the survey (response rate = 11.3%). Of those, 53.4% were female, 32.9% were <46 years old and 9.9% had severe stress. PCA extracted three main factors: fear of infection, worries because of professional responsibilities, and worries because of restricted mobility. These factors had significant dose-dependent association with stress and were significantly associated with more frequent handwashing by dental academics (B = 0.56, 0.33, and 0.34) and avoiding crowded places (B = 0.55, 0.30, and 0.28). Low country fatality rates were significantly associated with more handwashing (B = -2.82) and avoiding crowded places (B = -6.61). Training on public health emergencies was not significantly associated with behavior change (B = -0.01 and -0.11).

Conclusions: COVID-19 had a considerable psychological impact on dental academics. There was a direct, dose-dependent association between change in behaviors and worries but no association between these changes and training on public health emergencies. More change in behaviors was associated with lower country COVID-19 fatality rates. Fears and stresses were associated with greater adoption of preventive measures against the pandemic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239961PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523990PMC
October 2020

Extracellular glucose is crucially involved in the fate decision of LPS-stimulated RAW264.7 murine macrophage cells.

Sci Rep 2020 06 29;10(1):10581. Epub 2020 Jun 29.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Pyroptosis, a type of inflammatory cell death, is dependent on the inflammatory caspase-mediated cleavage of gasdermin D (GSDMD), and the subsequent pore formation on plasma membranes through which interleukin (IL)-1β and IL-18 are released from cells. During proinflammatory activation, macrophages shift their metabolism from aerobic oxidative phosphorylation to anaerobic glycolysis. Hypoxia-inducible factor (HIF)1α is involved in the induction of IL-1β gene expression as well as the metabolic shift towards glycolysis. However, the relationships between pyroptosis and glycolysis, as well as between pyroptosis and HIF1α are poorly investigated. Here we show that lipopolysaccharide (LPS) stimulation of RAW264.7 murine macrophage cells results in pyroptosis when cells are cultured in high glucose medium. During pyroptosis, HIF1α activation occurs transiently followed by downregulation to sub-basal levels. HIF1α downregulation and pyroptosis are observed when cells are stimulated with LPS under high glucose conditions. We also found that intracellular levels of methylglyoxal (MGO), a side product of glycolysis, increase when cells are stimulated with LPS under high glucose conditions. The addition of glycolysis inhibitor and rapamycin suppresses HIF1α downregulation and pyroptosis. These results show that glycolysis plays a crucial role not only in pro-inflammatory activation, but also in pyroptosis in LPS-stimulated RAW264.7 macrophages.
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http://dx.doi.org/10.1038/s41598-020-67396-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324593PMC
June 2020

Preparation of dentin standard samples for age estimation based on increased aspartic acid racemization rate by heating.

Leg Med (Tokyo) 2019 May 18;38:25-31. Epub 2019 Mar 18.

Department of Forensic Dentistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Age estimation in adults based on aspartic acid racemization (AAR) provides fewer errors and higher precision than that based on bone morphology for the identification of cadavers. The technique has been established in some labs as a routine method. However, as the essential requisites for the technique, a wide age range of teeth of the same type as the target tooth must be collected for calibration for each examination. We investigated whether dentin standard samples could be prepared by increasing the AAR rate via heat. Powdered dentin was prepared from a maxillary first premolar (13 years) and heated for 0-72 h at 110 °C. The extent of AAR increased significantly with heating time and the correlation was strong (r = 0.913; p < 0.01). Similar results were found for a mandibular canine (24 years, r = 0.948; p < 0.01) and a maxillary third molar (20 years, r = 0.944; p < 0.01). We attempted to estimate the age of four maxillary first premolars of persons aged 25-58 years by using the heated samples (18 years, 12 h to 7 days). The differences between the actual and estimated ages were within ±5 years. The stability of the AAR rates in the powdered dentin during storage at 22-25 °C, 4 °C, and -30 °C was examined after 1 year and no significant changes had occurred. We were able to prepare dentin standard samples and created a calibration curve. This is a pilot study that needs to be validated before it can be used in forensic practice.
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http://dx.doi.org/10.1016/j.legalmed.2019.03.005DOI Listing
May 2019

Formation of high molecular weight p62 by CORM-3.

PLoS One 2019 8;14(1):e0210474. Epub 2019 Jan 8.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.

CORM-3 is a water-soluble carbon monoxide (CO)-releasing molecule developed for possible therapeutic use of CO. CORM-3 belongs to a group of metal carbonyl compounds that contain transition metals and carbonyls as the central scaffold and coordinated ligands, respectively. CORM-3 has been reported to be reactive with many proteins in eukaryotes including mammals. Among them, several extracellular proteins, such as lysozyme, as well as plasma albumin and fibronectin, have been shown to interact directly with CORM-3. p62 is an intracellular adaptor protein required for targeting ubiquitinated (Ub) proteins to lysosomal degradation through autophagy. p62 has been shown to undergo self-oligomerization via covalent crosslinking in response to treatment with verteporfin, a benzoporphyrin derivative used for photodynamic therapy. Here we show that CORM-3 also interacts directly with p62. When applied to mouse embryonic fibroblasts (MEFs) at a high concentration (1 mM), CORM-3 causes the formation of reduction- and detergent-resistant high molecular weight (HMW)-p62. HMW-p62 accumulates more in atg5-/- MEFs than in wild type (WT) MEFs, showing the elimination of HMW-p62 through autophagy. HMW-p62 is also generated in H9c2 rat cardiomyoblastoma as well as A549 human alveolar epithelial cells, suggesting that HMW-p62 formation is not specific to MEFs, but, rather, is a general event in mammalian cells. HMW-p62 formation by CORM-3 can be reproduced using purified p62 in vitro, demonstrating the direct interaction between CORM-3 and p62. These results show that p62 is a CORM-3-interactive intracellular protein.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210474PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324786PMC
October 2019

Interaction of carbon monoxide-releasing ruthenium carbonyl CORM-3 with plasma fibronectin.

Toxicol In Vitro 2018 Aug 23;50:201-209. Epub 2018 Mar 23.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Inhaled carbon monoxide (CO) gas is highly toxic, but the human body produces low levels of CO for vasoregulation and other purposes. Given the established protective roles of low concentrations of CO gas against a panel of pathological insults, CO-releasing molecules (CORMs) have been developed and examined in disease models both in vitro and in vivo. Among CORMs, CORM-3 [Ru(CO)Cl(glycinate)], a ruthenium carbonyl compound, has been extensively studied since it is water-soluble and is suitable for in vivo application. As one of the most prominent features of CO gas is its anti-fibrotic effect, we examined the effects of CORM-3 on mouse embryonic fibroblasts (MEFs). The application of 1 mM CORM-3 to MEFs resulted in the decreased syntheses of collagens I and III within 24 h, confirming an anti-fibrotic effect. To our surprise, CORM-3 caused a rapid (within 1 h) dissociation of cell-associated plasma fibronectin (FN) from the cells, which is associated with formation of a reduction-resistant oligomer of plasma FN. This aberrant oligomerization of plasma FN was reproduced using purified FN in vitro. Furthermore, we showed that RuCl, but not another water-soluble CORM, CORM-A1 [NaHBCO], also oligomerized plasma FN in vitro. FN depletion from the serum substantially ameliorates cell death by prolonged (72 h) exposure to CORM-3, suggesting a detrimental role of FN oligomerization on cell death. Taken together, we reveal for the first time that FN is a CORM-3-interactive plasma protein, and that the CORM-3-FN interaction is involved in the death of fibroblasts.
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http://dx.doi.org/10.1016/j.tiv.2018.03.010DOI Listing
August 2018

Necrosis in human neuronal cells exposed to paraquat.

J Toxicol Sci 2018 ;43(3):193-202

Paraquat (PQ) is an herbicide that was once used worldwide, but is now prohibited in many nations due to its high toxicity to humans. However, there are still rare cases of the fetal intoxication of PQ, which was purchased prior to the prohibition in Japan. In this study, several cell death pathways, the mitochondrial stress response, and autophagy were examined in SH-SY5Y cells exposed to PQ. The results reveal the decrease of a mitochondrial stress sensitive-BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) protein, the suppression of autophagic flux, and the lack of apoptosis as well as other regulated forms of necrosis, such as necroptosis and ferroptosis. Taken together, our preliminary survey of cellular responses against PQ shows that, although responses of mitochondria and autophagy are observed, subsequent cell death is necrosis. Mechanism of PQ-induced SH-SY5Y cell death should be complicated and cannot be explained thoroughly by already-known mechanisms.
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http://dx.doi.org/10.2131/jts.43.193DOI Listing
August 2018

Effects of an interactive simulation material for clinical dentistry on knowledge acquisition and memory retention in dental residents.

J Med Dent Sci 2017 ;64(4):43-52

Department of Educational Media Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University.

With the development of technology, the knowledge and skills needed to become a dentist are increasing. Computer-assisted simulation learning materials have been utilized for dental education because of their high efficiency and efficacy. However, it is not well understood which material design is strongly associated with an education effect. We therefore investigated the effects of interactivity with learning materials on learners' knowledge acquisition, memory retention, and anxiety reduction. Learning effects and degree of anxiety were compared between dental residents who learned using an interactive-type material, which required decision making and provided feedback (Group I, n=26), and those who learned using a display-type material, which merely displayed the appropriate action on a computer screen (Group D, n=23). Quiz scores immediately after learning and 3 weeks later were significantly higher in Group I than those in Group D (p<0.001 and 0.016, espectively). Regarding anxiety, state anxiety after learning with interactive material was significantly decreased in Group I (p<0.05), whereas no significant change was observed in Group D. Our results suggest that interactivity with computerassisted simulation materials is more effective for knowledge acquisition, memory retention, and anxiety reduction.
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http://dx.doi.org/10.11480/jmds.640401DOI Listing
August 2018

Ataxia telangiectasia and rad3 related (ATR)-promyelocytic leukemia protein (PML) pathway of the DNA damage response in the brain of rats administered arsenic trioxide.

J Toxicol Pathol 2017 Oct 3;30(4):333-337. Epub 2017 Jul 3.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

To examine the responses of promyelocytic leukemia protein (PML) to arsenic, rats (male, 6 weeks old, Sprague Dawley) were administered a single intraperitoneal dose of 5 mg/kg arsenic trioxide (ATO). The protein was examined in the heart, lung, liver, and brain 6 and 48 hours after administration: a significant response of PML was observed in the brain. Oxidative DNA modification was also observed in the brain as revealed by increased immunoreactivity to anti-8-hydroxy-2'-deoxyguanosine (8-OHdG) antibody. In contrast, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) stain reactivity was only slightly increased, suggesting oxidative cellular stress without apoptotic cell death in the ATO-administered rat brain. Among the DNA damage response pathways, the ATR-Chk1 axis was activated, while the ATM-Chk2 axis was not, implying that the PML response is associated with activation of the ATR-Chk1 DNA repair pathway in the brain.
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http://dx.doi.org/10.1293/tox.2017-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660956PMC
October 2017

Restoration of YAP activation rescues HL-1 cardiomyocytes from apoptotic death by ethanol.

J Toxicol Sci 2017 ;42(5):545-551

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University.

We reported previously that when mouse atrium-derived HL-1 cardiomyocytes undergo apoptosis upon exposure to 2% ethanol, the cellular cytoskeleton is severely disrupted and the anti-apoptotic transcriptional co-activator Yes-associated protein (YAP) is inactivated. Consistent with our previous observations, the expression of connective tissue growth factor (CTGF), an anti-apoptotic growth factor and a target of YAP, decreases in a time-dependent manner during exposure to 2% ethanol. The restoration of YAP activation rescues the cells from apoptosis: both the retrovirus-mediated expression of constitutively active YAP and the stabilization of the actomyosin cytoskeleton by jasplakinolide prevent cell death. In contrast, YAP inhibitors have no effect on cell death, confirming the inactivation of YAP in ethanol-exposed cells. Thus, a decrease in actin tension and YAP inactivation should be crucially involved in the cytotoxicity of ethanol on HL-1 cardiomyocytes.
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http://dx.doi.org/10.2131/jts.42.545DOI Listing
January 2018

A CO-releasing molecule prevents annexin A2 down-regulation and associated disorders in LPS-administered rat lung.

Biochem Biophys Res Commun 2017 Jun 25;487(3):748-754. Epub 2017 Apr 25.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

To investigate septic lung injuries and the possible relief from injury by carbon monoxide (CO), rats were intraperitoneally (i.p.) administered water or the water-soluble CO-releasing molecule CORM (30 mg/kg body weight), followed by the successive administration of PBS or lipopolysaccharide (LPS, 15 mg/kg body weight, 6 h). The results in four experimental groups (control, LPS, LPS + CORM, CORM, n = 3 or 4 in each groups) were examined. Histological examination revealed the intravascular aggregation of erythrocytes in the lungs of the LPS group, and serological analysis showed a significant increase in D-dimer in the LPS group. Both the aggregation and D-dimer increase were ameliorated in the LPS + CORM group, suggesting that LPS-induced DIC in the lung is ameliorated by CORM. Proteomic as well as immunoblot analyses revealed that the levels of annexin A (AnxA) were significantly decreased in the LPS group, but were at control levels in the LPS + CORM group. Concordant with the levels of AnxA, the levels of both LC3 and collagen VI (COL VI) were decreased in the LPS group but not in the LPS + CORM group. Given the established roles of AnxA in fibrinolysis as well as intracellular vesicle trafficking, AnxA down-regulation should play an important role in the pathogenesis of septic lung injuries.
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http://dx.doi.org/10.1016/j.bbrc.2017.04.131DOI Listing
June 2017

Hydrogen sulfide donor NaHS induces death of alveolar epithelial L2 cells that is associated with cellular shrinkage, transgelin expression and myosin phosphorylation.

J Toxicol Sci 2016 ;41(5):645-54

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University.

Hydrogen sulfide (H2S) is a highly toxic gaseous molecule that causes death to humans exposed to high concentrations. H2S is absorbed into the body through the alveolar epithelium and other tissues. The aim of this study is to evaluate the molecular mechanism underling acute lung injury caused by the inhalation of high concentrations of H2S. Rat lung epithelium-derived L2 cells were exposed to a H2S donor, NaHS, at concentrations of 2-4 mM for 1-6 hr. NaHS caused shrinkage and death of the cells without caspase activation. An actin-binding protein, transgelin, was identified as one of the NaHS-inducible proteins in the cells. NaHS increased myosin light chain (MLC) phosphorylation, indicating that actomyosin-mediated cellular contractility and/or motility could be increased after NaHS exposure. The administration of ML-7, a myosin light chain kinase (MLCK) inhibitor, accelerated cell death after NaHS exposure. Based on these data, we conclude that the increase in MLC phosphorylation in response to NaHS exposure is a cellular protective reaction against NaHS toxicity. Enhancements in smooth muscle cell properties such as transgelin expression and actomyosin-mediated contractility/motility might be involved in cell survival after NaHS exposure.
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http://dx.doi.org/10.2131/jts.41.645DOI Listing
April 2017

Differences between Computer-Based and Paper-Based Assessments of the Clinical Reasoning Competency of Dental Students.

Kokubyo Gakkai Zasshi 2016 Mar;83(1):25-33

Clinical reasoning competency is essential for an appropriate clinical dental treatment. Among the tools for the assessment of clinical reasoning competency, computer-based testing (CBT) is considered more useful than paper-based testing (PBT), because teachers can control the timing of information given to the examinees. Such timings could possibly affect the thinking process of examinees. However, few studies reported differences of reasoning between the two testing modes. In the present study, we developed an assessment of clinical reasoning and applied it using CBT and PBT to compare the examinees' performance. The participants comprised 60 students in the fifth-year class in 2012 of the School of Dentistry, Faculty of Dentistry, Tokyo Medical and Dental University. The tests comprised 25 problems, each with four questions, totaling 100 questions. The contents of the questions were the same in CBT and PBT. The students were assigned to CBT (Group C, n = 30) and PBT (Group P, n = 30) groups, with an almost equal gender ratio in the groups. The difference between scores was analyzed with a univariate analysis of variance. No significant intergroup differences were found regarding the test duration, total score, and average score of each question. The number of problems with perfect marks was higher in Group P than in Group C (P < 0.05), probably because Group P students could access the information of the previous question (s) within a problem. Thus, the differences of the examinees' performance between the two testing modes were small.
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March 2016

Direct Exposure to Ethanol Disrupts Junctional Cell-Cell Contact and Hippo-YAP Signaling in HL-1 Murine Atrial Cardiomyocytes.

PLoS One 2015 28;10(8):e0136952. Epub 2015 Aug 28.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Direct exposure of cardiomyocytes to ethanol causes cardiac damage such as cardiac arrythmias and apoptotic cell death. Cardiomyocytes are connected to each other through intercalated disks (ID), which are composed of a gap junction (GJ), adherens junction, and desmosome. Changes in the content as well as the subcellular localization of connexin43 (Cx43), the main component of the cardiac GJ, are reportedly involved in cardiac arrythmias and subsequent damage. Recently, the hippo-YAP signaling pathway, which links cellular physical status to cell proliferation, differentiation, and apoptosis, has been implicated in cardiac homeostasis under physiological as well as pathological conditions. This study was conducted to explore the possible involvement of junctional intercellular communication, mechanotransduction through cytoskeletal organization, and the hippo-YAP pathway in cardiac damage caused by direct exposure to ethanol. HL-1 murine atrial cardiac cells were used since these cells retain cardiac phenotypes through ID formation and subsequent synchronous contraction. Cells were exposed to 0.5-2% ethanol; significant apoptotic cell death was observed after exposure to 2% ethanol for 48 hours. A decrease in Cx43 levels was already observed after 3 hours exposure to 2% ethanol, suggesting a rapid degradation of this protein. Upon exposure to ethanol, Cx43 translocated into lysosomes. Cellular cytoskeletal organization was also dysregulated by ethanol, as demonstrated by the disruption of myofibrils and intermediate filaments. Coinciding with the loss of cell-cell adherence, decreased phosphorylation of YAP, a hippo pathway effector, was also observed in ethanol-treated cells. Taken together, the results provide evidence that cells exposed directly to ethanol show 1) impaired cell-cell adherence/communication, 2) decreased cellular mechanotransduction by the cytoskeleton, and 3) a suppressed hippo-YAP pathway. Suppression of hippo-YAP pathway signaling should be effective in maintaining cellular homeostasis in cardiomyocytes exposed to ethanol.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136952PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552866PMC
May 2016

An Autopsy Case of Acute Massive Hematochezia Caused by Superior Mesenteric Vein Thrombosis: A First Report in Forensic Medicine.

J Forensic Sci 2016 Jan 13;61(1):271-3. Epub 2015 Aug 13.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Superior mesenteric vein thrombosis (SMVT) is an uncommon cause of intestinal ischemia and massive gastrointestinal bleeding. This report describes a man with alcoholic liver cirrhosis, who died of massive hematochezia due to SMVT. A medicolegal autopsy disclosed a thrombus at the superior mesenteric vein and hemorrhagic infarction of the bowel wall, an area also within the territory of the superior mesenteric vein. Liver cirrhosis, an enlarged spleen, and esophageal varices without rupture were also observed, but ulcers and variceal bleeding were not. Other organs showed no significant findings. His blood alcohol level was 0.14% w/v. Thus, this man died from severe hematochezia associated with SMVT due to liver cirrhosis and alcohol dehydration, which can lead to coagulopathy and rapid progress of thrombus formation. This is the first report on an alternate cause for massive gastrointestinal hemorrhage with a cirrhotic patient in a forensic autopsy.
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http://dx.doi.org/10.1111/1556-4029.12903DOI Listing
January 2016

An autopsy case of vagus nerve stimulation following acupuncture.

Leg Med (Tokyo) 2015 Mar 11;17(2):120-2. Epub 2014 Nov 11.

Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Electronic address:

Acupuncture is one of the most popular oriental medical techniques in China, Korea and Japan. This technique is also popular as alternative therapy in the Western World. Serious adverse events are rare following acupuncture, and fatal cases have been rarely reported. A male in his late forties died right after acupuncture treatment. A medico-legal autopsy disclosed severe haemorrhaging around the right vagus nerve in the neck. Other organs and laboratory data showed no significant findings. Thus, it was determined that the man could have died from severe vagal bradycardia and/or arrhythmia resulting from vagus nerve stimulation following acupuncture. To the best of our knowledge, this is the first report of a death due to vagus nerve injury after acupuncture.
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http://dx.doi.org/10.1016/j.legalmed.2014.11.001DOI Listing
March 2015

Use of a gelatin hydrogel membrane containing β-tricalcium phosphate for guided bone regeneration enhances rapid bone formation.

Dent Mater J 2014 ;33(5):674-80

Section of Oral Implantology and Regenerative Dental Medicine, Department of Masticatory Function Rehabilitation, Tokyo Medical and Dental University.

The purpose of this study was to evaluate a thin gelatin hydrogel membrane containing β-tricalcium phosphate (G-TCP) for use in guided bone regeneration, a technique that we developed. G-TCP membranes were fabricated from gelatin and β-TCP powder, freezedried, and cross-linked by heating. The resulting G-TCP membranes were as thin as collagen membranes, with high mechanical integrity. Proliferation and differentiation of rat bone marrow stromal cells (BMSCs) on G-TCP and collagen membranes were examined. On both membranes, BMSCs proliferated well and expressed alkaline phosphatase. However, more bone-like mineralized tissue formed on G-TCP membranes than on collagen membranes at 4 weeks. The effects of G-TCP and collagen membranes on bone regeneration in rat parietal bone defects were histologically examined. Bone bridges with mature uniform bone were observed under G-TCP membranes as early as 2 weeks. These results indicate that G-TCP is a GBR membrane that is comparable or superior to collagen membrane.
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http://dx.doi.org/10.4012/dmj.2014-123DOI Listing
September 2016

Distinct effects of methamphetamine on autophagy-lysosome and ubiquitin-proteasome systems in HL-1 cultured mouse atrial cardiomyocytes.

Toxicology 2013 Oct 7;312:74-82. Epub 2013 Aug 7.

Section of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

The aim of this study is to investigate the molecular mechanism underling the cardiotoxicity of methamphetamine, a psychostimulant drug that is currently abused in the world. A mouse atrial cardiac cell line, HL-1, which retains phenotypes of cardiac cells and serves as a useful model for examining cardiac pathophysiology, was used for this purpose. During treatment with 1mM methamphetamine (MAP) for 3-48h, massive but transient cytoplasmic vacuolization (3-12h) followed by an intracellular accumulation of granules (24-48h) was observed under light microscopy. The vacuoles were surrounded by the lysosome membrane marker LAMP1, while the granules colocalized with the autophagy markers LC3 and p62 as well as ubiquitinated proteins. Western blot analysis showed that LC3 was activated during MAP administration, although p62 was not degraded but rather accumulated. Concordant with p62 accumulation, the nuclear translocation of an anti-oxidative transcription factor, Nrf2, and the subsequent induction of its target gene, HO-1, was observed, suggesting an impairment of autophagic protein degradation and the subsequent activation of the p62/Nrf2/HO-1 pathway. In addition, proteomic analysis revealed a reduction in myosin heavy chain (MHC) protein levels during MAP administration. The ubiquitination of MHC and the induction of the muscle sarcomere protein-specific E3 ubiquitin ligases MuRF1 and atrogin-1 were proved by immunoprecipitation and quantitative real-time PCR, respectively. Taken together, the vacuolization of lysosomes and the subsequent accumulation of autophagosomes indicate an impairment of autophagic protein degradation during MAP administration; on the other hand, the ubiquitination and subsequent degradation of MHC indicate the proper progression of proteasomal degradation.
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http://dx.doi.org/10.1016/j.tox.2013.07.016DOI Listing
October 2013

Peri-implantitis progression around thin sputtered hydroxyapatite-coated implants: clinical and radiographic evaluation in dogs.

Int J Oral Maxillofac Implants 2013 May-Jun;28(3):701-9

Department of Implantology abd Regenerative Dental Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Purpose: Soft and hard tissue responses to experimental peri-implantitis around thin sputter hydroxyapatite (HA)-coated implants were evaluated and compared to the responses to implants with other surface treatments.

Materials And Methods: Forty-eight dental implants with four different surfaces--machined (M), sandblasted/acid-etched (SA), 1-μm thin sputter HA-coated (S), and plasma-sprayed HA-coated (P)--were inserted into the mandibles of six beagle dogs. Three months later, experimental peri-implantitis was induced with ligatures to allow plaque accumulation. After a 4-month period of active breakdown, the ligatures were removed, and plaque accumulation continued for 5 additional months (progression period). Radiographic marginal bone levels, probing depths, clinical attachment levels, and modified Gingival Index were evaluated at baseline, after the active breakdown period, and after the progression period.

Results: Significant increases in mean probing depths and clinical attachment levels were seen around all implants after active breakdown, but no significant differences were found during the progression period. Radiographic analysis revealed marginal bone loss of 1 to 1.7 mm during the active breakdown period. Additional bone loss occurred during the progression period (M 0.2 mm, SA 0.3 mm, S 0.2 mm, P 0.4 mm).

Conclusion: Comparable tissue behavior was demonstrated around dental implants with all four surfaces under peri-implantitis conditions. Thin sputter HA-coated implants possess the favorable osteoconductive properties of calcium phosphate coatings without exacerbating further peri-implant tissue breakdown during the progression of peri-implantitis.
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http://dx.doi.org/10.11607/jomi.2891DOI Listing
April 2014

Rho-kinase inhibitor Y-27632 attenuates arsenic trioxide toxicity in H9c2 cardiomyoblastoma cells.

Cardiovasc Toxicol 2013 Sep;13(3):267-77

Section of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

The purpose of this study is to examine the molecular mechanism underlying the toxicity of arsenic trioxide (ATO) in cardiac cells. H9c2 rat cardiomyoblastoma cells undergo apoptosis during exposure to the concentrations of ATO > 10 μM for 24 h. The process is accompanied by the activation of caspases and is suppressed by the pan-caspase inhibitor z-VAD. Since ATO-induced H9c2 cell death is suppressed by Rho-kinase (ROCK) inhibitor Y-27632, but not by any antioxidants tested, apoptosis by ATO seems to be initiated through a ROCK-dependent and reactive oxygen species-independent mechanism. During the execution of apoptosis by ATO, the induction of autophagy is also observed. Importantly, autophagy is accelerated in cells treated with ATO plus Y-27632, although Y-27632 alone does not induce autophagy. The cytoprotective effect of Y-27632 against ATO toxicity is abrogated by the co-administration of an autophagy inhibitor, 3-methyladenine, suggesting that autophagy contributes to the cytoprotection by Y-27632. Taken together, the data indicate that the activation of ROCK is required for apoptotic H9c2 cardiomyoblastoma cell death by ATO, and that the ROCK inhibition not only inhibits caspase-dependent apoptotic machinery, but also causes a rise in the cytoprotective autophagy processes during ATO exposure.
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http://dx.doi.org/10.1007/s12012-013-9206-2DOI Listing
September 2013

Accelerated and enhanced bone formation on novel simvastatin-loaded porous titanium oxide surfaces.

Clin Implant Dent Relat Res 2014 Oct 7;16(5):675-83. Epub 2013 Feb 7.

Department of Prosthodontics, University of Dental Medicine, Yangon, Myanmar; Department of Oral Implantology and Regenerative Dental Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan.

Background: With increasing application of dental implants in poor-quality bones, the need for implant surfaces ensuring accelerated osseointegration and enhanced peri-implant bone regeneration is increased.

Purpose: A study was performed to evaluate the osseointegration and bone formation on novel simvastatin-loaded porous titanium oxide surface.

Materials And Methods: Titanium screws were treated by micro-arc oxidation to form porous oxide surface and 25 or 50 μg of simvastatin was loaded. The nontreated control, micro-arc oxidized, and simvastatin-loaded titanium screws were surgically implanted into the proximal tibia of 16-week-old male Wistar rats (n = 36). Peri-implant bone volume, bone-implant contact, and mineral apposition rates were measured at 2 and 4 weeks. Data were analyzed by one-way analysis of variance followed by Tukey's post hoc test.

Results: New bone was formed directly on the implant surface in the bone marrow cavity in simvastatin-loaded groups since 2 weeks. Bone-implant contact values were significantly higher in simvastatin-loaded groups than control and micro-arc oxidized groups at both time points (p < .05). Peri-implant bone volume and mineral apposition rate of simvastatin-loaded groups were significantly higher than control and micro-arc oxidized groups at 2 weeks (p < .05).

Conclusions: These data suggested that simvastatin-loaded porous titanium oxide surface provides faster osseointegration and peri-implant bone formation and it would be potentially applicable in poor-quality bones.
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http://dx.doi.org/10.1111/cid.12045DOI Listing
October 2014

Feasibility of alpha tricalcium phosphate for vertical bone augmentation.

J Investig Clin Dent 2014 May 17;5(2):109-16. Epub 2012 Dec 17.

Department of Oral Implantology and Regenerative Dental Medicine, Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan; Department of Prosthodontics, University of Dental Medicine, Yangon, Myanmar.

Aim: Inadequate vertical bone compromises dental implant positioning and subsequent restoration. This study was carried out to investigate the feasibility of alpha tricalcium phosphate (α-TCP) for vertical bone augmentation.

Methods: Nine cortical perforations were made on each side of the parietal bone of rat calvaria under continuous saline coolant. Polytetrafluoroethylene cylinders were placed under the periosteum and α-TCP particles were applied in the cylinders in the TCP group while the cylinders were left empty in the control group. The animals were sacrificed at 4 and 8 weeks after surgery and analyzed radiologically and histologically.

Results: The augmented bone volumes in the control and TCP groups were 91.5 ± 25.6% and 76.5 ± 49.8% (mean ± SD) of the original bone at 4 weeks, and 136.3 ± 59.7% and 139 ± 62.4% at 8 weeks respectively. There was no significant difference between control and test groups. At 4 weeks the bone height was augmented by 168.8 ± 26.7% and 128.8 ± 62% in the control and TCP groups respectively (not significant), whereas significantly higher vertical bone was achieved in the TCP group than in the control group at 8 weeks (251 ± 32% vs 179.2 ± 30.3%, P < 0.05).

Conclusion: After 8 weeks α-TCP is effective in maintaining space under periosteum and potentially would be applicable in vertical bone augmentation.
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http://dx.doi.org/10.1111/jicd.12022DOI Listing
May 2014

Critical roles of Rho-associated kinase in membrane blebbing and mitochondrial pathway of apoptosis caused by 1-butanol.

Toxicol In Vitro 2012 Sep 4;26(6):849-55. Epub 2012 May 4.

Section of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Alcohols are widely used as industrial solvents and chemical intermediates but can cause serious damage to human health. Nevertheless, few studies have addressed the molecular mechanisms underlying the cytotoxicity of industrial alcohols, with the notable exception of ethanol. The goal of our current study is to elucidate the molecular mechanism of cytotoxicity caused by primary alcohols containing longer carbon chains than ethanol. We find that 1-butanol induces morphological changes in H9c2 cardiomyoblastoma including nuclear condensation and membrane blebbing, both of which are features of apoptotic response. Moreover, a decrease in the mitochondrial membrane potential, the cytosolic release of cytochrome c, and the activation of caspase 9 and 3 was observed, thus revealing the activation of the mitochondrial apoptotic pathway by 1-butanol. The addition of Y-27632, a specific inhibitor of Rho-associated kinase (ROCK), suppressed the membrane blebbing and mitochondrial apoptotic pathway. In comparison z-VAD-fmk, a pan-caspase inhibitor, did not inhibit membrane blebbing but did prevent cell death following exposure to 1-butanol. These results indicate that mitochondrial pathway of apoptosis and membrane blebbing are parallel phenomena that occur downstream of ROCK. This kinase thus plays an essential role in 1-butanol cytotoxicity and subsequent cell death in H9c2 cells.
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http://dx.doi.org/10.1016/j.tiv.2012.04.027DOI Listing
September 2012

Autopsy findings of a patient with rapidly progressive massive ascites caused by alcoholic cirrhosis.

Leg Med (Tokyo) 2011 May 28;13(3):148-50. Epub 2011 Jan 28.

Section of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

A 54-year-old man, who lived alone, was hospitalized due to rapid deterioration of the general condition over a three-week period caused by alcoholic cirrhosis. One month after he left hospital, he was found dead in his house by his friend. Three days before he was found dead, he had met his friend and seemed to be in poor condition. Autopsy was conducted by a medical examiner to clarify the cause of death. Externally, signs of severe jaundice were apparent over the whole body, along with extensive abdominal swelling and edema of the extremities. Autopsy findings demonstrated that the abdominal cavity contained an amount of massive turbid and slight pale reddish brown ascites (23 l). There were no findings of severe peritoneal inflammation. The liver (650 g) was elastic hard and had a micro-nodular surface, which showed severe atrophy. Microscopic examination of the liver showed clear pseudolobule with severe fibrosis in the stroma. There were no significant changes in the heart or brain. The stomach was empty and only a slight amount of intestinal contents. There was no ethanol detected in the blood or urine. The direct cause of his death was circulatory dysfunction due to massive accumulation of the ascites. The reasons for the massive ascites accumulation over 20 l in this case were (1) that he had no serious complications other than ascites; and (2) he did not have any medical treatment just before his death.
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http://dx.doi.org/10.1016/j.legalmed.2010.12.006DOI Listing
May 2011
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