乳幼児の予期せぬ突然死の分類を支援するベイジアンネットワークモデルの構築についての概念実証研究

京都大学新制・課程博士博士(医学)甲第24201号医博第4895号京都大学大学院医学研究科医学専攻(主査)教授 西浦 博, 教授 森田 智視, 教授 松村 由美学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Mitochondrial fission in hepatocytes as a potential therapeutic target for nonalcoholic steatohepatitis

[Aim] The mitochondria are highly plastic and dynamic organelles; mitochondrial dysfunction has been reported to play causative roles in diabetes, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). However, the relationship between mitochondrial fission and NAFLD pathogenesis remains unknown. We aimed to investigate whether alterations in mitochondrial fission could play a role in the progression of NAFLD. [Methods] Mice were fed a standard diet or choline-deficient, L-amino acid-defined (CDAA) diet with vehicle or mitochondrial division inhibitor-1. [Results] Substantial enhancement of mitochondrial fission in hepatocytes was triggered by 4 weeks of feeding and was associated with changes reflecting the early stage of human nonalcoholic steatohepatitis (NASH), steatotic change with liver inflammation, and hepatocyte ballooning. Excessive mitochondrial fission inhibition in hepatocytes and lipid metabolism dysregulation in adipose tissue attenuated liver inflammation and fibrogenesis but not steatosis and the systemic pathological changes in the early and chronic fibrotic NASH stages (4- and 12-week CDAA feeding). These beneficial changes due to the suppression of mitochondrial fission against the liver and systemic injuries were associated with decreased autophagic responses and endoplasmic reticulum stress in hepatocytes. Injuries to other liver cells, such as endothelial cells, Kupffer cells, and hepatic stellate cells, were also attenuated by the inhibition of mitochondrial fission in hepatocytes. [Conclusions] Taken together, these findings suggest that excessive mitochondrial fission in hepatocytes could play a causative role in NAFLD progression by liver inflammation and fibrogenesis through altered cell cross-talk. This study provides a potential therapeutic target for NAFLD

Individual Keratinocyte Necroses in the Epidermis Are Apoptotic Keratinocytes in the Skin

The patient was a 44-year-old woman with Stevens–Johnson syndrome due to receiving Baktar® (sulfamethoxazole trimethoprim) medication at our outpatient dermatology clinic. The epidermis, dermis, and subcutaneous adipose tissue samples showed numerous necrotic keratinocytes in the epidermis. Apoptotic nuclei were visualized as diaminobenzidine brown deposits with immunoperoxidase staining for cleaved caspase-3. The cleaved caspase-3-positive findings were consistent with eosinophilic material that appeared to be necrotic cells within the epidermis. Therefore, these eosinophilic materials may be apoptotic bodies. Generally speaking, eosinophilic cells are considered necrotic keratinocytes, especially in Japan. To the best of our knowledge, no studies have used apoptotic immunohistochemical markers to examine whether these structures are apoptotic in a human specimen

Fatal Dieulafoy lesion with IgG4-related disease: An autopsy case report

Dieulafoy lesions are rare vascular malformations of the gastrointestinal tract; however, they can lead to fatal vascular bleeding. Immunoglobulin G4-related disease (IgG4-RD) is a rare systemic fibroinflammatory disease involving multiple organs, including the vasculature. To date, no autopsy reports of Dieulafoy lesions with IgG4-RD have been described in the literature. A 48-year-old man was found dead in his home with hematochezia. Postmortem computed tomography revealed high-density gastric contents and an enlarged iso-density area in the pancreas, indicating gastric hemorrhage and mass-forming lesions. Macroscopic and histological examinations revealed an ulcer of the body of the stomach with a large amount of hemorrhage from the enlarged artery in the submucosal layer, confirming the rupture of the Dieulafoy lesion. Moreover, lymphocyte infiltrations with increased IgG4 positive cells were found in the pancreas, thyroid gland, and arteries in non-ulcer regions of the stomach, suggesting IgG4-RD. Serum biochemical analysis showed elevated levels of inflammatory mediators, such as IgE, soluble-interleukin-2 receptor, and C-reactive protein. These findings suggest that systemic inflammation caused by IgG4-RD could, at least in part, contribute to the development of Dieulafoy lesions and fatal rupture of the lesion. This case report highlights the importance of autopsy research focusing on Dieulafoy lesions and IgG4-RD to promote awareness and a better understanding of the relationships between these treatable diseases to establish earlier and effective interventional strategies for better patient outcomes

Circumstances and factors of sleep-related sudden infancy deaths in Japan.

BackgroundSudden unexpected death in infancy (SUDI) comprises both natural and unnatural causes of death. However, few epidemiological surveys have investigated SUDI in Japan.ObjectiveThis retrospective study was conducted to investigate the latest trends of circumstances and risk factors of SUDI cases in which collapse occurred during sleep.MethodsForensic pathology sections from eight universities participated in the selection of subjects from 2013 to 2018. Data obtained from the checklist form were analyzed based on information at postmortem.ResultsThere were 259 SUDI cases consisting of 145 male infants and 114 female infants with a mean birth weight of 2888 ± 553 and 2750 ± 370 g, respectively. Deaths most frequently occurred among infants at 1 month of age (18%). According to population data as the control, the odds ratio (95% confidence interval) of mother's age ≤19 years was 11.1 (6.9-17.7) compared with ages 30-39. The odds ratio for the fourth- and later born infants was 5.2 (3.4-7.9) compared with the frequency of first-born infants. The most frequent time of day for discovery was between 7 and 8 o'clock, and the time difference from the last seen alive was a mean of 4.1 h. Co-sleeping was recorded for 61%, and the prone position was found for 40% of cases at discovery. Mother's smoking habit exhibited an odds ratio of 4.5 (2.9-5.8).ConclusionThis study confirmed the trends that have been observed for sudden infant death syndrome; particularly, very high odds ratios were evident for teenage mothers and later birth order in comparison with those in other developed countries. Neglect was suspected in some cases of the prolonged time to discovery of unreactive infants. To our knowledge, this is the first report of an extensive survey of SUDI during sleep in Japan

Gradual Telomere Shortening and Increasing Chromosomal Instability among PanIN Grades and Normal Ductal Epithelia with and without Cancer in the Pancreas

<div><p>A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence <i>in situ</i> hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, −2 and −3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and −2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer.</p></div

Relationship between telomere length and presence of atypical mitotic figures including anaphase bridges.

<p>(a-c) Representative atypical mitotic figures. Arrows indicate multipolar mitosis (a), ring mitosis (b), and an anaphase bridge (c). (d and e) Correlation between NTCR and mitosis for the lesions as a whole (d) and overall minus cancer (e). Data are shown as the percentage of total mitotic Figures among the total cell count. (f and g) Correlation between NTCR and percentage of atypical mitoses or anaphase bridges among the lesions as a whole (f) and overall minus cancer (g). Data are shown as the percentage of atypical mitoses or anaphase bridges among the total number of mitotic figures.</p

Telomere length in normal duct epithelium from autopsy and surgically resected cases.

<p>(a) NTCR in the normal duct epithelium in 150 autopsy and 69 surgically resected cases was negatively correlated with age in the cases overall (n = 219, black), the control group (n = 91, blue) and the PanIN group (n = 92, green), but the relationship was not statistically significant in the pancreatic cancer group (n = 36, red). (b) Comparison of NTCR in the normal duct epithelium between the control, PanIN and pancreatic cancer groups. *<i>P<0</i>.<i>05</i> vs control. **<i>P<0</i>.<i>01</i> vs control. (c) NTCR in the normal duct epithelium from individuals aged over 50 years (n = 182). Blue, control (n = 57); green, PanIN (n = 189); red, pancreatic cancer group (n = 36). (d) Comparison of NTCR in the normal duct epithelium among the control, PanIN and pancreatic cancer groups. *<i>P<0</i>.<i>05</i> vs control.</p