Hitoshi Abiru

Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression.

Liver sinusoidal endothelial cells (LSECs) are involved in the transport of nutrients, lipids, and lipoproteins, and LSEC injury occurs in various liver diseases including nonalcoholic fatty liver disease (NAFLD). However, the association between LSEC injury and NAFLD progression remains elusive. Accordingly, in this study, we aimed to elucidate the precise role of LSEC in the pathophysiology of NAFLD using two different mouse models, namely the choline-deficient, L-amino acid-defined and high-fat diet models. Administration of these diets resulted in liver metabolic dysregulation mimicking human NAFLD, such as steatosis, ballooning, lobular inflammation, and fibrosis, as well as central obesity, insulin resistance, and hyperlipidemia. LSEC injury appeared during the simple steatosis phase, and preceded the appearance of activated Kupffer cells and hepatic stellate cells (HSCs). These results indicate that LSEC injury may have a ‘gatekeeper’ role in the progression from simple steatosis to the early nonalcoholic steatohepatitis (NASH) stage, and LSEC injury may be necessary for the activation of Kupffer cells and HSCs, which in turn results in the development and perpetuation of chronic liver injuries. Taken together, our data provide new insights into the role of LSEC injury in NAFLD/NASH pathogenesis.

Sorbin and SH3 Domain-Containing Protein 2 Is Released From Infarcted Heart in the Very Early Phase: Proteomic Analysis of Cardiac Tissues From Patients

Background Few proteomic studies have examined human cardiac tissue following acute lethal infarction. Here, we applied a novel proteomic approach to formalin‐fixed, paraffin‐embedded human tissue and aimed to reveal the molecular changes in the very early phase of acute myocardial infarction. Methods and Results Heart tissue samples were collected from 5 patients who died within 7 hours of myocardial infarction and from 5 age‐ and sex‐matched control cases. Infarcted and control myocardia were histopathologically diagnosed and captured using laser microdissection. Proteins were extracted using an originally established method and analyzed using liquid chromatography–tandem mass spectrometry. The label‐free quantification demonstrated that the levels of 21 proteins differed significantly between patients and controls. In addition to known biomarkers, the sarcoplasmic protein sorbin and SH3 domain‐containing protein 2 (SORBS2) was greatly reduced in infarcted myocardia. Immunohistochemical analysis of cardiac tissues confirmed the decrease, and Western blot analysis showed a significant increase in serum sorbin and SH3 domain‐containing protein 2 in acute myocardial infarction patients (n=10) compared with control cases (n=11). Conclusions Our advanced comprehensive analysis using patient tissues and serums indicated that sarcoplasmic sorbin and SH3 domain‐containing protein 2 is released from damaged cardiac tissue into the bloodstream upon lethal acute myocardial infarction. The proteomic strategy presented here is based on precise microscopic findings and is quite useful for candidate biomarker discovery using human tissue samples stored in depositories.

Circulating Extracellular Histones Are Clinically Relevant Mediators of Multiple Organ Injury

Extracellular histones are a damage-associated molecular pattern (DAMP) involved in the pathogenesis of various diseases. The mechanisms of histone-mediated injury in certain organs have been extensively studied, but an understanding of the pathophysiological role of histone-mediated injury in multiple organ injury remains elusive. To elucidate this role, we systemically subjected C57BL/6 mice to various doses of histones and performed a chronological evaluation of the morphological and functional changes in the lungs, liver, and kidneys. Notably, histone administration ultimately led to death after a dose-dependent aggravation of multiple organ injury. In chronological studies, pulmonary and hepatic injuries occurred within 15 minutes, whereas renal injuries presented at a later phase, suggesting that susceptibility to extracellular histones varies among organs. Histones bound to pulmonary and hepatic endothelial cells immediately after administration, leading to endothelial damage, which could be ameliorated by pretreatment with heparin. Furthermore, release of another DAMP, high-mobility group protein box 1, followed the histone-induced tissue damage, and an antibody against the molecule ameliorated hepatic and renal failure in a late phase. These findings indicate that extracellular histones induce multiple organ injury in two progressive stages-direct injury to endothelial cells and the subsequent release of other DAMPs-and that combination therapies against extracellular histones and high-mobility group protein box 1 may be a promising strategy for treating multiple organ injury.

Ectopic cervical thymus associated with infant death: 2 case reports and literature review

An ectopic cervical thymus is a rare congenital anomaly that can be located anywhere along the developmental pathway of thymic descent. Most lesions manifest as a cystic mass and have an indolent course. Two fatal cases associated with ectopic cervical thymus in the form of a solid mass are presented in conjunction with a review of the clinicopathological characteristics of the solid form. This report emphasizes the importance of considering a diagnosis of ectopic cervical thymus in infants with neck masses, with or without obstructive symptoms, to prevent possibly fatal outcomes.

The effectiveness and limitations of triphenyltetrazolium chloride to detect acute myocardial infarction at forensic autopsy.

AbstractTriphenyltetrazolium chloride (TTC) is one of the most conventional stains to detect infarcted area of the heart in animal experiments. However, its availability and limitations have not been thoroughly discussed in the forensic field. Here, authors stained human hearts with TTC soon after the harvest. Photographs of the samples were analyzed using image analysis software, which evaluated the occupying ratio of the stained area on the surface of each slice. The results showed that the stainability of TTC declines with the length of the postmortem interval (PMI). Specimens reacted well to TTC within 1.5 days after death and then decreased the stainability logarithmically with PMI (y = − 0.294 In (x) + 1.0441; x = PMI, y = TTC-stained area / total myocardial area, R2 = 0.5673). Samples with old myocardial infarction produced clear TTC contrast; normal tissue is vivid red, and fibrotic myocardium is white discoloration. In acute myocardial infarction cases where death occurred within 9 hours after the attack, however, the detection of infarcted area was very difficult even when PMI was less than 1.5 days. In summary, the TTC method may be useful within 1.5 days after death, but short suffering period before death disturbs its staining efficiency.

Effects of cocaine on the rat cerebral commissure.

We investigated the effects of cocaine on the corpus callosum, the nerve fibre bundle that connects the bilateral cerebral hemispheres. Our experiments in rats confirmed that, in the control group, the mid‐sagittal area of the corpus callosum in the adult male was significantly larger than this area in the female. Early postnatal exposure to cocaine abolished this sexual dimorphism, that is, cocaine‐treated males had a significantly smaller callosal area than the control males. Cocaine induced no significant changes in the weight of the body or brain. There were no significant sex differences in the midline sagittal area of the anterior commissure, and no apparent effects of cocaine exposure were determined in this structure. These findings suggest that early postnatal exposure to cocaine abolishes the sexual differentiation of the corpus callosum in male rats.

Transmesenteric hernia due to double-loop formation in the small intestine: A fatal case involving a toddler

We report a unique case of transmesenteric hernia resulting in death, which went undiagnosed during a recent hospital visit. The victim was a 2.5-year-old girl who - with the exception of chronic constipation - had no medical history. One night she complained of abdominal pains and was taken to a pediatric hospital where doctors performed an abdominal X-ray and echography. No significant findings suggesting bowel obstruction (e.g. air-fluid levels or dilation of the bowel) were obtained on examinations and bloody feces were not observed in this particular episode. As her abdominal pain gradually attenuated, the doctor allowed her to return home. A few hours later, she lost consciousness and expired despite resuscitation efforts attempted at an emergency hospital. A subsequent autopsy revealed that the small bowel had herniated through a defect in the mesentery resulting in two consecutive and inversely forming loops, in which each loop protruded on either side of the mesentery. This rare morphological anatomy seems to have progressed in a two-step process. The girls mild abdominal pain was likely induced by herniation and formation of the first intestinal loop, followed by severe shock occurring when the subsequent intestinal segment invaginated into the same defect forming the second loop on the opposite side of the mesentery. This case illustrates the difficulty of diagnosing transmesenteric hernia due to the presentation of unspecific symptoms; especially in infants and toddlers. Furthermore, this report demonstrates the value of a complete autopsy in cases of sudden and unexpected deaths involving children.

Effects of postnatal exposure to cocaine on the development of the rat corpus callosum

We investigated the effects of cocaine on the development of the corpus callosum in rats. From postnatal days 1 (P1) to 10 (birth = P0), cocaine (10 mg/kg) was subcutaneously injected in the pups, and saline, at the same volume, was administered to control pups. The animals were sacrificed at 110 days of age and a midsagittal section of the callosum was obtained. Morphometric measurement of the corpus callosum was performed in this section. In the control group, but not in the cocaine group, males had larger callosa than females. The cocaine treatment significantly decreased the total callosal area in male rats. These findings indicate that early postnatal cocaine abolishes the sexual differentiation of the corpus callosum.

Bile canalicular abnormalities in the early phase of a mouse model of sclerosing cholangitis.

BACKGROUND The bile canaliculus is the smallest and first biliary channel and is formed by two or three adjacent hepatocytes. Previous studies of chronic cholangiopathies such as primary sclerosing cholangitis have focused on the bile ductules. However, little is known about the pathological alterations in bile canaliculi in the early phase of cholangiopathies. AIM To characterize the bile canalicular morphology in the early phase of sclerosing cholangitis we used 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced mouse model of sclerosing cholangitis. METHODS Mice were fed a diet with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (0.1%). Serum biochemical, histological, immunohistochemical, and electron microscopic analyses were performed 1, 2, 4, and 7 days after feeding. RESULTS All experimental groups showed significantly increased serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels. From day 1, bile canalicular abnormalities such as dilatation and meandering and loss of microvilli were observed. After bile canalicular abnormalities had appeared, substantial infiltration of inflammatory cells was observed amongst the necrotic cells and periductal region. After these inflammatory changes, cholangiocytes proliferated in the portal area and formed ductular reactions. Finally, periductal fibrosis appeared. CONCLUSION This study provides novel evidence of the occurrence of bile canalicular abnormalities during the early phase of sclerosing cholangitis.

Subdural hemorrhage: A unique case involving secondary vitamin K deficiency bleeding due to biliary atresia

Extrahepatic biliary atresia (EHBA) is a rare disease characterized by progressive and obliterative cholangiopathy in infants and is one of the major causes of secondary vitamin K deficiency bleeding (VKDB) due to cholestasis-induced fat malabsorption. Breast feeding increases the tendency of bleeding in EHBA patients because breast milk contains low amounts of vitamin K. A 2-month-old female infant unexpectedly died, with symptoms of vomiting and jaundice prior to death. She had been born by uncomplicated vaginal delivery and exhibited normal growth and development with breastfeeding. There was no history of trauma. She received vitamin K prophylaxis orally. In an emergency hospital, a CT scan showed a right intracranial hematoma and mass effect with midline shift to the left. In the postmortem examination, severe atresia was observed in the whole extrahepatic bile duct. Histologically, cholestasis, periductal fibrosis, and distorted bile ductules were noted. The gallbladder was not identified. A subdural hematoma and cerebellar tonsillar herniation were found; however, no traumatic injury in any part of the body was observed. Together, these findings suggest that the subdural hemorrhage was caused by secondary vitamin K deficiency resulting from a combination of cholestasis-induced fat malabsorption and breastfeeding. Subdural hemorrhage by secondary VKDB sometimes occurs even when vitamin K prophylaxis is continued. This case demonstrated that intrinsic factors, such as secondary VKDB (e.g., EHBA, neonatal hepatitis, chronic diarrhea), should also be considered in infant autopsy cases presenting with subdural hemorrhage.