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Kupffer cells (KCs) are key players in maintaining tissue homeostasis and are involved in various liver diseases. However, the roles of KCs in the pathogenesis of cholangiopathy are largely unknown. We aimed to investigate the precise roles of KCs in both the progression and regression phases of the 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC)-induced cholangiopathy model. In the early phase of DDC-induced cholangiopathy, the number of KCs significantly increased over time. Moreover, KCs were associated with abnormal phenotypic changes in other liver cells, such as hepatocytes, biliary epithelial cells, liver sinusoidal endothelial cells, and hepatic stellate cells. In contrast, KC depletion by clodronate administration suppressed the progression of the disease, and maintained the phenotypes of other cells. In the regression phase, the numbers of KCs significantly decreased, and the cells redifferentiated to their quiescent state. In contrast, KC depletion delayed the recovery of cells by maintaining other liver cells in an active state. These findings suggest that KCs play detrimental roles in the progression phase; however, they are beneficial in the regression phase by mediating interactions between other liver cells. Our data provide new insights into the roles of KCs in the pathogenesis of cholangiopathy.

The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms o

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.

Triphenyltetrazolium 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, R = 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.

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.

[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.

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 girl's 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.

Pituitary abscess is a rare disease presenting with nonspecific clinical symptoms, and diagnosis is often difficult. This disease is potentially life-threatening, but most cases have a chronic and indolent course. We report a case of a 60-year-old man with a pituitary abscess associated with pituitary adenoma who died 5 days after the onset of clinical symptoms without a definitive diagnosis. Postmortem computed tomography and autopsy findings revealed a sellar mass with cystic change and extension toward the optic chiasm. Histopathology of the lesion demonstrated an abscess with suppurative meningitis and encephalitis. The disturbance of the cardiac autonomic nervous system because of hypothalamus involvement was suggested as the cause of rapid progression and death. This case provides useful information for clinicians to avoid a lethal outcome.

Thioredoxin-interacting protein (TXNIP), which has a tumor-suppressive function, is underexpressed in some human cancers. The function of TXNIP in vivo in carcinogenesis is not fully understood. Here, we show TXNIP to be downregulated in human bladder cancer according to grade and stage and also that loss of TXNIP expression facilitates bladder carcinogenesis using a mouse bladder cancer model. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer was found in 100% of Txnip knockout (KO) mice at week 8 of 0.025% BBN administration but in only 22% of wild-type (WT) mice at the same point. Among growth stimulators, phospho-extracellular signal-regulated kinase (pERK) expression was stronger during bladder carcinogenesis in Txnip-KO mice than in WT mice. We then evaluated TXNIP's effects on ERK activation through various growth stimulators and their receptors. Overexpression of TXNIP in human bladder cancer cells attenuated pERK expression upon stimulation with stromal cell-derived factor-1 (SDF-1) but not with epidermal growth factor or insulin-like growth factor-1. In Txnip-KO mice, immunohistochemical analysis showed enhanced expression of C-X-C chemokine receptor type 4 (CXCR4), the receptor of SDF-1, and of pERK in urothelial cells during BBN-induced bladder carcinogenesis. Finally, subcutaneous injection of CXCR4 antagonist, TF14016, attenuated pERK in urothelial cells and suppressed bladder carcinogenesis. These data indicate that TXNIP negatively regulates bladder carcinogenesis by attenuating SDF-1-CXCR4-induced ERK activation. This signal transduction pathway can be a potent target in preventing or treating bladder cancer.