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.
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 of sublethal tubular cell injury.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Little is known about the relationship between splenic arteriolar hyaline and cause of death. The purpose of this retrospective study was to evaluate the clinicopathological significance of splenic ...arteriolar hyaline in autopsy cases and estimate the applicability of hyaline for diagnosing the cause and rapidity of death.
Archival data and histological slides from 82 cases were reviewed retrospectively. One section of each spleen was evaluated microscopically. The tinctorial pattern of splenic arteriolar hyaline was examined with Heidenhain's Azan trichrome stain, and the relationships between this pattern and age, cause of death, and rapidity of death were investigated.
Fifty-four cases demonstrated hyaline change, with 3 different tinctorial patterns: red, blue, and a combination of red and blue. The 3 patterns coexisted in various proportions in each tissue section. Frequency of the blue pattern increased with age (P < 0.01) and was unrelated to cause of death. By contrast, the red pattern was unrelated to age and appeared with different frequency according to cause of death. The red pattern appeared with significantly higher frequency in the circulatory disease group and the drowning and asphyxia group (both P < 0.01). Moreover, the presence of the red pattern had high specificity for the detection of rapidly fatal cases. The combination of the 2 colors was excluded from clinicopathological analyses due to its admixed nature.
Estimation of splenic arteriolar hyaline with Heidenhain's Azan trichrome stain is useful for assessment of the cause and rapidity of death.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1132441651796836.
Abstract 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.
Abstract Objectives An ectopic cervical thymus (ECT) is regarded as a rare congenital anomaly; therefore, the optimal diagnostic and therapeutic strategy remains a debatable matter. We designed a ...study to elucidate the clinicopathological characteristics of ECTs in consecutive, unselected infant autopsies, to help guide case management. Methods We searched for ECTs in all of the 21 consecutive, unselected infant autopsy cases performed at our institution over a period of 3 years, and all ECT consensus diagnoses were confirmed by histological examination. The following clinical characteristics were evaluated in cases with ECTs: age, gender, birth week and weight, clinical symptoms due to the ECT(s), position on discovery of death, cause of death, ECT contribution to the cause of death, and concomitant congenital disorders. The anatomical features evaluated included the location, number, size, color, shape, and margins of the ECTs, and the presence of a mediastinal thymus. Histological findings of the ECT(s) and the mediastinal thymus were compared within each individual. Fusion of the parathyroid and the ECT was also investigated histologically. Spearman's rank correlation coefficient ( ρ ) and the corresponding P value were calculated to determine if there was an association between ECT diameter and age. Results We detected 10 ECT lesions in seven cases (33%) among the 21 infant autopsy cases. The ECT cases involved five boys and two girls, with ages ranging from 1 day to 4 months. There were no reports of a positive family history of sudden death or antemortem clinical symptoms due to ECT in any of the cases. The ECTs were considered incidental regarding the cause of death, with the exception of one case that was extremely rare. Most ECTs were localized to the inferior thyroid, ranging from 0.4 to 1.9 cm in size. Size demonstrated a significant negative correlation with age ( ρ = −0.75 and P = 0.034). Conclusions This study revealed that ECT is an essentially benign anomaly that occurs frequently during the development of the thymus, and may disappear over the first few years of life. These results suggest a conservative approach to the management of ECTs would be appropriate.
Summary Background Mammography is the only proven method for breast cancer screening that reduces mortality, although it is inaccurate in young women or women with dense breasts. We investigated the ...efficacy of adjunctive ultrasonography. Methods Between July, 2007, and March, 2011, we enrolled asymptomatic women aged 40–49 years at 42 study sites in 23 prefectures into the Japan Strategic Anti-cancer Randomized Trial (J-START). Eligible women had no history of any cancer in the previous 5 years and were expected to live for more than 5 years. Randomisation was done centrally by the Japan Clinical Research Support Unit. Participants were randomly assigned in 1:1 ratio to undergo mammography and ultrasonography (intervention group) or mammography alone (control group) twice in 2 years. The primary outcome was sensitivity, specificity, cancer detection rate, and stage distribution at the first round of screening. Analysis was by intention to treat. This study is registered, number UMIN000000757. Findings Of 72 998 women enrolled, 36 859 were assigned to the intervention group and 36 139 to the control group. Sensitivity was significantly higher in the intervention group than in the control group (91·1%, 95% CI 87·2–95·0 vs 77·0%, 70·3–83·7; p=0·0004), whereas specificity was significantly lower (87·7%, 87·3–88·0 vs 91·4%, 91·1–91·7; p<0·0001). More cancers were detected in the intervention group than in the control group (184 0·50% vs 117 0·32%, p=0·0003) and were more frequently stage 0 and I (144 71·3% vs 79 52·0%, p=0·0194). 18 (0·05%) interval cancers were detected in the intervention group compared with 35 (0·10%) in the control group (p=0·034). Interpretation Adjunctive ultrasonography increases sensitivity and detection rate of early cancers. Funding Ministry of Health, Labour and Welfare of Japan.
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