A case of plastic bronchitis with a remarkable response to steroids.

Plastic bronchitis can cause fatal airway obstruction. An 85-year-old woman with no medical history presented to the emergency department of our hospital with progressing respiratory failure and hemoptysis. Bronchoscopy revealed a fibrin-type cast thrombus in the trachea, and plastic bronchitis was diagnosed. Initial treatment involved airway thrombus removal, and the patient survived. However, bleeding persisted for 6 days, and respiratory status showed slight improvement despite ventilatory management. Steroids were administered for concomitant acute respiratory distress syndrome, and there was marked improvement in both airway hemorrhage and respiratory failure. The patient was extubated, the steroid dose was reduced, and no rebleeding was observed. The patient was discharged from the hospital 1 month after the onset of symptoms. Blood tests were positive for the myeloperoxidase-anti-neutrophil cytoplasmic antibody; however, no biopsy was performed, and no specific symptoms were observed. A definitive diagnosis was therefore not reached. The causes of plastic bronchitis are numerous, and there are no standardized diagnostic criteria or treatment guidelines for this condition. The present case suggests that steroids may be effective in some patients with plastic bronchitis.

Microparticles and Nucleosomes Are Released From Parenchymal Cells Destroyed After Injury in a Rat Model of Blunt Trauma.

We investigated the relationships between circulating procoagulants and trauma severity, including cellular destruction, and the effects of thrombin generation on procoagulants in a rat blunt trauma model. The rats were subjected to tumbling blunt trauma, where they were tumbled for 0, 250, 500, or 1000 revolutions. Creatine kinase, nucleosome, and microparticle plasma levels increased gradually with trauma severity. Strong interrelationships were observed among creatine kinase, nucleosome, and microparticle levels. Time to initiation of thrombin generation shortened with increasing trauma severity. In accordance with trauma severity, prothrombin activity decreased, but the thrombin generation ratio increased. Time to initiation of thrombin generation and the thrombin generation ratio correlated with creatine kinase levels. In an in vitro study, a homogenized muscle solution, which included massive nucleosomes and microparticles, showed accelerated thrombin generation of plasma from healthy subjects. Procoagulants, such as microparticles and nucleosomes, are released from destroyed parenchymal cells immediately after external traumatic force, activating the coagulation cascade. The procoagulants shorten the time to initiation of thrombin generation. Furthermore, although coagulation factors are consumed, the thrombin generation ratio increases.

Fibrin/fibrinogen degradation products (FDP) at hospital admission predict neurological outcomes in out-of-hospital cardiac arrest patients.

OBJECTIVE: This study aimed to test the hypothesis that coagulation, fibrinolytic markers and disseminated intravascular coagulation (DIC) score (International Society on Thrombosis and Haemostasis) at hospital admission of out-of-hospital cardiac arrest (OHCA) patients can predict neurological outcomes 1 month after cardiac arrest. METHODS: In this retrospective, observational analysis, data were collected from the Sapporo Utstein Registry and medical records at Hokkaido University Hospital. We included patients who experienced OHCA with successful return of spontaneous circulation (ROSC) between 2006 and 2012 and were transferred to Hokkaido University Hospital. From medical records, we collected information about the following coagulation and fibrinolytic factors at hospital admission: platelet count; prothrombin time; activated partial thromboplastin time; plasma levels of fibrinogen, D-dimer, fibrin/fibrinogen degradation products (FDP), and antithrombin; and calculated DIC score. Favorable neurological outcomes were defined as a cerebral performance category 1-2. RESULTS: We analyzed data for 315 patients. Except for fibrinogen level, all coagulation variables, fibrinolytic variables, and DIC score were associated with favorable neurological outcomes. In the receiver operating characteristic curve analysis, FDP level had the largest area under the curve (AUC; 0.795). In addition, the AUC of FDP level was larger than that of lactate level. CONCLUSIONS: All of the coagulation and fibrinolytic markers, except for fibrinogen level, and DIC score at hospital admission, were associated with favorable neurological outcomes. Of all of the variables, FDP level was most closely associated with favorable neurological outcomes in OHCA patients who successfully achieved ROSC.

The response time threshold for predicting favourable neurological outcomes in patients with bystander-witnessed out-of-hospital cardiac arrest.

OBJECTIVE: It is well established that the period of time between a call being made to emergency medical services (EMS) and the time at which the EMS arrive at the scene (i.e. the response time) affects survival outcomes in patients who experience out-of-hospital cardiac arrest (OHCA). However, the relationship between the response time and favourable neurological outcomes remains unclear. We therefore aimed to determine a response time threshold in patients with bystander-witnessed OHCA that is associated with positive neurological outcomes and to assess the relationship between the response time and neurological outcomes in patients with OHCA. METHODS: This study was a retrospective, observational analysis of data from 204,277 episodes of bystander-witnessed OHCA between 2006 and 2012 in Japan. We used classification and regression trees (CARTs) and receiver operating characteristic (ROC) curve analyses to determine the threshold of response time associated with favourable neurological outcomes (Cerebral Performance Category 1 or 2) 1 month after cardiac arrest. RESULTS: Both CARTs and ROC analyses indicated that a threshold of 6.5min was associated with improved neurological outcomes in all bystander-witnessed OHCA events of cardiac origin. Furthermore, bystander cardiopulmonary resuscitation (CPR) prolonged the threshold of response time by 1min (up to 7.5min). The adjusted odds ratio for favourable neurological outcomes in patients with OHCA who received care within ≤6.5min was 1.935 (95% confidential interval: 1.834-2.041, P<0.001). CONCLUSIONS: A response time of ≤6.5min was closely associated with favourable neurological outcomes in all bystander-witnessed patients with OHCA. Bystander CPR prolonged the response time threshold by 1min.

Tumor endothelial cells acquire drug resistance by MDR1 up-regulation via VEGF signaling in tumor microenvironment.

Tumor endothelial cells (TECs) are therapeutic targets in anti-angiogenic therapy. Contrary to the traditional assumption, TECs can be genetically abnormal and might also acquire drug resistance. In this study, mouse TECs and normal ECs were isolated to investigate the drug resistance of TECs and the mechanism by which it is acquired. TECs were more resistant to paclitaxel with the up-regulation of multidrug resistance (MDR) 1 mRNA, which encodes the P-glycoprotein, compared with normal ECs. Normal human microvascular ECs were cultured in tumor-conditioned medium (CM) and became more resistant to paclitaxel through MDR1 mRNA up-regulation and nuclear translocation of Y-box-binding protein 1, which is an MDR1 transcription factor. Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and Akt were activated in human microvascular ECs by tumor CM. We observed that tumor CM contained a significantly high level of VEGF. A VEGFR kinase inhibitor, Ki8751, and a phosphatidylinositol 3-kinase-Akt inhibitor, LY294002, blocked tumor CM-induced MDR1 up-regulation. MDR1 up-regulation, via the VEGF-VEGFR pathway in the tumor microenvironment, is one of the mechanisms of drug resistance acquired by TECs. We observed that VEGF secreted from tumors up-regulated MDR1 through the activation of VEGFR2 and Akt. This process is a novel mechanism of the acquisition of drug resistance by TECs in the tumor microenvironment.

Heterogeneity of tumor endothelial cells: comparison between tumor endothelial cells isolated from high- and low-metastatic tumors.

An important concept in tumor angiogenesis is that tumor endothelial cells (TECs) are genetically normal and homogeneous. However, we previously reported that TECs differ from normal ECs. Whether the characteristics of TECs derived from different tumors differ remains unknown. To elucidate this, in this study, we isolated two types of TECs from high-metastatic (HM) and low-metastatic (LM) tumors and compared their characteristics. HM tumor-derived TECs (HM-TECs) showed higher proliferative activity and invasive activity than LM tumor-derived TECs (LM-TECs). Moreover, the mRNA expression levels of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF) receptors 1 and 2, VEGF, and hypoxia-inducible factor-1α, were higher in HM-TECs than in LM-TECs. The tumor blood vessels themselves and the surrounding area in HM tumors were exposed to hypoxia. Furthermore, HM-TECs showed higher mRNA expression levels of the stemness-related gene stem cell antigen and the mesenchymal marker CD90 compared with LM-TECs. HM-TECs were spheroid, with a smoother surface and higher circularity in the stem cell spheroid assay. HM-TECs differentiated into osteogenic cells, expressing activated alkaline phosphatase in an osteogenic medium at a higher rate than either LM-TECs or normal ECs. Furthermore, HM-TECs contained more aneuploid cells than LM-TECs. These results indicate that TECs from HM tumors have a more pro-angiogenic phenotype than those from LM tumors.

Distribution of neutral amino acid transporter ASCT 1 in the non-neuronal tissues of mice.

Distribution of ASCT1, a neutral amino acid transporter, in non-neuronal peripheral tissues of adult and developing mice was examined by immunohistochemistry and immunoelectron microscopy. Immunoreactivity for ASCT1 in the digestive system was localized in basal cells of stratified squamous epithelia from oral parietes to nonglandular region of the stomach, chief cells of the glandular stomach, acinar cells of the salivary gland and exocrine pancreas, and Paneth's cells of the small intestine, in all of which the basolateral membrane was selectively immuno-labeled. In the liver of adult mice, ASCT1 immunoreactivity was detected on the plasma membrane of hepatocytes surrounding central veins, and a temporal expansion of immunoreactive hepatocytes was observed in the embryonic and CCl4-treated adult livers. ASCT1 was also localized on the plasma membranes of proximal uriniferous tubule epithelial cells in the kidney of adult mice, and those of supporting cells in the medulla of adrenal gland. These results suggest that ASCT1 is expressed in various non-neuronal peripheral tissues in mice, and it contributes to the amino acid transport throughout non-neuronal tissues.