Vascular hyperpermeability in severe influenza

Multiorgan failure with vascular hyperpermeability is the final outcome in the progression of seasonal influenza virus pneumonia and influenza-associated encephalopathy, and it is also common in infection with highly pathogenic avian influenza virus. However, the precise molecular mechanism by which influenza virus infection causes vascular endothelial cell hyperpermeability remains poorly defined. We investigated the mechanisms of hyperpermeability of human umbilical vein endothelial cells infected with influenza A virus (IAV)/Puerto Rico/8/34 (PR8) (H1N1). The levels of β-catenin, a key regulatory component of the vascular endothelial-cadherin cell adhesion complex, were markedly decreased during infection for 28 h, with increments of vascular hyperpermeability measured by transendothelial electrical resistance. Lactacystin (at 2 μM), a proteasome inhibitor, inhibited the decrease in β-catenin levels. Since the N-terminal phosphorylation of β-catenin by glycogen synthase kinase (GSK)-3β is the initiation step of proteasome-dependent degradation, we examined the effects of GSK-3β suppression by RNA interference in endothelial cells. IAV-infection-induced β-catenin degradation was significantly inhibited in GSK-3β-knockdown cells, and transfection of cells with recombinant β-catenin significantly suppressed IAV-induced hyperpermeability. These findings suggest that IAV infection induces GSK-3β-mediated β-catenin degradation in the adherens junctional complexes and induces vascular hyperpermeability. The in vitro findings of β-catenin degradation and activation of GSK-3β after IAV infection were confirmed in lungs of mice infected with IAV PR8 during the course of infection from day 0 to day 6. These results suggest that GSK-3β-mediated β-catenin degradation in adherens junctions is one of the key mechanisms of vascular hyperpermeability in severe influenza

Long-term survivor diagnosed with arrhythmogenic right ventricular cardiomyopathy/dysplasia

The subject was a 70 year-old man who survived for 31 years after being diagnosed with right ventricular cardiomyopathy, having undergone right ventricular (RV) aneurysmectomy at the age of 39. His arrhythmia and syncopal attacks were effectively abolished after the original aneurysmectomy. Although he frequently suffered from right heart failure, hemodialysis improved his status. However, the patient died due to worsening anasarca caused by RV low output syndrome. Autopsy results indicated extensive replacement of the RV myocardium with fibrous and fatty tissues. This case suggests that patients with arrhythmogenic RV cardiomyopathy, but without left ventricular abnormalities and rapid ventricular arrhythmia, have a relatively favorable prognosis, although RV abnormalities may be progressive

<ORIGINAL REPORT>X-ray scanning analytical microscopic and scanning electron microscopic studies of an unusual case of dens invaginatus

A mass was extirpated from the region of the maxillary right third molar of a 20 year-old patient. It was proved to be an extreme and unerupted case of dens invaginatus. The clinical and histopathological features have been presented in a previous paper. Ameloblasts and odontoblasts were noted along the surface of enamel or dentin. In the present study, X-ray scanning analytical microscopy (XSAM), a newly developed technique, together with scanning electron microscopy (SEM) was applied for the study of this malformed tooth. SEM study showed a strange arrangement of well-formed enamel and dentin in normal structures. The distribution of calcium (Ca) and phosphorus (P) was clearly observed by the XSAM method. It revealed that the bulk of dentin was composed of two kinds of dentin quite different in mineral content while their SEM appearances were similar. The part of the dentin near the dentinoenamel junction had much higher Ca and P concentrations than the outer parts. In conclusion, the disagreement between the microscopic findings and the XSAM findings suggests the importance of applying various methods in studies to obtain a comprehensive understanding of such malformation. In addition, the present investigation also points out the complexity of the disturbance ranging within the term dens invaginatus

A Giant Thymic Cyst Accompanied by Acute Mediastinitis

We encountered a rare case of thymic cyst accompanied by mediastinitis. A 39-year-old Japanese male presented with fever and chest pain. The chest CT revealed a mass composed of a lobular cystic lesion with inflammation, suggesting the onset of mediastinitis. A definitive histological diagnosis was not obtained, and we performed a thymectomy. Pathologically, the thymic cyst was accompanied by multiple cavities, mimicking thymic cysts, caused by the inflammatory abscess. The surrounding adipose tissue showed inflammatory cell infiltrations with chronic fibrosis. These findings indicate that clinicians should be aware that thymic cysts may cause severe mediastinitis

Pulmonary Enteric Adenocarcinoma Harboring a BRAF G469V Mutation

Pulmonary enteric adenocarcinoma (PEAC) is a rare subtype of lung cancer that should be differentiated from colorectal cancer metastasis. Little is known about its genetic background. An 84-year-old male with adenocarcinoma of the lung underwent left upper lobectomy. The histology of the surgical specimen was suggestive of PEAC. Gastrointestinal and colorectal fiberscopy revealed no evidence of colorectal cancer. Next-generation sequencing of the tumor identified a G469V substitution in serine/threonine-protein kinase B-raf (BRAF). Based on the higher prevalence of the G469 substitution in BRAF-mutant lung adenocarcinoma than in BRAFmutant colorectal cancer, the tumor likely originated from the lung. Identification of mutational genotype may be of some help in distinguishing PEAC from the lung metastasis of colorectal cancer

Development of "A Training Course to Cultivate the Abilities Required for Teachers," a Program to Bring on Teachers with a High Degree of Specialization and Practical Leadership - Towards the Building of a Program for Undergraduate Education

学級崩壊，心の病に陥る教師，増えるクレーマー等々の現実に，学生たちも教員採用試験に合格してから，教壇に立つことの責任の重さ，自分の指導力の未熟さを痛感し，押しつぶされそうになる。この状態を少しでも克服していくため教師力育成講座を開講することとした。不易と流行の両方の観点から具体的な教育課題を現職の小・中学校長に提案してもらい，それらの課題解決を通して教師力を育成していくことを目指す。また，他学部の教員志望学生や大学院生等にも参加を呼びかけ，志を一にする学生同士が互いに切磋琢磨し，より幅広い確かな教師力の育成に資するものである。Circumstances surrounding today’s schools are becoming increasingly harsh, as evidenced by the prevalence of dysfunctional classrooms, teachers who suffer mental illnesses, and excessively demanding students and their parents who complain at every opportunity. Even after passing the teacher employment examinations, students become overwhelmed with the daunting responsibilities of standing at the podium as a teacher, and are made painfully aware of their immature leadership skills. To overcome these problems as much as possible, we have decided to offer a training course to cultivate the abilities required for teachers. The aims are to have individuals currently serving as elementary and middle school principals propose concrete educational challenges from the perspectives of continuity and change, and to have the participants nurture their "power as teachers" through addressing those challenges. Students of other departments as well as graduate students hoping to become teachers are also encouraged to take part. The friendly competition and camaraderie among students who share the same aspirations and interests will contribute to fostering an even broader and sound power as teachers

Survival and prognostic factors in patients undergoing pulmonary metastasectomy for lung metastases from retroperitoneal sarcoma

Background Soft-tissue sarcomas are rare malignancies that consist of many different histologic subtypes and arise in various locations in the body. In patients with lung metastases from retroperitoneal sarcomas, the long-term outcomes and prognostic factors are unknown. This study is a retrospective review of patients undergoing pulmonary metastasectomy for retroperitoneal sarcoma metastases at one institution, with the purpose of determining prognostic factors and clinical outcomes. Methods This is a single-center, retrospective cohort study of patients undergoing pulmonary metastasectomy for lung metastases from various sarcomas at Okayama University Hospital from January 2006 to December 2018. The Kaplan-Meier method and log-rank test were used for the analyses, and cut-off values of continuous variables were determined by a receiver operating characteristic curve analysis. Results Twenty-four patients underwent the first pulmonary metastasectomy for lung metastases from retroperitoneal sarcoma in our hospital. Leiomyosarcoma was the most common histologic subtype of retroperitoneal sarcoma (79.2%, n = 19). Median overall survival was 49.9 months, and the 3-year and 5-year survival rates after the first pulmonary metastasectomy were 62.5% and 26.4% respectively. In univariate analysis, age >= 56 years, disease-free interval = 27 mm) were associated with poor survival. Conclusion Pulmonary metastasectomy can be considered as an effective management strategy in retroperitoneal sarcoma patients with lung metastases in appropriately selected cases, just as it is for other sarcomas

Biochemical Analysis of the Human Mismatch Repair Proteins hMutSα MSH 2 G674A -MSH6 and MSH2-MSH6 T1219D

The heterodimeric human MSH2-MSH6 protein initiates DNA mismatch repair (MMR) by recognizing mismatched bases that result from replication errors. Msh2G674A or Msh6T1217D mice that have mutations in or near the ATP binding site of MSH2 or ATP hydrolysis catalytic site of MSH6 develop cancer and have a reduced lifespan due to loss of the MMR pathway (Lin, D. P., Wang, Y., Scherer, S. J., Clark, A. B., Yang, K., Avdievich, E., Jin, B., Werling, U., Parris, T., Kurihara, N., Umar, A., Kucherlapati, R., Lipkin, M., Kunkel, T. A., and Edelmann, W. (2004) Cancer Res. 64, 517–522; Yang, G., Scherer, S. J., Shell, S. S., Yang, K., Kim, M., Lipkin, M., Kucherlapati, R., Kolodner, R. D., and Edelmann, W. (2004) Cancer Cell 6, 139–150). Mouse embryonic fibroblasts from these mice retain an apoptotic response to DNA damage. Mutant human MutSα proteins MSH2G674A-MSH6wt and MSH2wt-MSH6T1219D are profiled in a variety of functional assays and as expected fail to support MMR in vitro, although they retain mismatch recognition activity. Kinetic analyses of DNA binding and ATPase activities and examination of the excision step of MMR reveal that the two mutants differ in their underlying molecular defects. MSH2wt-MSH6T1219D fails to couple nucleotide binding and mismatch recognition, whereas MSH2G674A-MSH6wt has a partial defect in nucleotide binding. Nevertheless, both mutant proteins remain bound to the mismatch and fail to promote efficient excision thereby inhibiting MMR in vitro in a dominant manner. Implications of these findings for MMR and DNA damage signaling by MMR proteins are discussed