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Koichi Yamamura,* Masafumi Nojiri,* Kazuaki Nishiki, Ryo Kato, Shohei Shinomiya, Yutaka Takahara, Taku Oikawa, Takeshi Ishizaki, Hirohisa Toga, Shiro Mizuno Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan*These authors contributed equally to this workCorrespondence: Shiro Mizuno, Department of Respiratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan, Tel +81-76-218-8157, Fax +81-76-286-0980, Email shirotan@kanazawa-med.ac.jpPurpose: Oxidative stress is known to activate tumor suppressor p53, which inhibits cell cycle progression and induces apoptosis. Levels of p53 in lung tissues from patients with chronic obstructive pulmonary disease (COPD) are increased compared with levels in nonsmokers or smokers without emphysema. A polymorphism in p53 codon 72 (rs1042522) is associated with emphysematous changes in patients with COPD. However, whether oxidative stress in the serum is associated with the p53 polymorphism and disease severity in COPD patients is unclear.Patients and Methods: A total of 251 patients with a history of smoking more than 10 pack-years were enrolled in this study, and serum levels of derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), and d-ROMs/BAP ratio (oxidative stress index; OSI) were measured. The percent low-attenuation area (LAA%) and cross-sectional area of the erector spinae muscles (ESMCSA) at the Th12 level were calculated from chest high-resolution computed tomography images. p53 codon 72 C/G genotyping was performed using polymerase chain reaction–restriction fragment length polymorphism analysis.Results: In patients carrying the p53 GG genotype, LAA% was significantly higher than in those carrying the CC genotype. d-ROM levels and OSI were associated with COPD severity and correlated with airflow limitation and markers of muscle atrophy (ESMCSA and creatinine/cystatin C ratio). Associations between markers of oxidative stress and COPD severity were observed primarily in patients carrying the p53 codon 72 GG genotype.Conclusion: Susceptibility to pulmonary emphysema and responses to oxidative stress may be affected by the p53 gene polymorphism.Keywords: oxidative stress, low attenuation area, sarcopenia, smoking status

Kazuaki Nishiki, Masafumi Nojiri, Ryo Kato, Shohei Shinomiya, Taku Oikawa, Takeshi Ishizaki, Hirohisa Toga, Shiro Mizuno Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, JapanCorrespondence: Shiro MizunoDepartment of Respiratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, 920-0293, JapanTel +81-76-218-8157Fax +81-76-286-0980Email shirotan@kanazawa-med.ac.jpPurpose: Muscle atrophy is a major clinical feature of chronic obstructive pulmonary disease (COPD) and is considered a predictor of mortality in COPD patients. Recently, the cross-sectional area (CSA) of the erector spinae muscles measured by chest computed tomography (CT) scans (ESMCSA) has been reported as a clinical parameter reflecting disease severity and future prognosis in patients with COPD. In addition, the serum creatinine (Cr)/cystatin C (CysC) ratio has been considered a quantitative marker of residual muscle mass, because serum Cr levels are affected by muscle mass, and correction by CysC counteracts the effect of renal function on serum Cr levels. The purpose of this study was to assess whether the serum Cr level corrected by serum CysC can be used as a predictive marker of pulmonary function and disease severity in patients with COPD.Patients and Methods: A total of 99 patients without COPD and 201 patients with COPD, with a smoking history of more than 10 pack-years were enrolled in this study, and serum Cr and CysC levels were measured. On chest high-resolution CT images, %low attenuation area (LAA%) (≤ 960 Hounsfield units (HU)) and ESMCSA at the Th12 level were identified.Results: There was a significant correlation between the ESMCSA and the Cr/CysC ratio. The Cr/CysC ratio was significantly associated with forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) values, especially in former smokers.Conclusion: The serum Cr/CysC ratio could be a convenient substitute for the measurement of muscle atrophy and pulmonary function testing in patients with COPD.Keywords: muscle atrophy, low attenuation area, sarcopenia, smoking status

This study examines the relationship between the green-based school with students’ environmental attitudes and behavior. Sustainable development has become the solution and commitment to save the earth from destruction due to human behavior. Environmental education plays an important role in creating an environmentally literate society. Adiwiyata School, an official form of environmental education, is one of the efforts to increase sustainable development through education as a way to improve student's environmental attitude and behavior. The research design used multiple case studies utilizing the observation method and questionnaire distribution to Adiwiyata and non-Adiwiyata schools. A New Ecological Paradigm (NEP) scale and a General Ecological Behavior (GEB) scale are used to measure student's environmental attitudes and behavior change. As a result, the green-based school creates influences in student's environmental attitudes (9.3%) and environmental behavior (12.3%).

Traditional dwellings have undergone constant change in recent decades as a result of modernization. Though the change is physically visible, a theoretically indiscernible tradition is maintained as a way of sustaining social and cultural systems. A hypothetical assumption asserts that a symbolic cultural value, a ‘traditional core,’ exists as a sustainable system that functions within a modernized structure. This study begins by identifying the traditional core in question and proceeds to investigate its power over contemporary, modernized forms of dwelling. The study’s approach takes on the basic theory of physical change and the key ideas of structuralism. The main findings concern these two interrelated aspects, which are the result of a sustainable system, namely the hybrid dwelling, and the authoritative power that social and cultural systems have over house form.

BACKGROUND: Avulsion fracture of the lateral ankle ligaments is often undetected on early radiographs. The epidemiology and treatment of such avulsion fractures have received much less attention than the epidemiology and treatment of rupture of these ligaments. HYPOTHESIS: The clinical characteristics of avulsion fracture are different from those of ligament rupture. Unlike nonoperative treatment of lateral ligament rupture, nonoperative treatment of avulsion fracture does not yield satisfactory results. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 169 consecutive patients with severe inversion injury were classified into a ligament rupture group or avulsion fracture group on the basis of physical examination findings and anterior talofibular ligament and calcaneofibular ligament radiographic views. Age, sex, activity level, and the mechanism of injury were analyzed. Patients in both groups were treated by casting. Follow-up examination of 152 patients included clinical assessment and functional evaluation based on the Karlsson system. RESULTS: Avulsion fracture was diagnosed in 44 (26%) of the 169 patients and was most common among children and patients over 40 years of age. Sedentary level activity and low-energy injury were more common in the avulsion fracture group than in the ligament rupture group (77% vs 37%, respectively, P = .001; 68% vs 43%, respectively, P =.004). Nonoperative treatment of avulsion fracture (mean Karlsson score, 89.1 points) yielded satisfactory results that were comparable with those of nonoperative treatment of ligament rupture (mean Karlsson score, 88.4 points) (P = .123). Osseous union was achieved in 65% of the patients with avulsion fracture. CONCLUSION: Avulsion fracture of the lateral ankle ligaments in cases of severe inversion injury is more common than previously believed. Because of the high incidence and difficulty of detection in children, a high level of suspicion is necessary in order to obtain an accurate diagnosis of avulsion fracture in cases of severe inversion injury and to achieve adequate stability. [ABSTRACT FROM AUTHOR]

Background: The functional outcome following ankle fractures that involve a posterior malleolar fragment is often not satisfactory, and treatment of this type of fracture remains controversial. Thorough knowledge of the pathologic anatomy of the posterior malleolar fracture is essential for planning appropriate treatment. Thus, we conducted a computed tomographic study to clarify the pathologic anatomy of the posterior malleolar fracture.Methods: Between 1999 and 2003, fifty-seven consecutive patients with a unilateral ankle fracture with one or more posterior fragments were managed at our hospital. We reviewed the patients' preoperative computed tomographic scans to determine (1) the ratio of the posterior fragment area to the total cross-sectional area of the tibial plafond and (2) the angle between the bimalleolar axis and the major fracture line of the posterior malleolus. Each fracture was categorized according to the location of the major fracture line on the computed tomographic image at the level of the tibial plafond.Results: The fifty-seven fractures were categorized into three types: (1) the posterolateral-oblique type (thirty-eight fractures; 67%), (2) the medial-extension type (eleven fractures; 19%), and (3) the small-shell type (eight fractures; 14%). Two of the eleven medial-extension fractures extended to the anterior part of the medial malleolus. A total of nine of the eleven medial-extension fractures actually consisted of two fragments [corrected] The conditions are not exclusive of one another; for example, in the case of one of the fractures exhibiting two fragments, the fracture also extended to the anterior part of the medial malleolus [corrected] The average area of the fragment comprised 11.7% of the cross-sectional area of the tibial plafond for posterolateral-oblique fractures and 29.8% for medial-extension fractures. In the cases of seven of the nine fractures that comprised >25% of the tibial plafond, the fracture line extended to the medial malleolus. The angles between the bimalleolar axis and the major fracture line of the posterior malleolus varied.Conclusions: The fracture lines associated with posterior malleolar fractures appear to be highly variable. A large fragment extending to the medial malleolus existed in almost 20% of the posterior malleolar fractures in the current study, and some fragments involved almost the entire medial malleolus. Because of the great variation in fracture configurations, preoperative use of computed tomography may be justified. The information obtained from this study will be helpful for conducting basic research of this condition and for determining appropriate surgical approaches. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia, characterized by skeletal muscle atrophy and physical inactivity, is a manifestation of chronic obstructive pulmonary disease (COPD) and is associated with a poor prognosis. The serum creatinine (Cr)/cystatin C (CysC) ratio has been proposed as a marker of sarcopenia, given its correlation with total skeletal muscle mass, and as a prognostic indicator in COPD. This study aimed to evaluate the usefulness of the serum Cr/CysC ratio as a prognostic determinant in these patients., Methods: A total of 124 outpatients with COPD were enrolled in this study. Their serum Cr and CysC levels were measured. Survival time analyses were conducted to compare mortality rates between the low and high serum Cr/CysC ratio groups. Multivariate analysis was performed to investigate the association between various factors., Results: Using a serum Cr/CysC cut-off value of 0.885, the mortality rate (per 1000 person-years) for overall mortality was significantly higher in the low serum Cr/CysC ratio group (69.2 versus 28.6; hazard ratio, 2.47; 95% confidence interval, 1.06-5.79; p < 0.05). Similarly, the mortality rate due to respiratory disease was also higher (37.8 versus 8.2; hazard ratio, 4.68; 95% confidence interval, 1.05-20.9; p < 0.05). Multivariate Cox proportional hazards analysis revealed that serum Cr/CysC was an independent risk factor for respiratory disease mortality, regardless of age and airflow limitations., Conclusions: The serum Cr/CysC ratio could be a valuable clinical parameter for identifying sarcopenia and severe airflow obstruction. The study findings highlight the utility of this ratio as a prognostic predictor in patients with COPD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Lung surfactant accumulates in the lamellar body (LB) via not only the secretory (anterograde) pathway but also the endocytic (retrograde) pathway. Our previous studies suggested that the major surfactant components, phosphatidylcholine and surfactant protein A take independent trafficking routes in alveolar type II cells. Thus, trafficking of surfactant protein B (SP-B), a major hydrophobic surfactant apoprotein, should be re-evaluated by a straightforward method. Radiolabeling of cells and subsequent cell fractionation were employed to pursue the sequential trafficking of newly synthesized SP-B in rabbit alveolar type II cells. The LB fraction was prepared by gradient ultracentrifugation. Immunoprecipitation from the culture medium, total cells, and LB fraction was carried out with anti-SP-B antibody. Newly synthesized [ 35 S]-pro-SP-B (~ 42 kDa) was detected in the cells after 1 h. An ~ 8-kDa mature form of [ 35 S]-SP-B was detected in the cells after 3 h and in the LB after 6 h. Mature [ 35 S]-SP-B was predominant in the cells after 24 h, and the dominant portion was present in the LB. In contrast, only a small amount of mature [ 35 S]-SP-B was present in the culture medium. Molecular processing of ~ 42 kDa [ 35 S]-pro-SP-B and transport to the LB was inhibited by brefeldin A, which disassembles the Golgi apparatus. These results suggest that newly synthesized SP-B is sorted to the LB via the Golgi and stored until exocytosis. This pathway is distinct from the pathways reported for phosphatidylcholine and surfactant protein A.

We experienced a resected case of metastatic lung tumor with a right displaced segmental bronchus (B1+3). The patient was an 82-year-old woman who had a history of surgery for transverse colon cancer. A chest computed tomography (CT) scan revealed a nodular shadow with an irregular margin( 3.1 cm in diameter) in the right upper lobe, which was suspected of a primary lung cancer. Chest CT and bronchoscopy revealed B1+3 displaced segmental bronchus. Thoracoscope-assisted right upper lobectomy was performed for diagnostic and therapeutic purposes. The pathological diagnosis was a metastatic lung tumor from the transverse colon cancer.

We report a rare case of lung adenocarcinoma combined with minute pulmonary meningothelial-like nodule (MPMN) in a young adult. A 39-year-old woman was referred to our department for abnormal shadow of the right lower lobe. Chest computed tomography (CT) showed a mass shadow, 11 mm in size, in right S6. Since fluorodeoxyglucose-positron emission tomography (FDG-PET) demonstrated a lesion with FDG activity, with an increased uptake value of 2.2, this lesion was suspected to be a lung cancer. Wedge resection of right S6 was performed via thoracoscopy. The intraoperative pathological diagnosis was invasive lung adenocarcinoma, and additional right S6 segmentectomy and lymph node dissection (ND1a) was performed. The final pathological diagnosis of the tumor was adenocarcinoma of the lung, and MPMN was incidentally found by pathology in reseced specimen.

Background: Genetic variation in the β 2 -adrenergic receptor (ADRB2) gene has been thought to have an important role in the differential response to β 2 -agonist therapy for asthma. However, previous studies have shown little evidence for an association between these ADRB2 variants and the bronchial dilator response (BDR) in chronic obstructive pulmonary disease (COPD) patients. This discrepancy could be explained by differences in the distribution and heterogeneity of pulmonary emphysema in COPD patients, since emphysema distribution and heterogeneity are thought to have a role in pulmonary function in COPD patients. We hypothesized that differences in emphysema distribution and heterogeneity may have masked significant alterations of the bronchodilator response among ADRB2 genotypes in COPD patients in previous studies., Methods: The BDR (induced by 20 μg of procaterol) was measured in 211 patients who had a smoking history of more than 10 pack/years and had undergone chest high resolution computed tomography examination. A low attenuations area (<960 Hounsfield Units) was identified and the emphysema heterogeneity index (EHI%) was calculated with a range in value from -100% to 100%. ADRB2 Arg16Gly genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis., Results: The BDR was augmented in patients with homogenous emphysema compared with those with upper-dominant emphysema. In patients carrying the AA genotype of ADRB2, the BDR was significantly increased in patients with upper-dominant emphysema, but not in patients with lower-dominant emphysema., Conclusion: Combination analysis of ADRB2 Arg16Gly polymorphism and EHI% may predict the effectiveness of β 2 -adrenergic receptor agonist treatment in patients with COPD and emphysema., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog (MDM2) single nucleotide polymorphism (SNP)309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema., Methods: This study included 365 patients with a smoking history, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by means of CT scanning. SNPs, MDM2 mRNA, and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and the effects on cell proliferation and MDM2 promoter activity were measured., Results: The polymorphisms of the p53 and MDM2 genes were associated with emphysematous changes in the lung and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLF proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE., Conclusions: Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Rab 3 8 small GTPase regulates intracellular transport in melanocytes and alveolar type II epithelial cells. Ruby rats carrying Rab 3 8 and other gene mutations exhibit oculocutaneous albinism, bleeding diathesis, and hence, are a rat model of human Hermansky-Pudlak syndrome (HPS). We previously showed that Long Evans Cinnamon (LEC) rats, one strain of the Ruby rats, developed aberrant lung surfactant homeostasis with remarkably enlarged lamellar bodies in alveolar type II cells., Methods: A replication-deficient recombinant adenovirus expressing rat Rab 3 8 (Ad-Rab 3 8) was constructed. Alveolar type II cells were isolated from the LEC rats and tested for lung surfactant phosphatidylcholine secretion. The rats were also examined whether exogenous expression of Ad- Rab 3 8 could rescue the altered lung surfactant homeostasis in the lungs., Results: Isolated type II cells infected with Ad-Rab 3 8 exhibited improved secretion patterns of [ 3 H]phosphatidylcholine, i.e. increased basal hyposecretion and decreased agonist-induced hypersecretion. Endobronchial administration of Ad-Rab 3 8 improved the morphology of type II cells and lamellar bodies, reducing their sizes close to those of wild-type rats. The increased amounts of phosphatidylcholine and surfactant protein B in the lamellar body fractions were decreased in the Ad-Rab 3 8 infected lungs., Conclusions: These results provide strong evidence that the aberrant lung surfactant homeostasis in the LEC rats is caused by Rab 3 8 deficit, and suggest that endobronchial delivery of the responsive transgene could be an effective method to ameliorate the abnormal lung phenotype in the animal model of HPS.

Background: Cigarette smoke induced oxidative stress has been shown to reduce silent information regulator 1 (Sirt1) levels in lung tissue from smokers and patients with COPD patients. Sirt1 is known to inhibit endothelial senescence and may play a protective role in vascular cells. Endothelial progenitor cells (EPCs) are mobilized into circulation under various pathophysiological conditions, and are thought to play an important role in tissue repair in chronic obstructive lung disease (COPD). Therefore, Sirt1 and EPC-associated mRNAs were measured in blood samples from patients with COPD and from cultured CD34 + progenitor cells to examine whether these genes are associated with COPD development., Methods: This study included 358 patients with a smoking history of more than 10 pack-years. RNA was extracted from blood samples and from CD34 + progenitor cells treated with cigarette smoke extract (CSE), followed by assessment of CD31, CD34, Sirt1 mRNA, miR-34a, and miR-126-3p expression by real-time RT-PCR., Results: The expression of CD31, CD34, Sirt1 mRNAs, and miR-126-3p decreased and that of miR-34a increased in moderate COPD compared with that in control smokers. However, no significant differences in these genes were observed in blood cells from patients with severe COPD compared with those in control smokers. CSE significantly decreased Sirt1 and increased miR-34a expression in cultured progenitor cells., Conclusion: Sirt1 expression in blood cells from patients with COPD could be a biomarker for disease stability in patients with moderate COPD. MiR-34a may participate in apoptosis and/or senescence of EPCs in smokers. Decreased expression of CD31, CD34, and miR-126-3p potentially represents decreased numbers of EPCs in blood cell from patients with COPD.

Objectives and Design: Hypersensitivity pneumonitis (HP) is a pulmonary disease caused by repeated exposure to various aspiration antigens, including bacteria and fungi. Although TLRs are known to be required for the generation of HP triggered by bacteria, the significance of fungal receptors remains unclear. The present study aimed to investigate whether Dectin-1 and Dectin-2 contribute to the development of experimental HP triggered by the fungus Trichosporon asahii (T. asahii) that causes summer-type HP., Materials and Methods: We investigated the binding between Dectin-Fc protein and T. asahii by a dot blot assay. We performed the histological and flow cytometric analysis in the HP model using Dectin-1-deficient (Dectin-1(-/-)) and Dectin-2(-/-) mice. We also investigated Th17/Th1 responses in lung cells, and measured an IL-17-promoting cytokine IL-23 from bone marrow-derived dendritic cells (BMDCs) by ELISA., Results: Dectin-1 bound more strongly to T. asahii than Dectin-2. Dectin-1(-/-) mice barely developed HP, whereas both wild-type mice and Dectin-2(-/-) mice developed similar lung diseases. Dectin-1 deficiency decreased the infiltration of neutrophils and monocyte-derived macrophages and repressed the expansion of lung CD4(+)IL-17A(+) cells. The production of IL-23 p19 was reduced in Dectin-1(-/-) BMDCs., Conclusions: These data suggested Dectin-1 plays a critical role in the development of fungus-induced HP.