巽 浩一郎

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication that occurs in association with various diseases including coagulation disorders. In rare cases, it is caused by hemophilia. A 48-year-old man was admitted to our hospital for a third time due to DAH. Although the cause of DAH could not be identified by bronchoscopy or laboratory tests, a good response to corticosteroids suggested idiopathic DAH with pulmonary capillaritis. The patient was diagnosed with hemophilia B based on the results of a detailed inquiry, a mildly prolonged activated partial thromboplastin time, and low factor IX activity. Hemophilia may be an underlying factor that exacerbates the bleeding of patients with DAH, even when they show a good response to corticosteroids.

BACKGROUND: Recent advances in multidetector computed tomography (MDCT) facilitate acquiring important clinical information for managing patients with COPD. MDCT can detect the loss of lung tissue associated with emphysema as a low-attenuation area (LAA) and the thickness of airways as the wall area percentage (WA%). The percentage of small pulmonary vessels <5 mm2 (% cross-sectional area [CSA] <5) has been recently recognized as a parameter for expressing pulmonary perfusion. We aimed to analyze the longitudinal changes in structural abnormalities using these CT parameters and analyze the effect of exacerbation and smoking cessation on structural changes in COPD patients. METHODS: We performed pulmonary function tests (PFTs), an MDCT, and a COPD assessment test (CAT) in 58 patients with COPD at the time of their enrollment at the hospital and 2 years later. We analyzed the change in clinical parameters including CT indices and examined the effect of exacerbations and smoking cessation on the structural changes. RESULTS: The CAT score and forced expiratory volume in 1 second (FEV1) did not significantly change during the follow-up period. The parameters of emphysematous changes significantly increased. On the other hand, the WA% at the distal airways significantly decreased or tended to decrease, and the %CSA <5 slightly but significantly increased over the same period, especially in ex-smokers. The parameters of emphysematous change were greater in patients with exacerbations and continued to progress even after smoking cessation. In contrast, the WA% and %CSA <5 did not change in proportion to emphysema progression. CONCLUSION: The WA% at the distal bronchi and the %CSA <5 did not change in parallel with parameters of LAA over the same period. We propose that airway disease and vascular remodeling may be reversible to some extent by smoking cessation and appropriate treatment. Optimal management may have a greater effect on pulmonary vascularity and airway disease than parenchymal deconstruction in the early stage of COPD.

A 30-year-old Japanese man was diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH) with lupus anticoagulants (LAs) in 2003. He underwent pulmonary endarterectomy after the placement of an inferior vena cava filter (IVCF) in 2004, and treatment with warfarin was continued. In 2014, IVCF occlusion and marked collateral circulation were noted during an examination for transient dyspnea; however, his warfarin level was within the therapeutic range for 88.9% of the time from 2003 to 2014. We herein report a rare case of CTEPH and LAs with IVCF occlusion; in such cases, intense treatment may be required.

Pulmonary endometriosis (PEM) is a rare disease characterized by the proliferation of ectopic endometrial tissue in the lungs, which presents as catamenial hemoptysis. A 20-year-old-woman was admitted for repeated hemoptysis. Chest CT revealed a ground-glass opacity that appeared consistently with her menstrual cycle. Our detailed inquiry revealed a history of artificial abortion, which was followed by the use of oral contraceptives and catamenial hemoptysis after the discontinuation of these medications. Surgical removal was performed and histopathological examinations confirmed PEM. This clinical course suggested hematogenous metastasis. An inquiry regarding the patient's history of uterine procedures and use of oral contraceptives was suggestive for the diagnosis of this disease.

Objective Osteoporosis, which is now recognized as a major comorbidity of chronic obstructive pulmonary disease (COPD), must be diagnosed by appropriate methods. The aims of this study were to clarify the relationships between bone mineral density (BMD) and COPD-related clinical variables and to explore the association of BMD with the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification in men. Methods We enrolled 50 Japanese men with clinically stable COPD who underwent dual-energy X-ray absorptiometry (DEXA), pulmonary function testing, and computerized tomography (CT) and who had completed a questionnaire (COPD assessment test [CAT]). We determined the association between the T-score and other tested parameters and compared the BMD of patients in each GOLD category. Results Twenty-three of the 50 patients (46.0%) were diagnosed with osteopenia, and 7 (14.0%) were diagnosed with osteoporosis. The BMD findings were significantly correlated with the CAT score, forced expiratory volume in 1 second percentage predicted (FEV1% predicted), low attenuation volume percentage (LAV%), and percentage of cross-sectional area of small pulmonary vessels (%CSA) on CT images. Notably, the median T-score of the GOLD category D participants was significantly lower than that of the participants in each of the other categories (A [-0.98], B [-1.06], C [-1.05], and D [-2.19], p&lt; 0.05). Conclusion Reduced BMD was associated with airflow limitation, extent of radiographic findings, and a poor quality of life (QOL) in patients with COPD. The BMD of GOLD category D patients was the lowest of all of the patients evaluated, and category D patients may benefit from active intervention for osteoporosis.

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by obstructive lesions and vasoconstriction of the pulmonary arteries. Early therapeutic interventions with vasodilator drugs are thought to be beneficial in PAH. However, it remains unknown whether the severity of intimal obstruction is associated with increased pulmonary arterial pressure and whether reduction of vasoconstriction in the earlier stage by these drugs has a beneficial effect. Therefore, the aims of this study were to investigate these issues in a rat model of severe PAH. Methods A rat model of severe PAH was created by injection of a vascular endothelial growth factor receptor blocker in combination with hypoxia for the first 3 weeks followed by normoxia for the next 9 weeks. To assess intimal obstruction, "the pulmonary artery occlusion index (PAOI)" was developed to digitize all lesions. The small pulmonary arteries were assessed by this index, and the association between right ventricular systolic pressure (RVSP) and PAOI was investigated. An endothelin receptor antagonist, ambrisentan, was administered by gavage to rats during either hypoxia (Prevention study group, n=25) or normoxia (Early treatment group, n=15). RESULTS: PAOI showed a positive correlation with RVSP, and both RVSP and PAOI increased gradually over time. There were no severe occlusive lesions in either group, but the density of partially occlusive lesions was significantly decreased in the Prevention study group. CONCLUSION: A novel PAOI index was developed, and this index was strongly correlated with RVSP. Furthermore, ambrisentan reduced luminal occlusive lesions more effectively when treatment was given during the first 2 weeks of hypoxia.

BACKGROUND: Modafinil is a wake-promoting drug and has been widely used for daytime sleepiness in patients with narcolepsy and other sleep disorders. A recent case series reported that daily oral modafinil alleviated hypercapnic respiratory failure in patients with COPD. However, the precise action of modafinil on respiration such as hypercapnic and/or hypoxic ventilatory responses remains unclear. The aim of this study is to clarify the effect of modafinil on the ventilatory control. METHODS: We investigated the hypothesis that modafinil enhances resting ventilation as well as the stimulatory ventilatory responses to hypercapnia and hypoxia. We addressed the issue by examining minute ventilation, respiratory rate and volume components using plethysmography, combined with a concurrent EEG monitoring of the level of wakefulness before and after administration of modafinil in two doses of 100 mg/kg and 200 mg/kg in unanesthetized mice. In addition, we monitored the effect of the lower dose of modafinil on mice locomotor activity in a freely moving condition by video-recording. RESULTS: Wakefulness, locomotor activity and variability of the breathing pattern in tidal volume were promoted by both doses of modafinil. Neither dose of modafinil increased the absolute values of resting ventilation or promoted the ventilatory responses to hypercapnia and hypoxia. Rather, higher dose of modafinil slightly suppressed respiratory rate in room air condition. CONCLUSIONS: Modafinil is conducive to the state of wakefulness but does not augment resting ventilation or the hyperventilatory responses to chemical stimuli in unanesthetized rodents.

慢性閉塞性肺疾患(COPD)では換気需要の増加の際に呼吸回数が増加し、その結果エアートラッピングが生じ肺内の残気量が増加していく。これを動的肺過膨張という。動的肺過膨張は労作時呼吸困難や運動耐用能低下に大きく関係している。その要因として肺過膨張による呼吸筋への負荷の増大や吸気筋の機能低下、また最大吸気量の減少に伴う運動負荷時の1回換気量の増加制限などが考えられる。中等度以上の気流閉塞を有するCOPD患者ではADL動作においても動的肺過膨張が認められる。また軽症の気流閉塞の患者においてさえ運動負荷時には動的肺過膨張が出現し運動耐用能を低下させうる。気管支拡張薬はエアートラッピングを軽減し肺過膨張を減少させることで労作時呼吸困難や運動耐用能を改善させる。(著者抄録)

Background: Modafinil is a wake-promoting drug and has been widely used for daytime sleepiness in patients with narcolepsy and other sleep disorders. A recent case series reported that daily oral modafinil alleviated hypercapnic respiratory failure in patients with COPD. However, the precise action of modafinil on respiration such as hypercapnic and/or hypoxic ventilatory responses remains unclear. The aim of this study is to clarify the effect of modafinil on the ventilatory control. Methods: We investigated the hypothesis that modafinil enhances resting ventilation as well as the stimulatory ventilatory responses to hypercapnia and hypoxia. We addressed the issue by examining minute ventilation, respiratory rate and volume components using plethysmography, combined with a concurrent EEG monitoring of the level of wakefulness before and after administration of modafinil in two doses of 100 mg/kg and 200 mg/kg in unanesthetized mice. In addition, we monitored the effect of the lower dose of modafinil on mice locomotor activity in a freely moving condition by video-recording. Results: Wakefulness, locomotor activity and variability of the breathing pattern in tidal volume were promoted by both doses of modafinil. Neither dose of modafinil increased the absolute values of resting ventilation or promoted the ventilatory responses to hypercapnia and hypoxia. Rather, higher dose of modafinil slightly suppressed respiratory rate in room air condition. Conclusions: Modafinil is conducive to the state of wakefulness but does not augment resting ventilation or the hyperventilatory responses to chemical stimuli in unanesthetized rodents.

Pulmonary nocardiosis is a rare but potentially serious infection typically in immunosuppressed patients (ISPs). It is also known to occur in immunocompetent patients (ICPs). However, little is currently known regarding the clinical characteristics and radiographic findings of pulmonary nocardiosis specifically in ICPs. In this study, 30 patients with pulmonary nocardiosis were identified and 10 were considered to be colonized. Of all patients with pulmonary nocardiosis, 12 patients were ICPs and 18 were ISPs. Although half of ISPs were infected by Nocardia nova, ICPs were affected by various Nocardia species. Compared with ISPs, chest CT findings of ICPs showed a higher prevalence of bronchiectasis (67% vs 6%, p < .01) and centrilobular nodular opacities (67% vs 11%, p < .01), both of which are often seen in pulmonary nontuberculous mycobacterial disease. Additionally, nontuberculous mycobacterium was isolated from 6 of 21 ICPs with positive Nocardia species culture. Therefore, we recommend that physicians carefully differentiate pulmonary nocardiosis from pulmonary nontuberculous mycobacterial disease in ICPs.

Pulmonary nocardiosis is a rare but potentially serious infection typically in immunosuppressed patients (ISPs). It is also known to occur in immunocompetent patients (ICPs). However, little is currently known regarding the clinical characteristics and radiographic findings of pulmonary nocardiosis specifically in ICPs. In this study, 30 patients with pulmonary nocardiosis were identified and 10 were considered to be colonized. Of all patients with pulmonary nocardiosis, 12 patients were ICPs and 18 were ISPs. Although half of ISPs were infected by Nocardia nova, ICPs were affected by various Nocardia species. Compared with ISPs, chest CT findings of ICPs showed a higher prevalence of bronchiectasis (67% vs 6%, p &lt;.01) and centrilobular nodular opacities (67% vs 11%, p &lt;.01), both of which are often seen in pulmonary nontuberculous mycobacterial disease. Additionally, nontuberculous mycobacterium was isolated from 6 of 21 ICPs with positive Nocardia species culture. Therefore, we recommend that physicians carefully differentiate pulmonary nocardiosis from pulmonary nontuberculous mycobacterial disease in ICPs. (C) 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

BACKGROUND/OBJECTIVES: Several studies have already shown the correlation between the right ventricle (RV) hemodynamic values and either glucose uptake or fatty acid uptake in the RV, respectively. However, there are few studies to compare the RV metabolic alteration before and after treatment for pulmonary hypertension. The aims of this study are to assess right ventricular glucose and fatty acid in chronic thromboembolic pulmonary hypertension (CTEPH) patients before and after pulmonary thromboendarterectomy and to examine whether there is a correlation between right ventricular glucose and fatty acid uptake. METHODS: To assess glucose and fatty acid accumulation in the RV, [(18)F] fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) and (123)I-β-methyl iodophenyl pentadecanoic acid (BMIPP) imaging were performed in CTEPH patients before (FDG: n=20, BMIPP: n=13) and after (FDG: n=12, BMIPP: n=8) thromboendarterectomy. RESULTS: Both [(18)F] FDG uptake and (123)I-BMIPP uptake in RV of post-PEA patients obviously decreased after this operation procedure (p<0.01). The right ventricle [(18)F] FDG uptake was also significantly correlated with (123)I-BMIPP uptake (r=0.45, p=0.04). CONCLUSIONS: In this study, we observed that both glucose and fatty acid accumulated in the RV of patients with CTEPH. Although the exact details of the altered energy metabolism in the stressed RV remain unknown, this is the first study to evaluate both glucose and fatty acid uptake before and after thromboendarterectomy in patients with CTEPH, even though the number of the patient is limited.

Cluster of differentiation 69 (CD69), known as an early activation marker of lymphocytes, has been demonstrated to regulate inflammatory events in various disease models. Although the increased number of CD69-expressed T lymphocytes in the lungs of patients with chronic obstructive pulmonary disease (COPD) has been reported, a functional role of CD69 in the pathogenesis of COPD remains unknown. To address to this question, CD69-deficient (CD69KO) mice and wild-type (WT) mice were subjected to a mouse model of porcine pancreatic elastase (PPE)-induced pulmonary inflammation and emphysema. In the two genotypes, PPE increased counts of macrophages, neutrophils and lymphocytes in bronchoalveolar lavage fluid (BALF) and induced emphysematous changes in the lung, whereas those two pathological signs were significantly enhanced in CD69KO mice compared to WT mice. Moreover, the PPE-induced levels of IL-17 and IL-6 in BALF were significantly higher in CD69KO mice than in WT mice at the acute inflammatory phase. Immunofluorescent studies showed that IL-17 and IL-6 were predominantly expressed in CD4+ and γδ T cells and macrophages, respectively. Concomitant administration of IL-17- and IL-6-neutralizing antibodies significantly attenuated the PPE-induced emphysematous changes in the two genotypes. These findings suggest that CD69 negatively regulates the development of PPE-induced emphysema in part at least through modulating function of IL-17-producing T cells.

Idiopathic pulmonary haemosiderosis (IPH) is a rare cause of diffuse alveolar haemorrhage during childhood, and its precise pathophysiology and long-term clinical course remain unclear. A 31-year-old man was diagnosed with IPH at four years of age and had recurrent episodes of haemoptysis. The patient's symptoms responded well to steroids. However, pulmonary fibrosis and the cystic region in the lung progressively worsened. At age 27, the patient developed polyarthritis with positive anti-cyclic citrullinated peptide antibodies. The patient also developed hand synovitis, which was diagnosed with ultrasonography. These results indicate complications from rheumatoid arthritis. The patient's dyspnoea gradually worsened, and at the age of 31, he developed pneumothorax and an acute exacerbation of IPH. The clinical course from ages 4 to 31 included progressive chronic respiratory failure because of pulmonary fibrosis, acute exacerbations, complications with rheumatoid arthritis, and deliberation regarding lung transplantation. The development of rheumatoid arthritis after the onset of IPH supports the theory of an autoimmune mechanism of IPH.

BACKGROUND: Approximately 80 % of mesothelioma specimens have the wild-type p53 gene, whereas they contain homozygous deletions in the INK4A/ARF locus that encodes p14 (ARF) and the 16 (INK4A) genes. Consequently, the majority of mesothelioma is defective of the p53 pathways. We examined whether zoledronic acid (ZOL), a third generation bisphosphonate, and adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55), which augments p53 levels in the infected tumors, could produce combinatory anti-tumor effects on human mesothelioma cells bearing the wild-type p53 gene. METHODS: Cytotoxicity of ZOL and Ad-delE1B55 was assessed with a WST assay. Cell cycle changes were tested with flow cytometry. Expression levels of relevant molecules were examined with western blot analysis to investigate a possible mechanism of cytotoxicity. Furthermore, the expressions of Ad receptors on target cells and infectivity were estimated with flow cytometry. Viral replication was assayed with the tissue culture infection dose method. RESULTS: A combinatory use of ZOL and Ad-delE1B55 suppressed cell growth and increased sub-G1 or S-phase populations compared with a single agent, depending on cells tested. The combinatory treatment up-regulated p53 levels and subsequently enhanced the cleavage of caspase-3, 8, 9 and poly (ADP-ribose) polymerase, but expression of molecules involved in autophagy pathways were inconsistent. ZOL-treated cells also increased Ad infectivity with a dose-dependent manner and augmented Ad replication although the expression levels of integrin molecules, one of the Ad receptors, were down-regulated. CONCLUSIONS: These findings indicated that ZOL and Ad-delE1B55 achieved combinatory anti-tumor effects through augmented apoptotic pathways or increased viral replication.

Sporadic and familial elastin mutations can occur in large vessel stenosis such as supravalvular aortic stenosis and narrowing of the descending aorta. However, there are very few reports regarding the arteriopathy of cerebral, pulmonary or abdominal arteries in elastin mutations. We herein report the case of a Japanese female patient presenting with multiple arteriopathy including moyamoya disease, a tortuosity of abdominal arteries and pulmonary hypertension due to peripheral pulmonary artery stenosis. This case suggests the possible progression of cerebral arteriopathy including moyamoya disease in patients with elastin mutations. © 2016 Wiley Periodicals, Inc.

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

Pulmonary vascular endothelial cells could contribute to maintain homeostasis in adult lung vasculature. "Tissue-resident" endothelial progenitor cells (EPCs) play pivotal roles in postnatal vasculogenesis, vascular repair, and tissue regeneration; however, their local pulmonary counterparts remain to be defined. To determine whether prominin-1/CD133 expression can be a marker of tissue-resident vascular EPCs in the pulmonary circulation, we examined the origin and characteristics of prominin-1/CD133-positive (Prom1(+)) PVECs considering cell cycle status, viability, histological distribution, and association with pulmonary vascular remodeling. Prom1(+) PVECs exhibited high steady-state transit through the cell cycle compared with Prom1(-) PVECs and exhibited homeostatic cell division as assessed using the label dilution method and mice expressing green fluorescent protein. In addition, Prom1(+) PVECs showed more marked expression of putative EPC markers and drug resistance genes as well as highly increased activation of aldehyde dehydrogenase compared with Prom1(-) PVECs. Bone marrow reconstitution demonstrated that tissue-resident cells were the source of >98% of Prom1(+) PVECs. Immunofluorescence analyses revealed that Prom1(+) PVECs preferentially resided in the arterial vasculature, including the resistant vessels of the lung. The number of Prom1(+) PVECs was higher in developing postnatal lungs. Sorted Prom1(+) PVECs gave rise to colonies and formed fine vascular networks compared with Prom1(-) PVECs. Moreover, Prom1(+) PVECs increased in the monocrotaline and the Su-5416 + hypoxia experimental models of pulmonary vascular remodeling. Our findings indicated that Prom1(+) PVECs exhibited the phenotype of tissue-resident EPCs. The unique biological characteristics of Prom1(+) PVECs predominantly contribute to neovasculogenesis and maintenance of homeostasis in pulmonary vascular tissues.

BACKGROUND: Alpha1-antitrypsin (ΑAT) deficiency (AATD), a condition of little or no AAT in the serum, is believed to be extremely rare in Japan. However, no such nationwide epidemiological survey has been conducted. The Respiratory Research Failure Group and Japanese Respiratory Society (JRS) cooperated to conduct this survey. METHODS: The survey questionnaire was sent by post to 1598 hospitals that have 200 or more beds (excluding mental hospitals), and by e-mail to members of the JRS. Hospitals failing to respond were followed-up by phone. RESULTS: 1467 hospitals replied [response rate=91.8% (1467/1598)], and 114 members responded. Of the 14 probands registered from 10 hospitals and one local practitioner, 9 had severe and 5 had mild AATD. Eleven of these patients were diagnosed with COPD, 1 with COPD and bronchiectasis, 1 with pulmonary emphysema without airflow obstruction, and the remaining 1 with bronchiectasis without airflow obstruction. Mutation analysis of the SERPINA1 gene was performed in 7 patients, 6 of whom (85.7%) had homozygous PI*Siiyama. The prevalence of AATD in Japan was thus estimated to be 24 patients, with a 95% confidence interval (22, 27). When asked if they would prescribe AAT augmentation therapy, 6 of the 10 (60.0%) of respondent attending physicians answered affirmatively if health insurance would cover the treatment. CONCLUSIONS: This nationwide survey confirmed that AATD is extremely rare in Japan. Six of 10 care-giving physicians would offer AAT augmentation therapy if the therapy were covered by health insurance in Japan.

BACKGROUND: In lymphangioleiomyomatosis (LAM), predicting lung disease progression is essential for treatment planning. However, no previous Japanese studies have attempted to predict the reductions in pulmonary function that occur in LAM patients. METHODS: The data for 89 LAM patients who had undergone ≥3 spirometry tests and whose data had been registered in the Japanese National Research Project on Intractable Diseases database between October 2009 and March 2014 were analyzed after excluding patients who had undergone (1) a lung transplant; (2) mTOR inhibitor treatment; or (3) thoracic drainage, pleurodesis, surgery, or thoracic duct ligation during the study period. The rates of change (slope) in pulmonary parameters were calculated, and their associations with clinical background factors were investigated. RESULTS: Among the whole study population, the median (quartiles) slope of forced expiratory volume in one second (FEV1) was -46.7 (-95.2; -15.0)mL per year. Episodes of conservatively treated pneumothorax during the study period were found to be associated with rapid reductions in FEV1 (% predicted). Pregnancy during the study period was associated with a reduction in FEV1 (% predicted). When the patients were divided into those who exhibited initial FEV1 (% predicted) values of >70% (Group A) and ≤70% (Group B), Group B displayed significantly faster reductions in FEV1 (% predicted) than Group A. CONCLUSIONS: LAM patients whose initial FEV1 (% predicted) values are ≤70% subsequently exhibit rapid reductions in their FEV1 values, and hence, require treatment. However, the FEV1 reduction rate varies markedly among individuals and should be monitored in all cases.

We report the first patient with pleuroparenchymal fibroelastosis (PPFE) to undergo living donor bilateral lobar lung transplantation. The patient was diagnosed with secondary PPFE as a late complication of chemotherapy that included high-dose cyclophosphamide for mature B-cell lymphocytic leukemia. Although the patient maintained complete remission, dry cough and back pain appeared 8 years after the chemotherapy. He had repeated bilateral pneumothoraces, and his respiratory condition gradually deteriorated because of progressive pleural thickening and parenchymal fibrosis. He underwent living-donor bilateral lobar lung transplantation with an inverse transplant on the left side.

Our understanding of chronic obstructive pulmonary disease (COPD) has changed dramatically over the past two decades, especially since the first launching of GOLD document in 2001. The first GOLD workshop reports showed the global strategy for the diagnosis, management and prevention of COPD at that time. Its goal was to increase awareness of COPD, and a nihilistic attitude toward COPD occupied a dominant position due to the disappointment with available treatment options. Thereafter, both pharmacologic and non-pharmacologic treatments' options have steadily progressed, while the 'COPD' notion has moved from an airflow limitation centric view to a complex and heterogeneous disease, which leads inevitably to the need for personalizing the assessment and treatment of patients with COPD.

BACKGROUND: Mean pulmonary arterial pressure (MPAP) is an important pulmonary hemodynamic parameter used in the management of patients with chronic thromboembolic pulmonary hypertension (CTEPH). We compared echocardiography-derived estimates of MPAP with right heart catheterization (RHC) to identify reliable noninvasive methods of estimating MPAP-derived RHC (MPAPRHC) in these patients. METHODS AND RESULTS: Echocardiography and RHC were performed in 56 patients with CTEPH (60.5±12.0 years; 44 females). We measured the tricuspid regurgitation (TR) pressure gradient (TRPG) using echocardiography. The mean systolic right ventricular (RV)-right atrial (RA) gradient was calculated by tracing the TR time velocity flow. Systolic and mean pulmonary artery pressures (SPAPTRand MPAPTR) estimated from TRPG and mean systolic RV-RA gradient were calculated by adding RA pressure based on the inferior vena cava. MPAPChemlawas calculated using Chemla's formula: 0.61×SPAPTR+2 mmHg. MPAPRHCand pulmonary vascular resistance were 35.9±11.3 mmHg and 6.6±3.6 Wood units, respectively. The mean difference from MPAPRHCand limits of agreement were -1.5 mmHg and -19.6 to 16.5 mmHg for MPAPTR, and -4.6 mmHg and -24.5 to 15.2 mmHg for MPAPChemla. Accuracy within 10 mmHg and 5 mmHg of MPAPRHCwas 80.4% and 46.4% for MPAPTR, and 71.4% and 48.2% for MPAPChemla, respectively. CONCLUSIONS: MPAPTRand MPAPChemlaare reliable estimates for MPAPRHCin patients with CTEPH. (Circ J 2016; 80: 1259-1264).

BACKGROUND: Moderate sedation has been commonly used for fiberoptic bronchoscopy (FB). However, patients may find FB under moderate sedation to be unpleasant. We therefore examined whether deep sedation was a useful premedication for FB. METHODS: We designed a prospective, randomized study using a patient questionnaire to address the perceptions of the procedures and complications of patients who underwent FB with deep sedation (deep sedation group) with midazolam in comparison with those who underwent FB with moderate sedation (moderate sedation group) with the same drug. Patients were asked to grade FB as being easy or difficult to tolerate. The primary endpoint was tolerability and the secondary endpoints included complications associated with the procedure. RESULTS: A total of 80 patients were included in the study. A significantly lower number of patients in the deep sedation group reported that the technique was difficult to tolerate (5.0% vs. 40.0%, moderate sedation group; P<0.001). However, the dose of oxygen required to maintain an oxygen saturation of ≥90% was higher in the deep sedation group (7.3±4.7 vs. 2.7±1.6 L/min; P<0.0001). There were no cases of prolonged oxygen desaturation or deaths related to FB in either group. CONCLUSION: In the present study, deep sedation had a beneficial effect on patient tolerance to FB. Although oxygen desaturation during FB represents a potentially serious complication, deep sedation may be considered to be a useful premedication for FB.

OBJECTIVE: Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making its administration difficult in an outpatient setting. Although a short hydration protocol for cisplatin has been recently developed, its safety is not fully understood. METHODS: Consecutive patients with lung or other cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who were receiving chemotherapy containing cisplatin at a dose of ≥60 mg/m(2) in a single administration were evaluated. Seventy-four patients were treated with a short hydration protocol consisting of 1750-2250 ml of hydration with mannitol and magnesium supplementation over a period of 3.75-4.75 h on Day 1. Sixty-nine patients were treated with a conventional hydration protocol consisting of 2100-2600 ml of hydration over 6.5-7.5 h on Day 1 with pre- and post-hydration on Days 0, 2 and 3. Toxicity was then compared between the two groups. RESULTS: An elevated serum creatinine level ≥grade 1 was significantly less frequent in the group receiving the short hydration protocol than in the group receiving conventional hydration. Other toxicities were similar between the two groups. Consequently, the completion rate for the planned treatment in the short hydration group (73.0%, 54/74) was significantly higher than that in the conventional hydration group (53.6%, 37/69). CONCLUSIONS: Short hydration is safe, making cisplatin-containing chemotherapy easier to perform.

Objective. To determine the prevalence of lung abnormalities on chest computed tomography (CT) in patients with microscopic polyangiitis (MPA), to assess the responsiveness of such abnormalities to initial treatment, and to assess associations between these abnormalities and patient and disease characteristics and mortality. Methods. We retrospectively identified 167 consecutive hospital-based patients with MPA in 3 hospitals in Japan. We longitudinally collected clinical information for 150 of these patients, for whom CT images obtained before treatment were available. We then determined the presence of 22 imaging components of lung abnormalities in these patients. Results. The vast majority of patients (97%) had at least 1 lung abnormality on chest CT images, including interstitial lung lesions (66%), airway lesions (66%), pleural lesions (53%), and emphysematous lesions (37%). In multivariate analyses, ground-glass opacity was associated with the Birmingham Vasculitis Activity Score, whereas 3 of 4 airway lesions were associated with myeloperoxidase-antineutrophil cytoplasmic antibodies. Latent class analysis identified a distinct group of patients with airway-predominant lung lesions. Airway lesions such as bronchiolitis and bronchovascular bundle thickening were among the components that showed improvement within 3 months of the initial treatment. An idiopathic pulmonary fibrosis pattern was the only chest CT variable that was independently associated with shorter survival. Conclusion. Abnormalities in a wide range of anatomic areas, including the whole airway, can be identified in the lungs of patients with MPA before treatment. The prevalence, clustering patterns, and responsiveness to treatment of individual lung abnormalities provide groundwork for informing future studies to understand the pathophysiology of MPA.

喀血患者における320列CTを用いたダイナミックスタディ(4Dスタディ)での体循環動脈について検討した。320列CTを用いた4Dスタディを行い、その後に血管造影検査・塞栓術を施行した9例(男性3名、女性6名、32〜83歳)を対象とした。いずれも喀血部位と血管造影検査で同定したシャント部位は一致した。シャントの体循環側の責任血管は気管支動脈8例、胸壁の動脈1例であった。肺血管は全て肺動脈で、全例で止血が得られた。4D画像では、全例で喀血の原因となっているシャント血流を確認した。7例において2D画像上で関心領域を設定でき、CT値の測定とそのダイナミックカーブの作成を行った。2例は背景肺のコンソリデーションの内部にシャント部位があり、肺血管の形態が認識できず、関心領域を設定できなかった。シャント部位のCT値のダイナミックカーブは二峰性の上昇を呈し、一つめのピークは肺動脈幹よりも低いCT値、二つめのピークは高いCT値を呈した。

BACKGROUND/AIM: Lysozyme (mucopeptide N-acetyl-muramyl hydrolase) is widely used as a mucolytic and anti-inflammatory agent in Japan. We evaluated the effects of long-term lysozyme administration on COPD exacerbation. METHODS: In a 1-year, randomized, double-blind, placebo-controlled, parallel trial, patients with moderate-to-severe COPD and one or more episodes of COPD exacerbation in the previous year before enrollment were selected. Lysozyme (270 mg) or placebo was administered orally for 52 weeks as an add-on to the standard therapies such as bronchodilators. COPD exacerbation, pulmonary function, and COPD assessment test scores were analyzed. An exacerbation was defined as worsening of more than one symptom of COPD (cough, sputum volume, purulent sputum, or breathlessness) leading to a change in medication. The primary endpoint was exacerbation rate. RESULTS: A total of 408 patients were randomly assigned to the lysozyme and placebo groups. The baseline characteristics were similar between the two groups. The exacerbation rate was not significantly different between the two groups (1.4 vs 1.2; P=0.292, Poisson regression). However, a subgroup analysis showed that lysozyme might reduce exacerbation rate in patients with airway-dominant phenotype (1.2 vs 1.6). Moreover, the median time to first exacerbation was longer in patients with airway-dominant phenotype in the lysozyme group than that in the placebo group. The levels of improvement in forced expiratory volume in 1 second and COPD assessment test scores were not statistically different between the groups, but were always greater in the lysozyme group than in the placebo group over the 52 weeks of the study. CONCLUSION: The effects of using lysozyme as an add-on to standard COPD therapy were not significantly different compared with placebo and were insufficient to prevent COPD exacerbation.

OBJECTIVE: We herein assessed the utility of computed tomography (CT) for the diagnosis and ascertainment of the severity of community-acquired pneumonia (CAP) in the elderly. METHODS: The utility of CT compared with chest radiography (CR) for the diagnosis of CAP was prospectively studied among elderly inpatients with clinical symptoms and signs indicative of CAP at the Department of Respiratory Medicine in Nissan Tamagawa Hospital during the one-year period from January 2013 to December 2013. Additionally, we evaluated whether the findings of CT were useful as predictive factors related to the mortality rate associated with CAP. RESULTS: One hundred and forty-two patients, 65 years of age or older, were surveyed upon hospital admission for suspected CAP. Of the 142 patients included, 127 (89.4%) had pneumonic infiltration diagnosed by CT, however, CR could not recognize pneumonic infiltration in 9.4% (12/127) of these patients. In 127 CAP-positive patients, bilateral pneumonic infiltration was more frequently detected by CT in non-survivors than survivors (79.0% vs. 53.7%; p <0.05). By a multivariable analysis to determine the prognostic factors related to mortality from CAP, oxygen desaturation showed the greatest odds ratio among the other predictive factors, followed by comorbid neoplastic disease, blood urea nitrogen ≥21 mg/dL, male gender, and bilateral pneumonic infiltration diagnosed by CT. CONCLUSION: We herein demonstrated that CT was superior to CR for diagnosing and evaluating the severity of CAP in elderly patients.

PURPOSE: Activation-induced cytidine deaminase (AID) is involved in somatic hypermutation and class switch recombination processes in the antibody formation. The AID activity induces gene mutations and could be associated with transformation processes of B cells. Nevertheless, the relation between AID expression and the prognosis of B cell lymphoma patients remains uncharacterized. METHODS: We examined expression levels of the AID gene in 89 lymph node specimens from lymphoma and non-lymphoma patients with Northern blot analysis and investigated an association with their survival. RESULTS: The AID gene was preferentially expressed in B cell lymphoma in particular in diffuse large B cell lymphoma and follicular lymphoma. We confirmed AID protein expression in the mRNA-positive but not in the negative specimens with Western blot analysis and immunohistochemical staining. Survival of the patients treated with cyclophosphamide-/doxorubicin-/vincristine-/prednisone-based chemotherapy demonstrated that the prognosis of diffuse large B cell patients was unfavorable in the mRNA-positive group compared with the negative group, and that AID expression levels were correlated with the poor prognosis. In contrast, AID expression was not linked with the prognosis of follicular lymphoma patients. CONCLUSIONS: AID expression is a predictive marker for an unfavorable outcome in DLBCL patients treated with the chemotherapy.

BACKGROUND: The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the C825T polymorphism in the G-protein β3 subunit gene (GNB3) are associated with the efficacy of phosphodiesterase-5 inhibitor (PDE-5I) in erectile dysfunction. In addition, GNB3 genotypes could be associated with clinical worsening in pulmonary hypertension (PH) treated with PDE-5I. However, no studies have described the synergistic effects of gene polymorphisms on drug efficacy in patients with PH. OBJECTIVES: We aimed to examine the effects of combined ACE/GNB3 polymorphisms on the efficacy of PDE-5I in patients with PH. METHODS: This was a retrospective uncontrolled study. Ninety patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH) were treated with PDE-5I. Freedom from clinical worsening and pre- and post-treatment parameters, including the 6-min walk distance (6MWD) and serum brain natriuretic peptide (BNP) levels, were compared between patients with ACE/GNB3 II/TT and non-II/TT genotypes. RESULTS: Time to clinical worsening was significantly longer in patients with the II/TT genotype than in those with the non-II/TT genotype (5-year freedom from clinical worsening: 100 vs. 48.8%, respectively; p = 0.018), even in patients with CTEPH alone. Post-treatment 6MWD and BNP levels in patients with the II/TT genotype tended to be better than those in patients with the non-II/TT genotype. The ACE/GNB3 genotype was a significant predictor of clinical worsening, even after adjusting for pulmonary vascular resistance and 6MWD. CONCLUSIONS: ACE and GNB3 polymorphisms may synergistically influence the efficacy of PDE-5I in patients with PH.

BACKGROUND: Partial anomalous pulmonary venous return (PAPVR) is characterized by an abnormal connection of the pulmonary vein (PV). The left-to-right shunt results in an increased pulmonary blood flow, which may be followed by developing pulmonary hypertension (PH). We found that computed tomography (CT) scans may be misinterpreted, potentially leaving anomalous PVs undetected when reviewing diagnostic findings of PAPVR patients. The purpose of this study was to delineate this risk and assess the usefulness of our interpretation methods. METHODS: We retrospectively reviewed the records of 8 patients diagnosed with PAPVR, diagnosed with right heart catheterization (RHC) findings, at our department between 1991 and 2013. Our CT screening method for assessing anomalous PVs consisted of two points: 1) confirming that four PVs were connected to the left atrium (LA) and 2) checking that the vena cava was not connected with anomalous PVs. The accuracy of this method was analyzed in a blinded manner. RESULTS: In 4 patients, anomalous PVs delineated on enhanced CT scan images obtained before RHC were undetected. The sensitivity and specificity of detecting PAPVRs using our protocol were 0.800 and 0.978, respectively. Four of 8 patients went on to develop PH. Age at the time of diagnosis was positively correlated with mean pulmonary arterial pressure (r=0.929, p=0.002). CONCLUSION: There is a potential risk of CT scan misinterpretation when looking for anomalous PVs. Careful interpretation of CT findings that focus on PVs may be useful for detecting PAPVR and obtaining a PH differential diagnosis.

BACKGROUND: The postoperative changes in the coagulation-fibrinolysis system and the association between the system and postoperative course of patients with chronic thromboembolic pulmonary hypertension (CTEPH) who have undergone pulmonary endarterectomy (PEA) remain unclear. METHODS AND RESULTS: Between 1986 and 2013, 117 patients (55.1±11.2 years, preoperative mean pulmonary arterial pressure 46.5±10.5 mmHg) underwent PEA, and 15 patients died during the perioperative period. We studied the association between the preoperative coagulation-fibrinolysis markers and surgical outcomes of all patients, and the long-term outcomes of the 102 survivors from the date of PEA. We also investigated the postoperative changes in coagulation-fibrinolysis markers and their association with residual pulmonary hypertension (PH) in 20 consecutive patients. Only an elevated factor VIII level was associated with perioperative death. Thrombomodulin and plasminogen values were significantly increased after PEA. Univariate logistic regression analysis revealed that D-dimer positivity at follow-up was a risk factor for residual PH. Patients with both an elevated fibrinogen level (≥291 mg/dl [median]) and decreased plasminogen activity (<100% [median]) had significantly worse disease-specific survival than the other patients (5-year disease-specific survival: 84.0% vs. 100%, respectively; P=0.0041 [log-rank test]). CONCLUSIONS: Preoperatively high fibrinogen and low plasminogen values in patients with CTEPH are associated with poor long-term postoperative outcome. PEA benefited not only the pulmonary hemodynamics but also the coagulation-fibrinolysis system of patients.

BACKGROUND: The third generation of bisphosphonates is clinically in use for patients of osteoporosis or malignancy-linked hypercalcemia. The agents can also produce anti-tumor effects on bone metastasis of several types of tumors. We recently found that one of the agents achieved cytotoxicity to mesothelioma in vitro and in an orthotopic animal model. Mesothelioma is resistant to a number of chemotherapeutic agents, and suppression of local tumor growth is beneficial to the patients since metastasis to extra-thoracic organs is relatively infrequent until a late stage. METHODS/DESIGN: We demonstrated in an orthotopic mouse model that an intrapleural but not intravenous injection of zoledronic acid, one of the third generation bisphosphonates, at a clinically equivalent dose suppressed the tumor growth. Nevertheless, a high concentration of zoledronic acid administrated in the pleural cavity produced pleural adhesion. We also showed that zoledronic acid produced synergistic cytotoxic effects with cisplatin, the first-line chemotherapeutic agent for mesothelioma. We then planned to conduct a phase I clinical study to investigate any adverse effects and a possible clinical benefits produced by an intrapleural administration of zoledronic acid to mesothelioma patients who became resistant to the first-line chemotherapeutic agents. The clinical trial is a dose escalation study starting with 0.4, 1, 4, 8 and 16 mg per person since safety of administration of zoledronic acid into the pleural cavity remains unknown. Each dose group consists of three persons and the protocol allows to repeat administration of the same dose into the pleural cavity at a 4-weeks interval. DISCUSSION: We will conduct a possible combinatory study of intrapleural administration of zoledronic acid and systemic administration of the first-line agent to a chemotherapy-naïve patient based on the maximum tolerance dose of zoledronic acid determined by the present clinical trial. We propose that administration of bisphosphonates in a closed cavity is a treatment strategy for tumors developed in the cavity probably through the direct cytotoxic activity. TRIAL REGISTRATION: UMIN clinical trials registry, Japan. Register ID: UMIN8093.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by occlusion of pulmonary arteries by organized chronic thrombi. Persistent hypoxemia and residual pulmonary hypertension (PH) following successful pulmonary endarterectomy (PEA) are clinically important problems; however, the underlying mechanisms remain unclear. We have previously reported that residual PH is closely related to severe pulmonary vascular remodeling and hypothesize that this arteriopathy might also be involved in impaired gas exchange. The purpose of this study was to evaluate the association between hypoxemia and pulmonary arteriopathy after PEA. METHODS AND RESULTS: Between December 2011 and November 2014, 23 CTEPH patients underwent PEA and lung biopsy. The extent of pulmonary arteriopathy was quantified pathologically in lung biopsy specimens. We then analyzed the relationship between the severity of pulmonary arteriopathy and gas exchange after PEA. We observed that the severity of pulmonary arteriopathy was negatively correlated with postoperative and follow-up PaO2 (postoperative PaO2: r = -0.73, p = 0.0004; follow-up PaO2: r = -0.66, p = 0.001), but not with preoperative PaO2 (r = -0.373, p = 0.08). Multivariate analysis revealed that the obstruction ratio and patient age were determinants of PaO2 one month after PEA (R2 = 0.651, p = 0.00009). Furthermore, the obstruction ratio and improvement of pulmonary vascular resistance were determinants of PaO2 at follow-up (R2 = 0.545, p = 0.0002). Severe pulmonary arteriopathy might increase the alveolar-arterial oxygen difference and impair diffusion capacity, resulting in hypoxemia following PEA. CONCLUSION: The severity of pulmonary arteriopathy was closely associated with postoperative and follow-up hypoxemia.

Pancreatic carcinoma is relatively resistant to chemotherapy and cell death induced by replication of adenoviruses (Ad) can be one of the therapeutic options. Transduction efficacy of conventional type 5 Ad (Ad5) is however low and the cytotoxic mechanism by replication-competent Ad was not well understood. We constructed replication-competent Ad5 of which the E1A promoter region was replaced with a transcriptional regulatory region of the midkine, the survivin or the cyclooxygenase-2 gene, all of which were expressed at a high level in human tumors. We also prepared replication-competent Ad5 that were activated with the same region but had the type 35 Ad-derived fiber-knob region (AdF35) to convert the major cellular receptor for Ad infection from the coxsackie adenovirus receptor to CD46 molecules. Replication-competent AdF35 that were activated with the exogenous region produced cytotoxic effects on human pancreatic carcinoma cells greater than the corresponding Ad5 bearing with the same regulatory region. Cells infected with the AdF35 showed cytopathic effects and increased sub-G1 fractions. Caspase-9, less significantly caspase-8 and poly (ADP-ribose) polymerase, but not caspase-3 was cleaved and expression of molecules involved in autophagy and caspase-independent cell death pathways remained unchanged. Nevertheless, H2A histone family member X molecules were phosphorylated, and N-acetyl-L-cystein, an inhibitor for reactive oxygen species, suppressed the AdF35-mediated cytotoxicity. These data indicated a novel mechanism of Ad-mediated cell death and suggest a possible clinical application of the fiber-knob modified Ad.

BACKGROUND AND OBJECTIVE: A major pathogenic factor for catamenial pneumothorax is thoracic endometriosis. However, thoracic endometriosis-related pneumothorax (TERP) can develop as either catamenial or non-catamenial pneumothorax (CP). Therefore, the aim of this study was to elucidate the clinical differences between catamenial and non-catamenial TERP. METHODS: The clinical and pathological data in female patients who underwent video-assisted thoracoscopic surgery at the Pneumothorax Research Center during an 8-year period were retrospectively reviewed. This study included 150 female patients with surgico-pathologically confirmed TERP. The subjects were divided into two groups, those having all of the pneumothorax episodes in the catamenial period (CP group) and those who did not (non-CP group). We compared the clinical characteristics and surgico-pathological findings between these two groups. RESULTS: Of the 150 TERP patients, 55 (36.7%) were classified in the CP group, and 95 (63.3%) in the non-CP group. In regard to the locations of endometriosis, all TERP patients had diaphragmatic endometriosis, while pleural implantation was recognized in 34 of the 55 (61.8%) patients in the CP group and 42 of the 95 (44.2%) patients in the non-CP group (P < 0.05). CONCLUSIONS: A significant difference in the proportion of patients with pleural endometriosis was observed between catamenial and non-catamenial TERP. The ectopic sites of the endometriosis may be responsible for the timing of the pneumothorax episodes.