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1.  Sudden multiple fractures in a patient with sarcoidosis in multiple organs 
BMJ Case Reports  2014;2014:bcr2013201408.
A 30-year-old man who incidentally fractured his right olecranon and other multiple phalanges was admitted to our hospital. He had a 2-year history of uveitis and bilateral hilar lymphadenopathy (BHL), and pulmonary sarcoidosis was diagnosed from transbronchial lung biopsy. Right elbow arthrodesis was performed, and biopsied specimens showed non-caseating epithelioid cell granuloma, suggesting osseous sarcoidosis. He was discharged uneventfully without further treatment, but BHL had progressed with the appearance of lung parenchymal lesions 3 months later. At that time, involvement of other organs was also noted on Gallium-67 scintigraphy, showing accumulations in BHL, axillary and inguinal lymph nodes, enlarged liver and spleen and subcutaneous areas. After initiation of steroid therapy, multiple organ involvement improved, and no further bone involvement has been recognised to date. Osseous sarcoidosis complicated by bone fracture is an extremely rare presentation, but should be considered in patients with sarcoidosis, especially when multiple organs are involved.
doi:10.1136/bcr-2013-201408
PMCID: PMC3987236  PMID: 24711466
2.  Antemortem diagnosis with multiple random skin biopsies and transbronchial lung biopsy in a patient with intravascular large B-cell lymphoma, the so-called Asian variant lymphoma 
BMJ Case Reports  2014;2014:bcr2013202661.
A 59-year-old, previously healthy man presented to our hospital, with a 3-month history of high fever, nocturnal sweating and exertional dyspnoea. Aggressive diagnostic procedures such as multiple random skin biopsies and transbronchial lung biopsy (TBLB) led to an antemortem diagnosis of intravascular large B-cell lymphoma (IVLBCL), which showed abundant CD20 atypical lymphocytes aggregated in lumina of small vessels. The 29 cases diagnosed with IVLBCL during their lifetime by TBLB were reviewed. Their clinical features included respiratory symptoms (hypoxaemia, dyspnoea and dry cough) and persistent fever. IVLBCL patients show various radiological patterns (ground glass opacities, multiple centrilobular nodules, interlobular septal thickening, interstitial shadows and thickening of bronchovascular bundles), suggesting lymphatic or haematological spread. Antemortem diagnosis of IVLBCL is difficult, but a multidisciplinary approach, with aggressive multiple random skin biopsies and/or TBLB, should be considered in patients with respiratory symptoms that are refractory to antibiotics or prednisolone treatment.
doi:10.1136/bcr-2013-202661
PMCID: PMC3962888  PMID: 24632902
3.  Outcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study 
Background
Although no report has demonstrated the efficacy of corticosteroid therapy for autoimmune pulmonary alveolar proteinosis (aPAP), we sometimes encounter patients who have received this therapy for various reasons. However, as corticosteroids can suppress alveolar macrophage function, corticosteroid therapy might worsen disease severity and increase the risk of infections.
Methods
For this retrospective cohort study, we sent a screening form to 165 institutions asking for information on aPAP patients treated with corticosteroids. Of the resulting 45 patients screened, 31 were enrolled in this study. We collected demographic data and information about corticosteroid treatment period, dose, disease severity score (DSS) over the treatment period, and complications.
Results
DSS deteriorated during corticosteroid therapy in 23 cases (74.1 %) and the estimated overall cumulative worsening rate was 80.8 % for the total observation period. The worsening rate was significantly higher in patients treated with high-dose prednisolone (>18.9 mg/day, n = 16) than treated with low-dose prednisolone (≤18.9 mg/day, n = 15) divided by median daily dose (p < 0.02). Of patients with worsening, one died of disseminated aspergillosis and another of respiratory failure. Infections newly emerged in 6 cases during corticosteroid therapy (p < 0.05). Median serum granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibody levels were similar to previously reported data in a large cohort study.
Conclusion
The results demonstrate that corticosteroid therapy may worsen DSS of aPAP, increasing the risk for infections.
Electronic supplementary material
The online version of this article (doi:10.1186/s12890-015-0085-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12890-015-0085-0
PMCID: PMC4534060  PMID: 26264717
4.  Molecular evolution of haemagglutinin (H) gene in measles virus 
Scientific Reports  2015;5:11648.
We studied the molecular evolution of the haemagglutinin (H) gene (full length) in all genotypes (24 genotypes, 297 strains) of measles virus (MeV). The gene’s evolutionary timescale was estimated by the Bayesian Markov chain Monte Carlo (MCMC) method. We also analysed positive selection sites. The MCMC tree indicated that the MeV H gene diverged from the rinderpest virus (same genus) about 250 years ago and that 24 MeV genotypes formed 3 lineages dating back to a 1915 ancestor (95% highest posterior density [HPD] 1882–1941) with relatively rapid evolution (mean rate: 9.02 × 10−4 substitutions/site/year). The 3 lineages diverged in 1915 (lineage 1, 95% HPD 1882–1941), 1954 (lineage 2, 95% HPD 1937–1969), and 1940 (lineage 3, 95% HPD 1927–1952). These 24 genotypes may have diverged and emerged between the 1940s and 1990s. Selective pressure analysis identified many negative selection sites on the H protein but only a few positive selection sites, suggesting strongly operated structural and/or functional constraint of changes on the H protein. Based on the molecular evolution of H gene, an ancestor MeV of the 24 genotypes emerged about 100 years ago and the structure of H protein has been well conserved.
doi:10.1038/srep11648
PMCID: PMC4486977  PMID: 26130388
5.  A Simple Method for Differentiating Complicated Parapneumonic Effusion/Empyema from Parapneumonic Effusion Using the Split Pleura Sign and the Amount of Pleural Effusion on Thoracic CT 
PLoS ONE  2015;10(6):e0130141.
Background
Pleural separation, the “split pleura” sign, has been reported in patients with empyema. However, the diagnostic yield of the split pleura sign for complicated parapneumonic effusion (CPPE)/empyema and its utility for differentiating CPPE/empyema from parapneumonic effusion (PPE) remains unclear. This differentiation is important because CPPE/empyema patients need thoracic drainage. In this regard, the aim of this study was to develop a simple method to distinguish CPPE/empyema from PPE using computed tomography (CT) focusing on the split pleura sign, fluid attenuation values (HU: Hounsfield units), and amount of fluid collection measured on thoracic CT prior to diagnostic thoracentesis.
Methods
A total of 83 consecutive patients who underwent chest CT and were diagnosed with CPPE (n=18)/empyema (n=18) or PPE (n=47) based on the diagnostic thoracentesis were retrospectively analyzed.
Results
On univariate analysis, the split pleura sign (odds ratio (OR), 12.1; p<0.001), total amount of pleural effusion (≥30 mm) (OR, 6.13; p<0.001), HU value≥10 (OR, 5.94; p=0.001), and the presence of septum (OR, 6.43; p=0.018), atelectasis (OR, 6.83; p=0.002), or air (OR, 9.90; p=0.002) in pleural fluid were significantly higher in the CPPE/empyema group than in the PPE group. On multivariate analysis, only the split pleura sign (hazard ratio (HR), 6.70; 95% confidence interval (CI), 1.91-23.5; p=0.003) and total amount of pleural effusion (≥30 mm) on thoracic CT (HR, 7.48; 95%CI, 1.76-31.8; p=0.006) were risk factors for empyema. Sensitivity, specificity, positive predictive value, and negative predictive value of the presence of both split pleura sign and total amount of pleural effusion (≥30 mm) on thoracic CT for CPPE/empyema were 79.4%, 80.9%, 75%, and 84.4%, respectively, with an area under the curve of 0.801 on receiver operating characteristic curve analysis.
Conclusion
This study showed a high diagnostic yield of the split pleura sign and total amount of pleural fluid (≥30 mm) on thoracic CT that is useful and simple for discriminating between CPPE/empyema and PPE prior to diagnostic thoracentesis.
doi:10.1371/journal.pone.0130141
PMCID: PMC4468172  PMID: 26076488
6.  Molecular evolution of the VP1, VP2, and VP3 genes in human rhinovirus species C 
Scientific Reports  2015;5:8185.
Human rhinovirus species C (HRV-C) was recently discovered, and this virus has been associated with various acute respiratory illnesses (ARI). However, the molecular evolution of the major antigens of this virus, including VP1, VP2, and VP3, is unknown. Thus, we performed complete VP1, VP2, and VP3 gene analyses of 139 clinical HRV-C strains using RT-PCR with newly designed primer sets and next-generation sequencing. We assessed the time-scale evolution and evolutionary rate of these genes using the Bayesian Markov chain Monte Carlo method. In addition, we calculated the pairwise distance and confirmed the positive/negative selection sites in these genes. The phylogenetic trees showed that the HRV-C strains analyzed using these genes could be dated back approximately 400 to 900 years, and these strains exhibited high evolutionary rates (1.35 to 3.74 × 10−3 substitutions/site/year). Many genotypes (>40) were confirmed in the phylogenetic trees. Furthermore, no positively selected site was found in the VP1, VP2, and VP3 protein. Molecular modeling analysis combined with variation analysis suggested that the exterior surfaces of the VP1, VP2 and VP3 proteins are rich in loops and are highly variable. These results suggested that HRV-C may have an old history and unique antigenicity as an agent of various ARI.
doi:10.1038/srep08185
PMCID: PMC4313092  PMID: 25640899
7.  Breakthrough Invasive Candida glabrata in Patients on Micafungin: a Novel FKS Gene Conversion Correlated with Sequential Elevation of MIC 
Journal of Clinical Microbiology  2014;52(7):2709-2712.
Candida glabrata strains sequentially isolated from blood developed resistance to micafungin (MICs from <0.015 to 4 μg/ml). A novel mutation identified in micafungin-resistant strains at bp 262 of FKS2 (containing a deletion of F659 [F659del]) was inserted into the homologous region in FKS1.
doi:10.1128/JCM.03593-13
PMCID: PMC4097732  PMID: 24789192
8.  Spontaneous Resolution of Pneumocystis jirovecii Pneumonia on High-Resolution Computed Tomography in a Patient with Renal Cell Carcinoma 
Patient: Male, 59
Final Diagnosis: Pneumocystis jirovecii pneumonia
Symptoms: Low grade fever
Medication: —
Clinical Procedure: Transbronchial lung biopsy
Specialty: Pulmonology
Objective:
Rare disease
Background:
Spontaneous resolution of Pneumocystis jirovecii pneumonia has rarely been reported.
Case Report:
A 59-year-old man presented to our hospital because of pyrexia (38°C) and shaking chills for 2 days. He had a history of right nephrectomy due to renal cell carcinoma and left upper lobectomy for lung metastasis in the last 1.5 years. Two months previously, he was treated with oral prednisolone (20 mg/day) plus the intravenous mTOR inhibitor, temsirolimus (25 mg/week), for brain metastasis. On radiological examination, thoracic computed tomography showed diffuse ground glass opacities spreading in bilateral middle to lower lung fields. Although transbronchial biopsy specimens and bronchoalveolar lavage fluid demonstrated the presence of accumulation of black-colored Pneumocystis jirovecii cysts in the lung, his chief complaints and radiological abnormalities disappeared completely with no treatment. This case demonstrates a unique clinical presentation of Pneumocystis jirovecii pneumonia, in that spontaneous resolution was noted on clinical and sequential radiological evaluations.
Conclusions:
Increasing numbers of cytotoxic drugs and biological therapies have emerged, and changes in the immune status due to underlying diseases or administration of immunosuppressive drugs might affect the inflammatory process of Pneumocystis jirovecii pneumonia, as in the present case.
doi:10.12659/AJCR.890947
PMCID: PMC4237073  PMID: 25396336
Multidetector Computed Tomography; Pneumocystis jirovecii; Remission, Spontaneous
9.  Novel aspects on the pathogenesis of Mycoplasma pneumoniae pneumonia and therapeutic implications 
Mycoplasma pneumoniae (Mp) is a leading cause of community acquired pneumonia. Knowledge regarding Mp pneumonia obtained from animal models or human subjects has been discussed in many different reports. Accumulated expertise concerning this critical issue has been hard to apply clinically, and potential problems may remain undiscovered. Therefore, our multidisciplinary team extensively reviewed the literature regarding Mp pneumonia, and compared findings from animal models with those from human subjects. In human beings, the characteristic pathological features of Mp pneumonia have been reported as alveolar infiltration with neutrophils and lymphocytes and lymphocyte/plasma cell infiltrates in the peri-bronchovascular area. Herein, we demonstrated the novel aspects of Mp pneumonia that the severity of the Mp pneumonia seemed to depend on the host innate immunity to the Mp, which might be accelerated by antecedent Mp exposure (re-exposure or latent respiratory infection) through up-regulation of Toll-like receptor 2 expression on bronchial epithelial cells and alveolar macrophages. The macrolides therapy might be beneficial for the patients with macrolide-resistant Mp pneumonia via not bacteriological but immunomodulative effects. This exhaustive review focuses on pathogenesis and extends to some therapeutic implications such as clarithromycin, and discusses the various diverse aspects of Mp pneumonia. It is our hope that this might lead to new insights into this common respiratory disease.
doi:10.3389/fmicb.2014.00410
PMCID: PMC4127663  PMID: 25157244
Mycoplasma pneumoniae pneumonia; animal models; epidemiology; pathology; pathogenesis
10.  Epidemiology of virus-induced asthma exacerbations: with special reference to the role of human rhinovirus 
Viral respiratory infections may be associated with the virus-induced asthma in adults as well as children. Particularly, human rhinovirus is strongly suggested a major candidate for the associations of the virus-induced asthma. Thus, in this review, we reviewed and focused on the epidemiology, pathophysiology, and treatment of virus-induced asthma with special reference on human rhinovirus. Furthermore, we added our preliminary data regarding the clinical and virological findings in the present review.
doi:10.3389/fmicb.2014.00226
PMCID: PMC4033317  PMID: 24904541
epidemiology; pathophysiology; treatment; human rhinovirus; asthma exacerbation
11.  Mechanic’s hands revisited: is this sign still useful for diagnosis in patients with lung involvement of collagen vascular diseases? 
BMC Research Notes  2014;7:303.
Background
The presence of “mechanic’s hands” is one of the clinical clues for collagen vascular diseases. However, the exact relevance of “mechanic’s hands” in collagen vascular diseases has not been well documented. The aim of this study was to clarify the relevance of “mechanic’s hands” to collagen vascular diseases including various skin lesions and interstitial pneumonia.
Methods
A retrospective review of the medical records of patients with “mechanic’s hands” at our hospital between April 2011 and December 2012 was conducted. A PubMed search was also conducted using the term “mechanic’s hands”.
Results
Four patients in our institution and 40 patients obtained from PubMed who had “mechanic’s hands” were identified. The most frequent diseases were DM/amyopathic DM (n = 24, 54.5%) and anti-ARS syndrome (n = 17, 38.6%). In these patients, the major skin lesions associated with “mechanic’s hands” were periungual erythema (n = 23, 52.3%), Gottron’s sign (n = 17, 38.6%), heliotrope rash (n = 10, 22.7%), Raynaud’s phenomenon (n = 9, 20.5%), and anti-ARS syndrome (n = 17, 38.6%). Six cases (2 DM, 4 anti-ARS syndrome) had only “mechanic’s hands”. Antibodies to anti-ARS (n = 24) were Jo-1 (n = 19), PL-7 (n = 3), OJ (n = 1), and PL-12 (n = 1).
Conclusion
The presence of “mechanic’s hands” together with diverse skin lesions could be a clinical clue to the diagnosis of lung involvement associated with collagen vascular diseases, especially in anti-ARS syndrome or DM/amyopathic DM.
doi:10.1186/1756-0500-7-303
PMCID: PMC4035896  PMID: 24886713
Anti-aminoacyl-transfer RNA synthetase (ARS) syndrome; Dermatomyositis; Mechanic’s hands; Skin lesions
12.  High-Resolution Computed Tomography Findings for Patients With Drug-Induced Pulmonary Toxicity, With Special Reference to Hypersensitivity Pneumonitis-Like Patterns in Gemcitabine-Induced Cases 
The Oncologist  2013;18(4):454-459.
This retrospective study examines the incidence and causes of drug-induced pulmonary toxicity and classifies high-resolution computed tomography findings for antitumor-therapy associated pulmonary toxicity based on characteristic patterns and pathological considerations, with a special focus on gemcitabine-induced pulmonary toxicity.
Background.
Gemcitabine (GEM) is widely used as a chemotherapeutic agent. However, pulmonary toxicity has been rarely observed with GEM use. This article aims to determine the incidence and causes of drug-induced pulmonary toxicity, and to classify the high-resolution computed tomography (HRCT) findings for antitumor therapy-associated pulmonary toxicity based on characteristic patterns and pathological considerations, with a special focus on GEM-associated pulmonary toxicity (GAPT).
Methods.
Medical records of all patients with drug-induced pulmonary toxicity seen at Kyorin University hospital between April 2006 and December 2011 were retrospectively reviewed. The study examined correlations between HRCT and the assessed pathological or clinical findings, with a specific focus on antitumor drugs.
Results.
We identified 66 patients with drug-induced pulmonary toxicity. Among the antitumor drugs, GEM was the primary offending agent (n = 8) for pulmonary toxicity followed by docetaxel and gefitinib. HRCT patterns for the eight GAPT patients included the non-specific interstitial pneumonia (NSIP; n = 5) and the hypersensitivity pneumonitis (HP)-like pattern (n = 3). In contrast, four patients in the study were found to have the HP-like pattern, with three cases associated with GEM and one case associated with imatinib mesylate. The transbronchial lung biopsy or video-assisted thoracic surgery specimens for these patients showed granuloma or organizing tissue with a random distribution that was independent of the respiratory bronchiole. These results appeared to correspond to the HRCT-determined centrilobular nodules.
Conclusion.
GEM was the leading cause of drug-induced pulmonary toxicity in the patients examined in this study. This toxicity appears as NSIP or an HP-like pattern during HRCT examinations. This HP-like pattern may be useful for diagnosing GEM-induced pulmonary toxicity, as well as demonstrating granuloma or organizing tissue during lung pathology examinations.
doi:10.1634/theoncologist.2012-0248
PMCID: PMC3639533  PMID: 23404815
Pulmonary toxicity; Gemcitabine; Hypersensitivity pneumonitis; High-resolution CT; Antitumor drugs; Lung pathology
13.  Secondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan 
Background
Secondary pulmonary alveolar proteinosis (sPAP) is a very rare lung disorder comprising approximately 10% of cases of acquired PAP. Hematological disorders are the most common underlying conditions of sPAP, of which 74% of cases demonstrate myelodysplastic syndrome (MDS). However, the impact of sPAP on the prognosis of underlying MDS remains unknown. The purpose of this study was to evaluate whether development of sPAP worsens the prognosis of MDS.
Methods
Thirty-one cases of sPAP and underlying MDS were retrospectively classified into mild and severe cases consisting of very low-/low-risk groups and intermediate-/high-/very high-risk groups at the time of diagnosis of MDS, according to the prognostic scoring system based on the World Health Organization classification. Next, we compared the characteristics, disease duration, cumulative survival, and prognostic factors of the groups.
Results
In contrast to previous reports on the prognosis of MDS, we found that the cumulative survival probability for mild MDS patients was similar to that in severe MDS patients. This is likely due to the poor prognosis of patients with mild MDS, whose 2-year survival rate was 46.2%. Notably, 75% and 62.5% of patients who died developed fatal infectious diseases and exacerbation of PAP, respectively, suggesting that the progression of PAP per se and/or PAP-associated infection contributed to poor prognosis. The use of corticosteroid therapy and a diffusing capacity of the lung for carbon monoxide of less than 44% were predictive of poor prognosis.
Conclusion
Development of sPAP during the course of MDS may be an important adverse risk factor in prognosis of patients with mild MDS.
doi:10.1186/1471-2466-14-37
PMCID: PMC3946190  PMID: 24597668
Proteinosis; Myelodysplastic syndrome; GM-CSF; WPSS; Secondary pulmonary alveolar proteinosis; MDS; PAP; Refractory anemia
14.  Evidence for Reactivation of Human Herpesvirus 6 in Generalized Lymphadenopathy in a Patient with Drug-Induced Hypersensitivity Syndrome 
Journal of Clinical Microbiology  2013;51(6):1979-1982.
The present case provides direct evidence of human herpesvirus 6 reactivation in resected lymph node tissue in a patient with drug-induced hypersensitivity syndrome. This case clearly demonstrates that appropriate pathological evaluation of lymphadenopathy for drug-induced hypersensitivity syndrome, which mimics malignant lymphoma in clinical, radiological, and pathological findings, is required.
doi:10.1128/JCM.00097-13
PMCID: PMC3716082  PMID: 23536404
15.  Virus-induced exacerbations in asthma and COPD 
Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and/or airflow limitation due to pulmonary emphysema. Chronic bronchitis, pulmonary emphysema, and bronchial asthma may all be associated with airflow limitation; therefore, exacerbation of asthma may be associated with the pathophysiology of COPD. Furthermore, recent studies have suggested that the exacerbation of asthma, namely virus-induced asthma, may be associated with a wide variety of respiratory viruses. COPD and asthma have different underlying pathophysiological processes and thus require individual therapies. Exacerbation of both COPD and asthma, which are basically defined and diagnosed by clinical symptoms, is associated with a rapid decline in lung function and increased mortality. Similar pathogens, including human rhinovirus, respiratory syncytial virus, influenza virus, parainfluenza virus, and coronavirus, are also frequently detected during exacerbation of asthma and/or COPD. Immune response to respiratory viral infections, which may be related to the severity of exacerbation in each disease, varies in patients with both COPD and asthma. In this regard, it is crucial to recognize and understand both the similarities and differences of clinical features in patients with COPD and/or asthma associated with respiratory viral infections, especially in the exacerbative stage. In relation to definition, epidemiology, and pathophysiology, this review aims to summarize current knowledge concerning exacerbation of both COPD and asthma by focusing on the clinical significance of associated respiratory virus infections.
doi:10.3389/fmicb.2013.00293
PMCID: PMC3787546  PMID: 24098299
asthma; COPD; respiratory virus; exacerbation; overlap syndrome; human rhinovirus; respiratory syncytial virus
16.  Cytokine production and signaling pathways in respiratory virus infection 
It has been confirmed that respiratory virus infections can induce abberant cytokine production in the host. These cytokines may be associated with both elimination of the virus and complications in the host, such as virus-induced asthma. Representative host defense mechanisms against pathogens, including bacteria and viruses, are mediated by the innate immune system. Cells of the innate immune system express essential molecules, namely pattern recognition receptors (PRRs), such as Toll-like receptors, nucleotide-binding oligomerization domain-like receptors, and retinoic acid-inducible gene-I-like receptors. These PRRs can recognize components of pathogens such as bacterial lipopolysaccharide, viral antigens, and their genomes (DNA and RNA). Furthermore, PRRs activate various signaling pathways resulting in cytokine production against pathogen infection. However, the exact mechanisms remain unknown. In this review, we mainly focus on the representative mechanisms of cytokine production through PRRs and signaling pathways due to virus infections, including respiratory virus infections. In addition, we describe the relationships between respiratory infections and virus-induced asthma.
doi:10.3389/fmicb.2013.00276
PMCID: PMC3774987  PMID: 24062733
cytokine; signaling pathway; respiratory virus; innate immunity; virus-induced asthma
17.  Anacardic acid, a histone acetyltransferase inhibitor, modulates LPS-induced IL-8 expression in a human alveolar epithelial cell line A549 
F1000Research  2013;2:78.
Objective and design: The histone acetylation processes, which are believed to play a critical role in the regulation of many inflammatory genes, are reversible and regulated by histone acetyltransferases (HATs), which promote acetylation, and histone deacetylases (HDACs), which promote deacetylation. We studied the effects of lipopolysaccharide (LPS) on histone acetylation and its role in the regulation of interleukin (IL)-8 expression. 
Material: A human alveolar epithelial cell line A549 was used in vitro.
Methods: Histone H4 acetylation at the IL-8 promoter region was assessed by a chromatin immunoprecipitation (ChIP) assay. The expression and production of IL-8 were evaluated by quantitative polymerase chain reaction and specific immunoassay. Effects of a HDAC inhibitor, trichostatin A (TSA), and a HAT inhibitor, anacardic acid, were assessed. 
Results: Escherichia coli-derived LPS showed a dose- and time-dependent stimulatory effect on IL-8 protein production and mRNA expression in A549 cells in vitro. LPS showed a significant stimulatory effect on histone H4 acetylation at the IL-8 promoter region by ChIP assay. Pretreatment with TSA showed a dose-dependent stimulatory effect on IL-8 release from A549 cells as compared to LPS alone. Conversely, pretreatment with anacardic acid inhibited IL-8 production and expression in A549 cells. 
Conclusion: These data suggest that LPS-mediated proinflammatory responses in the lungs might be modulated via changing chromatin remodeling by HAT inhibition.
doi:10.12688/f1000research.2-78.v1
PMCID: PMC3931454  PMID: 24627774
18.  A case of malignant peritoneal mesothelioma revealed with limitation of PET-CT in the diagnosis of thoracic metastasis 
Journal of Thoracic Disease  2013;5(1):E11-E16.
A 47-year-old man was referred to our hospital because of a 2-month history of dry cough, 2-kg weight loss, and a feeling of abdominal fullness. The PET-CT scan depicts the intense standard uptake values (SUVs) of the anterior and subphrenic lymphnodes, and intraperitoneal cavity, especially in the omentum, while, no uptake was found in the pleural cavity. Based on the pathological findings of the open lung biopsy specimens, he was diagnosed with malignant peritoneal mesothelioma of epithelioid type with thoracic metastasis. The present case demonstrated the some of the limitations of PET-CT in the diagnosis of malignant mesothelioma, which failed to detect pleural involvement despite aggressive invasion by this tumor.
doi:10.3978/j.issn.2072-1439.2012.08.19
PMCID: PMC3547994  PMID: 23372960
Malignant peritoneal mesothelioma; thoracic metastasis; open lung biopsy; fluorodeoxyglucose (FDG) positron emission tomography (PET) computed tomography
19.  High-resolution CT findings of patients with pulmonary nocardiosis 
Journal of Thoracic Disease  2012;4(6):577-582.
Background
Opportunistic pulmonary infection with Nocardia species is rare in humans, and only a few studies have radiologically analyzed patients with pulmonary nocardiosis using high-resolution computed tomography (HRCT).
Methods
We retrospectively reviewed the medical records of patients with pulmonary nocardiosis at our hospital between April 2006 and December 2011 to assess HRCT and clinical findings. We also searched the medical literature for pulmonary nocardiosis reported in Japan between 2002 and 2011 for comparison.
Results
We identified seven patients at our institution and 33 reported infections in Japan. Four of our patients were immunocompetent, whereas the other three had impaired cellular immunity due to type 2 diabetes mellitus or having been inappropriately treated with steroid. Thoracic HRCT revealed no zonal predominance, but tropism for distribution from the middle to the peripheral area, and radiological findings of nodules, cavitation, mass, consolidations, bronchial wall thickening, septal line thickening and ground glass opacity (GGO) were evident. The main HRCT finding in our study comprised nodules (n=5, 71.4%) <30 mm and four patients had multiple nodules as described in other reports. Furthermore, we discovered a crazy paving appearance (CPA) around nodules, cavities, masses or consolidations in five patients (71.4%).
Conclusions
Multiple nodules distributed from the middle to the peripheral area on HRCT might reflect pulmonary nocardiosis, and CPA seemed to be a worth paying attention to the diagnosis.
doi:10.3978/j.issn.2072-1439.2012.11.07
PMCID: PMC3506788  PMID: 23205281
Crazy paving appearance; multiple nodules; lung infections; opportunistic pathogen; pulmonary nocardiosis
20.  Molecular Evolution of Hemagglutinin (H) Gene in Measles Virus Genotypes D3, D5, D9, and H1 
PLoS ONE  2012;7(11):e50660.
We studied the molecular evolution of H gene in four prevalent Asian genotypes (D3, D5, D9, and H1) of measles virus (MeV). We estimated the evolutionary time scale of the gene by the Bayesian Markov Chain Monte Carlo (MCMC) method. In addition, we predicted the changes in structure of H protein due to selective pressures. The phylogenetic tree showed that the first division of these genotypes occurred around 1931, and further division of each type in the 1960–1970s resulted in four genotypes. The rate of molecular evolution was relatively slow (5.57×10−4 substitutions per site per year). Only two positively selected sites (F476L and Q575K) were identified in H protein, although these substitutions might not have imparted significant changes to the structure of the protein or the epitopes for phylactic antibodies. The results suggested that the prevalent Asian MeV genotypes were generated over approximately 30–40 years and H protein was well conserved.
doi:10.1371/journal.pone.0050660
PMCID: PMC3510160  PMID: 23209804
21.  The saw-tooth sign as a clinical clue for intrathoracic central airway obstruction 
BMC Research Notes  2012;5:388.
Background
The saw-tooth sign was first described by Sanders et al in patients with obstructive sleep apnea syndrome as one cause of extrathoracic central airway obstruction. The mechanism of the saw-tooth sign has not been conclusively clarified. The sign has also been described in various extrathoracic central airway diseases, such as in burn victims with thermal injury to the upper airways, Parkinson’s disease, tracheobronchomalacia, laryngeal dyskinesia, and pedunculated tumors of the upper airway.
Case presentation
A 61-year-old man was referred to our hospital with a two-month history of persistent dry cough and dyspnea. He was diagnosed with lung cancer located in an intrathoracic central airway, which was accompanied by the saw-tooth sign on flow-volume loops. This peculiar sign repeatedly improved and deteriorated, in accordance with the waxing and waning of central airway stenosis by anti-cancer treatments.
Conclusion
This report suggests that the so-called saw-tooth sign may be found even in intrathoracic central airway obstruction due to lung cancer.
doi:10.1186/1756-0500-5-388
PMCID: PMC3434110  PMID: 22838841
Saw-tooth sign; Obstructive sleep apnea syndrome; Intrathoracic central airway obstruction; Lung cancer; Three-dimensional thoracic computed tomography; Flow volume curve
22.  Identification of a mechanism for lung inflammation caused by Mycoplasma pneumoniae using a novel mouse model 
Results in Immunology  2011;1(1):76-87.
Human Mycoplasma pneumoniae (MP) pneumonia is characterized by alveolar infiltration with neutrophils and lymphocytes and lymphocyte/plasma cell infiltrates in the peri-bronchovascular area (PBVA). No mouse model has been able to mimic the pathological features seen in human MP pneumonia, such as plasma cell-rich lymphocytic infiltration in PBVA. To figure out the mechanism for inflammation by MP infection using a novel mouse model that mimics human MP pneumonia, mice were pre-immunized intraperitoneally with Th2 stimulating adjuvant, alum, alone or MP extracts with an alum, followed by intratracheal challenge with MP extracts. The toll-like receptor-2, which is the major receptor for mycoplasma cell wall lipoproteins, was strongly up-regulated in alveolar macrophages in a latter group after the pre-immunization but prior to the intratracheal challenge. Those findings demonstrated that acceleration of innate immunity by antecedent antigenic stimulation can be an important positive-feedback mechanism in lung inflammation during MP pneumonia.
doi:10.1016/j.rinim.2011.11.001
PMCID: PMC3850488  PMID: 24371556
MP, Mycoplasma pneumoniae; MP pneumonia, Mycoplasma pneumonia; AMs, alveolar macrophage; TLR, Toll-like receptor; IT, intratracheal challenge; BAL, bronchoalveolar lavage; PBVA, peri-bronchovascular area; PVA, perivascular area; PBA, peribronchiolare area; Mycoplasma pneumoniae pneumonia; Alveolar macrophage; Mice model; Toll-like receptor-2; Plasma cell; Mycoplasma pneumonia extracts
23.  Inhaled Granulocyte/Macrophage–Colony Stimulating Factor as Therapy for Pulmonary Alveolar Proteinosis 
Rationale: Inhaled granulocyte/macrophage–colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.
Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP.
Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a PaO2 of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar–arterial oxygen difference [A–aDO2] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 μg Days 1–8, none Days 9–14; × six cycles; 12 wk); low-dose therapy (125 μg Days 1–4, none Days 5–14; × six cycles; 12 wk), and follow-up (52 wk).
Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A–aDO2 of 12.3 mm Hg (95% confidence interval, 8.4–16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A–aDO2 and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year.
Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP.
Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).
doi:10.1164/rccm.200906-0978OC
PMCID: PMC2894410  PMID: 20167854

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