A "Catlike Cry" as a Symptom of Congenital Tracheoesophageal Fistula.

Congenital tracheoesophageal fistula is usually diagnosed at an early age, but may remain undetected into adulthood if atresia is absent and if the fistula is small. A tracheoesophageal fistula should be suspected in patients with unexplained episodes of respiratory distress or pneumonia; however, more subtle signs can be an important symptom for early recognition of the disease. Ono's sign is a well-known symptom of tracheoesophageal fistula, characterized by paroxysmal coughing triggered by swallowing of fluids. In the present case, air movement between the esophagus and the trachea through the fistula caused a high-pitched sound, which the patient described as a "catlike cry." The high-pitched sound ceased after surgical closure of the fistula. We report here the symptom of "catlike cry" as one manifestation of tracheoesophageal fistula.

Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages.

Alveolar macrophages play a crucial role in the pathogenesis of emphysema, for which there is currently no effective treatment. Bisphosphonates are widely used to treat osteoclast-mediated bone diseases. Here we show that delivery of the nitrogen-containing bisphosphonate alendronate via aerosol inhalation ameliorates elastase-induced emphysema in mice. Inhaled, but not orally ingested, alendronate inhibits airspace enlargement after elastase instillation, and induces apoptosis of macrophages in bronchoalveolar fluid via caspase-3- and mevalonate-dependent pathways. Cytometric analysis indicates that the F4/80(+)CD11b(high)CD11c(mild) population characterizing inflammatory macrophages, and the F4/80(+)CD11b(mild)CD11c(high) population defining resident alveolar macrophages take up substantial amounts of the bisphosphonate imaging agent OsteoSense680 after aerosol inhalation. We further show that alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-κB signalling. Given that the alendronate inhalation effectively induces apoptosis in both recruited and resident alveolar macrophages, we suggest this strategy may have therapeutic potential for the treatment of emphysema.

Conophylline suppresses hepatic stellate cells and attenuates thioacetamide-induced liver fibrosis in rats.

BACKGROUND & AIMS: Conophylline (CnP) is a vinca alkaloid purified from a tropical plant and inhibits activation of pancreatic stellate cells. We investigated the effect of CnP on hepatic stellate cells (HSC) in vitro. We also examined whether CnP attenuates hepatic fibrosis in vivo. METHOD: We examined the effect of CnP on the expression of α-smooth muscle actin (α-SMA) and collagen-1, DNA synthesis and apoptosis in rat HSC and Lx-2 cells. We also examined the effect of CnP on hepatic fibrosis induced by thioacetamide (TAA). RESULTS: In rat HSC and Lx-2 cells, CnP reduced the expression of α-SMA and collagen-1. CnP inhibited DNA synthesis induced by serum. CnP also promoted activation of caspase-3 and induced apoptosis as assessed by DNA ladder formation and TUNEL assay. In contrast, CnP did not induce apoptosis in AML12 cells. We then examined the effect of CnP on TAA-induced cirrhosis. In TAA-treated rats, the surface of the liver was irregular and multiple nodules were observed. Histologically, formation of pseudolobules surrounded by massive fibrous tissues was observed. When CnP was administered together with TAA, the surface of the liver was smooth and liver fibrosis was markedly inhibited. Collagen content was significantly reduced in CnP-treated liver. CONCLUSION: Conophylline suppresses HSC and induces apoptosis in vitro. CnP also attenuates formation of the liver fibrosis induced by TAA in vivo.

Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3 pathway.

Notch is an ancient cell-signaling system that regulates the specification of cell fate. This study examined the role of Notch in the epithelial-mesenchymal transition (EMT) and myofibroblast differentiation of cultured RLE-6TN cells (i.e., rat alveolar epithelial cells). The activation of Notch, either by ectopic expression of the Notch intracellular domain or by the co-culture of RLE-6TN cells with L-Jagged1 cells, induces the expression of smooth muscle α-actin (SMA) and other mesenchymal marker genes (collagen I and vimentin), and reduces the expression of epithelial marker genes (E-cadherin, occludin, and zonula occludens-1). The pharmacologic inhibition of the endogenous Notch signal significantly inhibited the transforming growth factor-ß (TGF-ß)-induced expression of SMA. Cell migratory capacity was increased by Notch. Luciferase assays revealed that the CC(A/T)(6)GG (CArG) box and the TGF-ß control element (TCE) are required for Notch-induced SMA gene transcription. DNA microarray analysis revealed that members of the TGF-ß family as well as Jagged1 were induced in RLE-6TN cells by Notch. Western blot analysis showed that Notch induced the phosphorylation of Smad3, and the TGF-ß receptor type I/activin receptor-like kinase 5 (ALK5) kinase inhibitor SB431542 markedly reduced the Notch-induced expression of SMA. Enzyme-linked immunosorbent assays confirmed the production of TGF-ß1 from RLE-6TN cells by Notch. Immunohistochemistry of a bleomycin-induced model of pulmonary fibrosis and lung specimens from patients with idiopathic interstitial pneumonias showed that Notch was strongly expressed in myofibroblasts, identified as SMA-positive cells. These data indicate that Notch induces myofibroblast differentiation through a TGF-ß-Smad3 pathway that activates SMA gene transcription in a CArG-dependent and TCE-dependent manner in alveolar epithelial cells. Our data also imply that Notch induces the EMT phenotype, with increased migratory behavior in pulmonary fibrosis.

[Comparison between pandemic H1N1 2009 influenza pneumonia and seasonal influenza pneumonia in adults].

We compared 126 cases of seasonal influenza pneumonia (seasonal flu) reported between January, 1996 and March, 2009, with 10 cases of laboratory-confirmed pandemic influenza (H1N1) 2009 influenza virus pneumonia (novel flu), based on clinical condition, computed tomography (CT) findings, severity, treatment, and prognosis, to clarify the characteristics of this novel flu. The mean age of subjects was 52.4 years in the novel flu group and 64 years in the seasonal flu group, and novel flu patients were younger than seasonal flu patients. Seasonal flu patients had more underlying diseases than did novel flu patients. The median duration from illness onset to hospitalization was 4 days in both groups. Primary viral pneumonia was present in 70% of novel flu cases and 31% of seasonal flu cases. The proportion of primary virus pneumonia was higher in novel flu patients, and the disease severity of the seasonal flu group was more severe than that of the novel flu group. White blood cell and lymphocyte counts were lower in novel flu patients, and chest CT images showed bilateral shadows and pure ground-glass opacities more frequently in the novel flu cases. There were no differences in treatment, number of days required for the fever to subside, or mortality between the groups.

[Clinical study of pneumocystis pneumonia in patients with rheumatoid arthritis].

We reviewed case of pneumocystis pneumonia (PCP) with rheumatoid arthritis. We administered the antirheumatic drug methotrexate (MTX) at the time of to 13 patients, corticosteroids to 11 patients and a tumor necrosis factor (TNF) inhibitor to 3 patients. Treatment for PCP was started on admission in all cases. We administered adrenocorticosteroids to all 13 patients with a PaO2 level < 70 Torr. Three patients were under respiratory management, and 4 patients died. By univariate analysis, prognostic indicators of death were: presence of acute respiratory distress syndrome (ARDS), peripheral blood neutrophil/lymphocyte ratio, serum albumin value, serum beta-D-glucan value, and AaDO2 and PaO2/FiO2 ratios. Readministration of a TNF inhibitor in 2 patients and MTX in 3 patients was possible after PCP remission. Even though we began treatment for PCP on the day of admission, 25% of patients died. PCP may occur in patients who are given MTX or a TNF inhibitor or both, and the clinician should endeavor to detect its onset as early as possible. Elucidation of the prognostic indicators of recovery may require multivariate analysis of many cases.

[Severe complications and their outcomes in 65 patients with Legionella pneumonia].

The aim of the current study was to investigate the lethal complications of Legionella pneumonia. Severe complications and their outcomes in 65 patients with Legionella pneumonia were studied. All patients who eventually had a fatal outcome or who had severe complications received antimicrobial agents active against Legionella on the admission day. Many patients in the severe complication category had multiple severe complications. Six deaths occurred (mortality rate 9.2%), 4 of which were due to septic shock/multiple organ dysfunction syndrome (MODS) (2 patients) or interstitial pneumonia/pulmonary fibrosis after Legionella pneumonia (2 patients), whereas the other 2 deaths were due to causes unrelated to Legionella pneumonia. Mortality rates for each severe complication were as follows: acute respiratory distress syndrome 27.3% (3 of 11); renal failure 33.3% (2 of 6); disseminated intravascular coagulation 33.3% (2 of 6); severe sepsis 0% (0 of 1); septic shock/MODS 66.7% (2 of 3); interstitial pneumonia/pulmonary fibrosis 50% (2 of 4). Despite prompt diagnosis and appropriate treatment with antimicrobial agents active against Legionella, the lethal complications of Legionella pneumonia are septic shock/MODS and interstitial pneumonia/pulmonary fibrosis.

[Mucoid impaction of the bronchi caused by Schizophyllum commune which developed after discontinuation of itraconazole administration].

We report the case of a 75-year-old woman with mucoid impaction of the bronchi (MIB) due to Schizophyllum commune who improved with itraconazole (ITCZ) administration and relapsed after discontinuation of the drug. She improved again after readministration of ITCZ, and MIB has not recurred. This patient was not suffering from asthma and has been well without steroid administration. Reports of respiratory disorders due to S. commune have been increasing, and cases of allergic bronchopulmonary mycosis (ABPM), fungus ball, lung abscess, and pneumonia have been reported. Including this report, 12 cases of ABPM and MIB due to S. commune have been reported by Japanese authors. Treatment in these 12 cases included anti-fungal agent in 6, single steroid therapy in 3, combination therapy in 2, and bronchial toilet in 1 case. S. commune is not well recognized; however, one should suspect this fungus to be the causative pathogen when Aspergillus species are not detected or anti-Aspergillus antibody is negative.

Ehlers-Danlos syndrome with recurrent spontaneous pneumothoraces and cavitary lesion on chest X-ray as the initial complications.

A 17-year-old-man developed left-sided pneumothorax in 1995. Chest computed tomography (CT) showed a thick-walled cavity in the left lower lobe. Video-assisted thoracic surgery was performed, and pathologic findings of the resected lung showed a cavity, organizing hematoma, and a fibrous nodule. Fragility of connective tissue was suspected, and biochemical and molecular analysis showed reduction of type III collagen production and point mutation of the COL3A1 gene. The patient was diagnosed as having vascular-type Ehlers-Danlos syndrome (EDS). From 2002, the patient developed hemoptysis and bloody sputum once a year. Chest CT detected several nodules and cavities, which were regarded as hematomas with or without excretion. Several vascular changes including aneurysmal formations have been found since 2002, and an aneurysm of the left ulnar artery was resected. The patient continues to be followed regularly on an outpatient basis. We report a rare case of vascular-type EDS who developed pulmonary symptoms as an initial complication.

[Primary ciliary dyskinesia. A case report and comparison with 4 previous cases].

We encountered a 59-year-old man, whose chief complaints were sputum and dyspnea on effort. He had suffered from sinusitis since childhood, and chest computed tomography showed bronchiectasis. Electron microscopic examination of bronchial mucosa biopsied by bronchoscopy showed defect of the inner dynein arm in most of his cilia. We diagnosed primary ciliary dyskinesia. Seminal analysis showed no abnormalities, and the etiology of infertility remains unclear. The present case is the fifth case treated at our hospital. In this paper, we compared this case with 4 cases (2 cases of Kartagener's syndrome and 2 cases of primary ciliary dyskinesia without situs invertus) of our hospital, and findings of previous reports. Primary ciliary dyskinesia should be included in the differential diagnosis even in cases of mild bronchiectasis or normal mobility of sperm. Primary ciliary dyskinesia has more variety in radiological and clinical findings than has been recognized.

[Nemaline myopathy detected with respiratory failure and right ventricular heart failure].

We describe the case of a 40-year-old woman who was admitted for dyspnea and pitting edema of the lower extremities. Severe type II respiratory failure and right ventricular heart failure were present. Non-invasive positive pressure ventilation (NIPPV) improved the symptoms and blood gas values. Since the results of respiratory function tests and computed tomography indicated neuromuscular disease, muscle biopsy was performed and nemaline myopathy was diagnosed. NIPPV was necessary due to severe hypoxia and hypercapnia caused by severe hypoventilation during sleep; however, daytime NIPPV was stopped within a few days, and the patient was discharged with instructions to continue NIPPV at night only. Since discharge, she has been followed-up on an outpatient basis for 8 years. Adult-onset nemaline myopathy with respiratory failure and right ventricular heart failure as presenting features is rare, and NIPPV can be useful in such cases.

Pioglitazone, a peroxisome proliferator-activated receptor gamma ligand, suppresses bleomycin-induced acute lung injury and fibrosis.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands have been shown to possess potent anti-inflammatory actions. Idiopathic interstitial pneumonia is defined as a specific form of chronic fibrosing lung disease characterized by progressive fibrosis which leads to deterioration and destruction of the lungs. OBJECTIVE: To investigate whether the PPARgamma ligand pioglitazone (PGZ) inhibited bleomycin (BLM)-induced acute lung injury and subsequent fibrosis. METHODS: BLM was administered intratracheally to Wistar rats which were then treated with PGZ. Rat alveolar macrophages were stimulated with BLM for 6 h with or without PGZ pretreatment for 18 h. MRC-5 cells (human lung fibroblasts) were treated with PGZ for 18 h. After the treatment, the cells were stimulated with transforming growth factor- beta (TGF-beta) for 6 h. RESULTS: PGZ inhibited BLM-induced acute lung injury and subsequent lung fibrosis when it was administered from day -7. PGZ treatment suppressed the accumulation of inflammatory cells in lungs and the concentration of tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-alpha production in alveolar macrophages. Furthermore, PGZ inhibited fibrotic changes and an increase in hydroxyproline content in lungs after instillation of BLM, even when PGZ was administered in the period from day 7 to day 28. Northern blot analyses revealed that PGZ inhibited TGF-beta-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells. CONCLUSION: These results suggest that activation of PPARgamma ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-alpha, procollagen I and CTGF expression. Beneficial effects of this PPARgamma ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARgamma as a molecular target in fibroproliferative lung diseases.

[Clinical investigation of arrhythmia appearing after resection for lung cancer].

BACKGROUND: Arrhythmia, especially atrial fibrillation (AF) is a common complication during the early postoperative period of thoracic surgery. OBJECTIVE: To (1) characterize arrhythmia appearing after lung cancer resection, (2) evaluate risk factors for postoperative arrhythmia. RESULTS: We retrospectively studied 131 patients who underwent primary lung cancer resection in our hospital between January 2005 and December 2006. The average age at diagnosis was 68 +/- 9 yr. Arrythmia occurred in 16 patients (11.3%) (12 AF, 1 PSVT, 2 PAC, 1 sinus bradycardia). Arrhythmia occurred at postoperative day 2.3 +/- 1.7 (mean, range 0 to 6), and improved in all cases within 3 days of onset either by treatment with antiarrhythmic agents or spontaneously. CONCLUSION: AF was the most common arrhythmia (12/16 patients, 75%) among the complications associated with lung cancer resection. It was assumed that postoperative AF would be transient and improved by optimal management. Our data suggest that age (> or = 70-years-old) and operation time (> or = 300 min) were regarded as risk factors for postoperative arrhythmia.

[A case of sarcoidosis with hypoxia showing slight ground glass opacities on chest CT].

A 62-year-old man had had renal dysfunction and hepatosplenomegaly since 2000. In 2006, he complained of general fatigue and hemodialysis therapy was initiated because his renal function had deteriorated worse. In May 2007, he was admitted to our hospital because his general fatigue took a turn for the worse. He also had hypoxia. A chest radiograph showed no abnormal shadows. A chest computed tomography showed ground glass opacities in both lower lobes slightly. However, 67Ga-citrate scintigraph showed marked accumulation of 67Ga-citrate in the lungs, liver, spleen and kidneys. Transbronchial lung biopsy (TBLB) and bone marrow biopsy showed noncaseating epithelioid cell granulomas, and anti-PAB antibody positive cells were detected in epithelioid cell granulomas in the TBLB specimens. Therefore we diagnosed sarcoidosis. Although we could not perform renal or liver biopsy, we assumed that he had renal and liver sarcoidosis. After oral corticosteroid therapy, his symptoms and image findings improved. We report a rare case of sarcoidosis with hypoxia showing slight ground glass opacities

[Case of Wegener's granulomatosis associated with mediastinal lymphadenopathy].

A 54-year-old asymptomatic man was admitted to our hospital because his abnormal chest radiograph finding became worse. A chest radiograph and a chest computed tomography showed a mass in the right upper lobe and mediastinal lymphadenopathy. Thoracoscopic partial lung resection was performed. The specimens showed vasculitis and geographic basophilic necrosis palisading histiocytes and neutrophils. Wegener's granulomatosis was diagnosed. After resection, mediastinal lympahdenopathy was gradually improved in spite of no drug therapy. We report a rare case of Wegener's granulomatosis associated with lymphadenopathy.

[A case of anaphylactoid purpura associated with nephrosis followed by pulmonary tuberculosis].

A 54-year old man was admitted to our hospital because of high fever, productive cough and purpura in both legs in June 2005. Urinalysis showed microscopic hematuria and proteinuria. Chest radiograph showed consolidation of right upper field. Because acid-fast bacilli and polymerase chain reaction test for Mycobacterium tuberculosis were positive in bronchial lavage fluid, we made a diagnosis of pulmonary tuberculosis, and prescribed antituberculosis therapy with isoniazid, rifampicin, ethambutol and pyrazinamide. In addition, anaphylactoid purpura was diagnosed by skin biopsy. In July 2005, renal function was deteriorated and nephrosis appeared. We treated with corticosteroid in addition to antituberculosis therapy. His symptoms and renal dysfunction improved. We report a rare case of an anaphylactoid purpura following occurence of pulmonary tuberculosis.

[A case of small cell lung carcinoma complicated by Lambert-Eaton myasthenic syndrome].

A 54-year old man was admitted with general fatigue, muscle weakness and dyspnea on effort. Medical examinations led to a diagnosis of small cell lung carcinoma (SCLC) with Lambert-Eaton myasthenic syndrome (LEMS). Marked improvement of SCLC and symptoms of LEMS were recognized twice during chemoradiotherapy. On his third admission, he showed muscle weakness, dysaethesia, and neurodysfunction of the bladder and rectum. We initially considered these symptoms to be due to spinal metastasis because MRI findings showed multiple spinal metastases. However, electoromyogram and nerve conduction study demonstrated that his muscle weakness resulted from LEMS though dysethesia and neurodysfunction of bladder and rectum were caused by spinal metastasis. We believe that it is important to perform electomyogram and nerve conduction studies, not only radiographic findings, to detect the "hidden" symptoms of LEMS.

[Case of HLA-DR8 positive sarcoidosis following polymyositis and Sjögren's syndrome].

A 69-year-old woman had been found to have idiopathic interstitial pneumonia (fibrotic NSIP) in 1997. Proximal muscle weakness appeared in April 2005. Chest CT revealed hilar and mediastinal lymphadenopathy. Polymyositis and Sjögren's syndrome were subsequently diagnosed. We assumed that the interstitial pneumonia had preceded polymyositis and Sjögren's syndrome. A muscle biopsy and transbronchial needle aspiration biopsy demonstrated noncaseating epithelioid cell granulomas. A diagnosis of sarcoidosis complicated with polymyositis and Sjögren's syndrome was made from these findings. Moreover, her HLA genotype contained DR8. HLA-DR8 is considered to be associated with polymyositis, Sjögren's syndrome, and sarcoidosis in Japanese patients. This case suggests the possibility that there are common immunological and genetical pathogenetic mechanisms in autoimmune diseases and sarcoidosis.

[Case of allergic bronchopulmonary aspergillosis successfully treated with itraconazole].

A 58-year-old woman had a productive cough but not from bronchial asthma. A chest radiograph revealed infiltrative shadows in right middlelung field on September, 2004. Aspergillus fumigatus was detected in a sputum culture. She was treated with oral itraconazole. After the treatment, infiltrative shadows on her chest radiograph disappeared. On October 2005, her peripheral blood showed eosinophilla, a high serum level of total immunoglobulin E (IgE), and a chest radiograph revealed new infiltrative shadows in both lung fields. A chest computed tomography revealed multiple nodular shadows and central bronchiectasis. We detected a mucoid plug which showed a large number of eosinophils pathologically by bronchoscopy. Aspergillus niger was detected in a bronchial lavage fluid. We therefore made a diagnosis of allergic bronchopulmonary aspergillosis (ABPA). The decreases of peripheral blood eosinophils and a serum IgE level were recognized and multiple nodular shadows disappeared by reinstitution of itraconazole. However, a chest computed tomography revealed new infiltrative shadows. Therefore, we treated her with the concomitant administration of oral itraconazole and inhaled corticosteroid. All laboratory data and image findings were improved. It is critical to consider the both aspects of allergy and infection in the treatment for ABPA.