巽 浩一郎

Spontaneous regression of a pulmonary lesion in patients with Wegener's granulomatosis (WG) is rare, and only a few such reports have been published. We describe a rare case of a patient with WG in which the pulmonary lesion regressed spontaneously. The patient was a 76-year-old man presenting with fever, sputum and cough. On serial CTs, he had a solitary nodule in the right lung that regressed spontaneously while new multiple nodules developed during a 1-month interval. Biopsy of the new lesions by video-assisted thoracostomy (VATS) established a diagnosis of WG. Treatment with glucocorticoid and cyclophosphamide significantly ameliorated his condition. Concordant with similar previous reports, the mechanisms behind spontaneous regression of pulmonary lesions in the present case seemed to include spontaneous improvement of infection or infarction caused by vasculitis, in addition to regression of the WG lesion itself. Although it occurs rarely, physicians should be aware of the phenomenon that pulmonary lesions in WG could progress and regress spontaneously.

A 72-year-old man with tongue carcinoma complained of dyspnea on exertion 18 days after starting treatment with S-1. Chest radiograph and CT scan suggested diffuse interstitial lesions with ground glass opacity on both lungs. Bronchoalveolar lavage and transbronchial lung biopsy revealed moderate lymphocyte infiltration with granuloma. Drug lymphocyte stimulation test was positive against tegafur, one of the components of S-1. These findings were consistent with S-1-induced lung injury. Both his symptoms and the radiographic findings were resolved dramatically after high-dose corticosteroid therapy. Clinicians should be aware that S-1 has the potential to cause lung injury when it is included in chemotherapy.

To study the role of p38 mitogen-activated protein kinase (p38) activity during the process of metastasis, p38alpha(+/-) mice were subjected to an in vivo metastasis assay. The number of lung colonies of tumor cells intravenously injected in p38alpha(+/-) mice was markedly decreased compared with that in wild-type (WT) mice. On the other hand, the time-dependent increase in tumor volume after subcutaneous tumor cells transplantation was comparable between WT and p38alpha(+/-) mice. Platelets of p38alpha(+/-) mice were poorly bound to tumor cells in vitro and in vivo compared with those of WT mice. E- and P-selectin mRNAs were markedly induced in the lung after intravenous injection of tumor cells. However, the induction of these selectin mRNAs in p38alpha(+/-) mice was weaker than that in WT mice. Furthermore, the resting expression levels of E-selectin in lung endothelial cells and P-selectin in platelets of p38alpha(+/-) mice were suppressed compared with those of WT mice. The number of tumor cells attached on lung endothelial cells of p38alpha(+/-) mice was significantly reduced compared with that of WT mice. The transmigrating activity of tumor cells through lung endothelial cells of p38alpha(+/-) mice was similar to that of WT mice. These results suggest that p38alpha plays an important role in extravasation of tumor cells, possibly through regulating the formation of tumor-platelet aggregates and their interaction with the endothelium involved in a step of hematogenous metastasis.

BACKGROUND: Angiotensin-converting enzyme (ACE) plays an important role in vascular remodeling in pulmonary hypertension, and ACE gene polymorphism is associated with exercise-induced pulmonary hypertension in Japanese patients with chronic obstructive pulmonary disease. The present study was designed to investigate if ACE-insertion (I)/deletion (D) polymorphism might be related to the susceptibility, severity, and disease outcome in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: ACE-I/D genotypes were determined in 95 consecutive CTEPH patients (46 underwent surgery, 49 received medical treatment) and 97 controls. The frequencies of genotypes and alleles were not significantly different between patients and controls. Clinical characteristics were compared among ACE genotypes (II, ID, DD). ACE D allele carrier (ID plus DD) was associated with a lower 6-min walk test distance compared with D allele non-carrier (II) (330+/-102 (mean +/- SD) vs 381 +/-85 m, p=0.046). Kaplan-Meier analysis in the medically treated group showed significantly deteriorated survival for D allele carriers compared with D allele non-carriers (p=0.0389). Multivariate analysis revealed that age (p=0.013), pulmonary vascular resistance (p=0.008), and D allele carrier status (p=0.021) were independent predictors of survival. CONCLUSION: ACE D allele carrier is possibly one of the prognostic factors for medically treated CTEPH patients.

BACKGROUND: Irinotecan, when combined with cisplatin, is an effective treatment for advanced non-small cell lung cancer (NSCLC). This constitutes a rationale for conducting a phase I study of chemoradiotherapy including this combination for locally advanced NSCLC. PATIENTS AND METHODS: Patients with locally advanced NSCLC and a performance status of 0 or 1 were eligible. The protocol consisted of escalating doses of irinotecan on days 1 and 15, and daily low-dose cisplatin (6 mg/m(2) daily for a total dose of 120 mg/m(2)) combined with concurrent hyperfractionated accelerated thoracic irradiation (1.5 Gy twice daily for a total dose of 60 Gy). RESULTS: The maximum tolerable dose was 50 mg/m(2) of irinotecan, and the dose-limiting toxicity was esophagitis. Tumor response was observed in 50% of cases, and the median survival time of the 12 patients enrolled was 10.1 months, including two patients with 5-year disease-free survival. A pharmacokinetics study demonstrated an accumulation of total platinum, but not of free platinum, during the 26-day treatment period. CONCLUSION: The recommended dose for phase II studies was determined.

Malignant tumors induce development of their own stromal tissues during the processes of growth, progression and metastasis. Since the vascular architecture among the various stromal elements is well known to facilitate tumor growth and has been a target of therapy, the importance of stromal fibroblasts has recently been established. To elucidate the interaction between the tumor and its stromal fibroblasts, the present study took advantage of a unique experimental model consisting of a human small-cell lung cancer cell line, WA-ht, and its mouse stromal fibroblast cell line, WA-mFib, both originally derived from a xenograft tumor in a mouse subcutis. Co-culture with the WA-mFib cells significantly augmented the plating efficiency of WA-hT cells in vitro, and their co-inoculation in nude mice shortened latency and tumor doubling time. Histochemical detection of beta-gal, transfected into WA-mFib cells, demonstrated their contribution to the nude mouse xenograft tumor formation as its tumor stroma. Elevated hepatocyte growth factor (HGF) from fibroblasts followed by elevated production of vascular endothelial growth factor (VEGF) from both tumor cells and fibroblasts were demonstrated by ELISA in supernatants of their co-culture, accompanied by enhanced colonogenicity of the tumor cells; these enhanced features were not observed in their respective monocultures. Antisense oligonucleotides to HGF cancelled these augmentation effects with co-culture. The findings highlight the substantial roles of tumor stromal fibroblasts, interacting with soluble growth factors, in promoting the malignant propensity of the tumor.

Hepatic steatosis occasionally progresses to nonalcoholic steatohepatitis. This study was designed to examine whether non-obese patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) were prone to develop hepatic steatosis and whether repeated hypoxemia contributed to the progression of steatohepatitis. This study included 83 OSAHS patients and 41 age-, body mass index (BMI)- and gender-matched non-OSAHS patients diagnosed by polysomnography. Hepatic steatosis was defined by a liver/spleen ratio <0.9 on abdominal computerized tomography, and latent steatohepatitis was evaluated based on serum levels of type III procollagen (P-III-P). Visceral fat (V-fat) accumulated much more in OSAHS patients. Liver/spleen ratios in OSAHS patients correlated negatively with BMI and, especially, with the amount of visceral fat. Serum levels of P-III-P in OSAHS patients correlated negatively with the average of oxygen saturation during sleep, and positively with BMI, the apnea-hypopnea index (AHI) and the amount of V-fat. Multiple regression analysis showed that average SaO(2) was the only explanatory variable for P-III-P values, but AHI, BMI and V-fat was not. These observations confirmed that non-obese patients with OSAHS are at a risk for visceral obesity, and suggested that oxygen desaturation during sleep is a risk for developing latent steatohepatitis, especially in patients with substantial hepatic steatosis.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by repeated oxygen desaturation. Obesity and visceral fat accumulation (VFA) are risk factors for the development of OSAHS. Circulating leptin increases in accordance with body mass index (BMI), and under experimental conditions intermittent hypoxia stimulates leptin production. METHODS: The primary objective of this study was to investigate whether hypoxemia during sleep influences the levels of circulating leptin and whether the location of body fat deposits, ie, the distribution of VFA and subcutaneous fat accumulation (SFA), affects circulating leptin levels in patients with OSAHA who are not obese. We assessed VFA and SFA by abdominal CT scan and measured circulating levels of leptin in 96 male patients with OSAHS and 52 male patients without OSAHS matched for BMI. To be matched for BMI in the two groups, patients whose BMIs were < 27 were selected for the OSAHS group. RESULTS: In the whole study group, circulating leptin levels correlated with BMI (r = 0.30), VFA (r = 0.44), SFA (r = 0.28), apnea-hypopnea index (AHI) [r = 0.48], sleep mean arterial oxygen saturation (Sao(2)) [r = 0.59], and sleep lowest Sao(2) (r = 0.37). Multiple regression analysis showed that average Sao(2) (p < 0.01) and lowest Sao(2) (p = 0.03) were explanatory variables for serum leptin values, but AHI (p = 0.054), BMI (p = 0.33), VFA (p = 0.11), and SFA (p = 0.36) were not. CONCLUSIONS: These results suggest that sleep hypoxemia may be the main determinant of circulating leptin levels, although the location of body fat deposits could contribute to the elevated circulating leptin levels in patients with OSAHS who are not obese.

OBJECTIVE: An alteration of high energy phosphate metabolism in muscles may contribute to exercise intolerance. The objective of this study was to clarify the changes in high energy phosphate metabolites in muscles during exercise in patients with non-hypoxaemic chronic obstructive pulmonary disease (COPD), which influences the impairment of muscle metabolism. METHODOLOGY: Calf muscle energy metabolism was studied in eight stable non-hypoxaemic COPD patients and eight control subjects, using 31P-magnetic resonance spectroscopy (MRS). MRS spectra were acquired at rest, during exercise at two levels of intensity, and during recovery. The control subjects exercised under both normoxic and hypoxic conditions. The intensity of exercise was standardized by the maximal isometric voluntary contraction (MVC) of the calf muscle and the cross-sectional area (CSA) of calf muscle. RESULTS: MVC and CSA were lower in COPD patients. No significant differences in intracellular pH, inorganic phosphate/phosphocreatine ratio or percentage recovery in inorganic phosphate/phosphocreatine ratio were observed between the two groups in muscles at rest, during exercise or during recovery. CONCLUSIONS: Muscle metabolites, during exercise standardized by muscle CSA and MVC, did not differ between non-hypoxaemic COPD patients and control subjects. MVC, CSA or both, are assumed to be closely related to muscle metabolism, as no difference in high energy phosphate metabolites was observed for COPD patients compared to control subjects when the load was standardized for MVC and CSA. This suggests that high energy metabolites are consumed to a similar extent in the same muscle volume in non-hypoxaemic COPD patients and control subjects.

BACKGROUND: Obesity and visceral fat accumulation (VFA) are risk factors for the development of obstructive sleep apnea-hypopnea syndrome (OSAHS), and a subgroup of OSAHS patients acquire hypoventilation. Circulating leptin, an adipocyte-derived signaling factor, increases in accordance with body mass index (BMI); under experimental conditions, leptin selectively decreases visceral adiposity and it is also a respiratory stimulant. OBJECTIVE: To investigate whether the location of body fat deposits, ie, the distribution of VFA and subcutaneous fat accumulation (SFA), contributes to hypoventilation and whether circulating levels of leptin are involved in the pathogenesis of hypoventilation, which is often observed in OSAHS. METHODS: We assessed VFA and SFA by abdominal CT scan, and measured lung function and circulating levels of leptin in 106 eucapnic and 79 hypercapnic male patients with OSAHS. RESULTS: In the whole study group, circulating leptin levels correlated with BMI (r = 0.56), VFA (r = 0.24), and SFA (r = 0.47), but not with Po(2) or sleep mean arterial oxygen saturation (Sao(2)). BMI, percentage of predicted vital capacity, FEV(1)/FVC ratio, apnea-hypopnea index, sleep mean Sao(2), VFA, and SFA were not significantly different between two groups. Circulating leptin levels were higher in the hypercapnic group than in the eucapnic group. Logistic regression analysis indicated that serum leptin was the only predictor for the presence of hypercapnia (beta = 0.21, p < 0.01). CONCLUSIONS: These results suggest that the location of body fat deposits may not contribute to the pathogenesis of hypoventilation, and circulating leptin may fail to maintain alveolar ventilation in hypercapnic patients with OSAHS.

We report a case of lymphangioleiomyomatosis (LAM) with a giant bulla. A 33-year-old woman was referred to our department for treatment of dyspnea. Chest computed tomography showed a giant bulla with many smaller bullae. To obtain a definitive diagnosis and relieve the dyspnea, we performed a lung biopsy and bullectomy, after which her symptoms and pulmonary function improved remarkably. She was commenced on progesterone, which improved her condition even further. This case report retrospectively follows the progression of her disease from the onset of symptoms 5 years before she was referred to us for treatment.

Expression of Fas ligand (FasL) in tumors produced antitumor effects by generating both inflammation and T cell-mediated immunity, although the Fas/FasL interaction induces an apoptotic process of Fas-positive activated T cells. Our previous study, however, showed that immunization of mice with ultraviolet (UV)-treated FasL-expressing tumors rather induced immune suppression to the tumors, whereas mice rejected UV-untreated FasL-expressing tumors and developed protective immunity subsequently. Since dendritic cells (DCs) control tumor-specific immune responses in vivo, we examined a possible role of DCs in the immune suppression induced. Administration of DCs that were cocultured with UV-treated FasL-expressing tumors did not influence the growth of parent tumors that were subsequently inoculated. Migration of immunocompetent cells into UV-treated FasL-expressing tumors was not significantly different from that into UV-untreated FasL-expressing tumors. However, production of immunosuppressive but not T helper type 1 cytokines was enhanced when UV-treated FasL-expressing tumors were administered. These data collectively suggest that the immune suppression induced by UV-treated FasL-expressing tumors was not attributable to tolerance of DCs, but due to cytokine-induced suppression of cell-mediated immunity.

The aetiology of chronic thromboembolic pulmonary hypertension (CTEPH) is largely unknown and may be heterogeneous, because there are several ethnic differences in the clinical characteristics of CTEPH. Female predominance and a higher ratio of chronic to acute pulmonary thromboembolism have been reported in Japan as compared with the USA. Because such ethnic differences may be controlled by genetic factors, the current study investigated HLA polymorphisms in Japanese patients with CTEPH. HLA typing by serological and/or DNA typing methods was performed (for HLA-A, B, DPB1, DRB1) in 80 patients and 678 controls, and the association of clinical characteristics with HLA alleles was studied. The frequencies of HLA-B*5201 (40 versus 24%) and DPB1*0202 (19 versus 6%) were significantly higher in the patients. HLA-B*5201 positive patients showed a significant female predominance. Total pulmonary vascular resistance and mixed venous oxygen tension were better in the HLA-B*5201 positive patients. In contrast, cardiac index and gas exchange parameters were worse in the HLA-DPB1*0202 positive patients. In the patients carrying HLA-B*5201 and/or -DPB1*0202, the frequency of deep vein thrombosis was significantly lower than the other patients. These observations suggested that both the susceptibility and clinical characteristics of chronic thromboembolic pulmonary hypertension were controlled in part by the HLA-B and -DPB1 loci. Copyright©ERS Journals Ltd 2005.

加齢は,脳の老化・上気道支持筋力の低下などにより,睡眠呼吸障害の発症因子になる.一方,肥満も睡眠呼吸障害に影響しうる.閉塞型睡眠時無呼吸低呼吸症候群老年者では肥満の程度は軽度であり,睡眠呼吸障害の程度も軽度であった.同症候群老年者における内臓脂肪蓄積は,睡眠呼吸障害の程度とは別に心血管系イベントと関係しうる可能性があり,老年者では無呼吸の程度による重症度判定では病態を評価しえない部分がある.

CD40-positive dendritic cells (DCs) are stimulated with CD40 ligand (CD40L) and subsequently secrete a number of cytokines including interleukin (IL)-23, which is involved in cell-mediated immune responses. Expression of CD40 ligand (CD40L) on tumors can activate host immune systems and produce antitumor effects against the tumors. We examined a possible mechanism of the antitumor responses: tumor cells expressing CD40 can transcribe DCs-derived cytokine genes by the expressed CD40L. For the purpose, CD40-positive All and -negative P29 murine lung tumors cells, both of the same origin, were transfected with the CD40L gene (A11/CD40L and P29/CD40L). The growth rate in vitro of A11/CD40L and P29/CD40L cells was not different from that of the respective parent tumors however, the growth in vivo of A11/CD40L tumors in syngeneic mice was significantly retarded and the growth retardation of P29/CD40L tumors was marginal. Transcription of the p40 and p19 genes, IL-25 subunit genes, was up-regulated in A11/CD40L cells compared with parent All cells, whereas this up-regulation was not observed in P29/CD40L cells. Since expression of IL-23 in tumors can produce antitumor effects, the present data suggest that the CD40/CD40L interaction can activate cytokine transcripts in certain tumors and consequently contribute to antitumor responses.

Although many cases of sarcoidosis are self-limiting with spontaneous remission, uncontrolled pulmonary granulomatosis with fibrosis produces intolerable long-term respiratory symptoms in a minority of patients. Individuals with chronic pulmonary sarcoidosis require an alternative therapy to corticosteroidal treatment because of its insufficient effectiveness. Although many researchers have considered infection as the triggering factor for this disease, the mechanisms by which the candidate causative organisms induce this disorder remain unclear. We report here that extrapulmonary sensitization to Propionibacterium acnes, which is one of the candidates to date, induced pulmonary Th-1 granulomas mainly in the subpleural and peribronchovascular regions often observed in sarcoidosis. These granulomas appear to be caused by indigenous P. acnes pre-existing in the lower respiratory tract of the normal lung, which is believed to be germ-free, and by an influx of P. acnes-sensitized CD4(+) T cells from the circulation. Importantly, the eradication of indigenous P. acnes with antibiotics alleviated the granulomatous lung disease. This is the first report to present clear evidence of the contribution of an indigenous pulmonary bacterium to the formation of granulomatous lesions in the lung. We propose that treatment targeting indigenous P. acnes in the lung may be a possible remedy for pulmonary sarcoidosis.

OBJECTIVE: The Global Initiative for Obstructive Lung Disease characterizes COPD as airflow limitation caused by parenchymal destruction and/or small airway disease. This report characterizes the clinical features of these two phenotypes of COPD in Japan. METHODOLOGY: COPD was diagnosed by spirometric airflow limitation (FEV(1)/FVC < 70%), and all subjects underwent chest CT scanning. Patients with diffuse low attenuation areas (LAA) on CT scan were categorized as the emphysema-dominant phenotype; those with little LAA were categorized as the airway disease-dominant phenotype. The two groups were compared to identify significant clinical or demographic differences. RESULTS: Of the 1438 patients analysed, 1294 (90%) were classified as having an emphysema-dominant phenotype and 144 (10%) as having an airway disease-dominant phenotype. The airway disease-dominant phenotype was: more common than the emphysema-dominant phenotype in women (15%vs. 7%, P < 0.01) and in non-smokers (6%vs. 2%, P < 0.05); was more commonly complicated by asthmatic features (35%vs. 21%, P < 0.01); and had higher IgE and eosinophil levels (P < 0.05) and less lung function impairment. CONCLUSION: This analysis is the first to clinically define two phenotypes of COPD in a Japanese epidemiological survey. There appear to be striking differences as well as overlap between these two groups. Further research is warranted to determine the significance of COPD phenotypes.

The clinical presentation of respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and desquamative interstitial pneumonitis (DIP) seems to be nonspecific, although well-defined pathologic features have been described. Therefore, the clinical pictures, laboratory, radiologic and bronchoalveolar lavage fluid (BALF) findings, and prognosis of 5 patients with RB-ILD were compared with those of 7 patients with DIP. Cell differentiation in BALF could be helpful to distinguish RB-ILD and DIP. Eosinophils were observed only in DIP. The proportion of macrophages was greater in RB-ILD, whereas that of neutrophils was greater in DIP. In RB-ILD, high-resolution computed tomography (HRCT) revealed diffuse centrilobular, nodular or patchy, ground-glass opacities and peripherally distributed, irregular linear opacities. In DIP, HRCT revealed diffuse, bilateral panlobular ground-glass opacities. Clinical symptoms, abnormal radiologic and laboratory findings improved in 6 months after quitting smoking in all patients with RB-ILD. On the other hand, all patients with DIP required systemic steroid therapy, and steroid therapy was difficult to withdraw in 2 years. RB-ILD could be distinguished from DIP, which is also recognized to be a smoking-related interstitial lung disease in terms of its good prognosis, although small numbers of patients in this study limit drawing a definite conclusion, and further studies are required to determine the long-term prognosis.

Irinotecan is an active cytotoxic agent for various cancers, and is converted to SN-38, its most active metabolite, by carboxylesterase converting enzyme (CCE) in vivo. Although the primary metabolic site is in the liver, ex vivo studies have proven that irinotecan is also converted to SN-38 in intestines, plasma and tumor tissues. The present study attempted to elucidate the in vitro conversion efficiency in human plasma, and to examine possible inter-individual variability and its clinical significance. Plasma samples were taken from 57 patients with lung cancer, 3 patients with benign pulmonary diseases and 9 healthy volunteers. After addition of 157 mM irinotecan to plasma, time courses of SN-38 concentration, measured by high-performance liquid chromatography (HPLC), were investigated. All subjects showed linear increase in SN-38 concentration during the first 60-min period, followed by a plateau. Mean and standard deviation of the conversion rate in the first 60 min were 515.9 +/- 50.1 pmol/ml/h (n = 69), with a coefficient of variation of 0.097. Although most of the subjects showed comparable conversion rates, 3 subjects had significantly higher conversion rates. In conclusion, the results of this study suggest that the enzyme activity of CCE in human plasma may show inter-individual variability.

We used a PCR and sequence procedure to analyze the Ig V(H) gene and the mutations in the 5' regulatory regions of BCL-6 genes in pulmonary lymphoproliferative disorders (mucosa-associated lymphoid tissue (MALT) lymphoma, HIV-related, EBV-related, and virus-negative lymphocytic interstitial pneumonia (LIP)). Eight of 20 (40%) pulmonary MALT lymphoma and 10 of 20 LIP (5 of 5 (100%) HIV-related, 2 of 5 (40%) EBV-related, and 3 of 10 (30%) virus-negative LIP) cases showed BCL-6 gene mutations. Intraclonal heterogeneity of the BCL-6 mutations was observed only in pulmonary MALT lymphoma cases whose Ig V(H) genes also showed intraclonal heterogeneity. Ongoing BCL-6 mutations might reflect re-entry into a germinal center pathway to further mutations. BCL-6 mutations in pulmonary MALT lymphoma and HIV-negative LIP showed some features (high transition to transversion ratio, standard polarity, and RGYW/WRCY bias) of Ig V(H) gene hypermutation, leading to the view that pulmonary MALT lymphomas and HIV-negative LIP are under the influence of germinal center hypermutation mechanisms. Because BCL-6 mutations in HIV-related LIP cases did not demonstrate features of Ig V(H) gene hypermutation, immunological reactions in HIV-related LIP are the result of a process different from that found in HIV-negative pulmonary lymphoproliferative disorders.

OBJECTIVE: Decreased expression of prostacyclin synthase (PGIS) is observed in the lung vasculature of patients with pulmonary arterial hypertension and the biosynthesis of prostacyclin (PGI2) may be impaired in chronic thromboembolic pulmonary hypertension (CTEPH). Whether it is genetically determined or develops as the disease progresses is unclear. A variable-number tandem repeat (VNTR) polymorphism has been detected in the 5'-upstream promoter region of the PGIS gene. It has been demonstrated that the alleles vary in size from three to seven repeats of nine base pairs, and transcriptional activity increased with the number of repeats. The purpose of the present study was to elucidate the association between the VNTR polymorphisms of the PGIS gene and CTEPH in Japanese subjects. METHODOLOGY: Ninety patients with CTEPH and 144 control subjects were investigated for the presence of VNTR polymorphisms. Sixty-two blood samples were obtained from CTEPH patients and the plasma concentrations of prostacyclin and thromboxane A2 metabolites were measured. RESULTS: VNTR polymorphisms in the prostacyclin synthase gene were grouped into L alleles (five, six and seven repeats) and S alleles (three and four repeats). The overall distribution of the alleles and genotypes were not significantly different between CTEPH patients and the control subjects. The patients with the LL genotype had higher plasma concentrations of 6-keto-prostaglandin F1alpha than patients with the LS and SS genotypes. CONCLUSIONS: Our results suggested that the specific VNTR polymorphism in the 5'-upstream promoter region of the PGIS gene regulated prostacyclin production, but did not seem to be associated with the development of CTEPH in this patient population.

Gliotoxin, one of the mycotoxins produced by Aspergillus fumigatus, has various, potent bioactivities. However, it has not been considered to be a toxic (or virulence) factor because of its slow production. The aim of the present study was to investigate the effects of aeration on the cytotoxicity of A. fumigatus culture filtrate, and to determine the optimal condition for the rapid production of gliotoxin from this fungus. Fungal culture filtrates were made in three different containers under various conditions of aeration and O2 concentration. These filtrates were compared in terms of their cytotoxicity on murine macrophages and analyzed by gas chromatography. The culture filtrate showed high cytotoxicity when it was made under highly aerated conditions, but it was significantly less cytotoxic when prepared under non-aerated conditions. The cytotoxic activity became evident within 15 h of culture at 20% O2, when the fungus had already started producing gliotoxin. The culture filtrates also contained some other as yet unidentified substances that might also to some extent contribute to the cytotoxicity. In light of these results, the authors propose that a highly aerated condition is responsible for the rapid production of gliotoxin, and that gliotoxin might play an important role in the respiratory infection by A. fumigatus, with other toxic substances acting additively or synergistically.

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease characterized by hamartomatous proliferation of abnormal smooth muscle cells in the lungs. Recently, severe LAM has been listed as an indicated disease for lung transplantation. A 34-yr-old woman with severe pulmonary cystic changes in a chest CT scan was diagnosed as having an isolated form of pulmonary LAM without genetic disorders. Despite intensive progesterone treatment, her pulmonary functions deteriorated rapidly. In January 2001, a left single-lung transplantation was performed from a cadaveric donor. The total operating time was 8 hours and 47 minutes. Total ischemic time was 5 hours and 59 minutes, which was within the permitted time limit. Except for right pneumothorax, the postoperative course was fairly good without any sign of rejection or infection in the allograft. For about two months after transplantation, bronchostenosis occurred in the left lower lobe bronchus, and necessitated a stent placement. During the following three months, stenosis of the bronchi in the anastomotic and peripheral sites occurred repeatedly, which also necessitated stent placement or balloon dilations on each occasion. Despite all the intensive treatment, the bronchostenosis of the peripheral sites still remains and improvement of her pulmonary functions has been poor. Moreover, a recent chest CT scan revealed a progression of the disease in the native lung. Consequently, we registered her as a candidate for transplantation of the right lung. Bronchostenosis should be kept in mind as a complication of lung transplantation.

Background. In multiple system atrophy (MSA) patients, a variety of sleep-related respiratory disturbances, including sleep apnea-hypopnea, are frequently manifested. Both nasal continuous positive airway pressure (CPAP) therapy and tracheostomy have been shown to be effective to treat sleep-related breathing disorders in patients with MSA. Case. A 62-year-old man with MSA accompanied by sleep apnea-hypopnea syndrome and marked obesity was admitted because of gradual worsening daytime sleepiness, fatigue and snoring. Arterial blood gas analysis showed hypoxemia and hypercapnia. Laryngoscopy revealed vocal cord abductor paralysis. He was first treated by CPAP therapy. Next, tracheostomy was performed to avoid sudden death due to vocal cord abductor paralysis. Conclusion. CPAP therapy and subsequent tracheostomy gradually improved daytime hypoxia and hypercapnia as well as sleep desaturation, suggesting that oxygen desaturation due to sleep disordered breathing and obesity may partly contribute to the pathogenesis of alveolar hypoventilation in the present case.

<p>慢性閉塞性肺疾患（COPD）は一つの疾患単位というよりは異質な病態の集合体であるため，治療は一様には行えない．特に，喘息病態合併の有無は治療反応性に影響しうる．COPDに喘息病態の合併があるときには，吸入ステロイド薬の使用を積極的に施行すべきである．COPDおよび気管支喘息の病態・治療は，慢性安定期と急性増悪時において異なる．病名治療でなく，病態および薬剤の特性を理解して，治療にあたる必要がある．</p>

Gliotoxin, one of the mycotoxins produced by Aspergillus fumigatus, has various, potent bioactivities. However, it has not been considered to be a toxic (or virulence) factor because of its slow production. The aim of the present study was to investigate the effects of aeration on the cytotoxicity of A. fumigatus culture filtrate, and to determine the optimal condition for the rapid production of gliotoxin from this fungus. Fungal culture filtrates were made in three different containers under various conditions of aeration and O2 concentration. These filtrates were compared in terms of their cytotoxicity on murine macrophages and analyzed by gas chromatography. The culture filtrate showed high cytotoxicity when it was made under highly aerated conditions, but it was significantly less cytotoxic when prepared under non-aerated conditions. The cytotoxic activity became evident within 15 h of culture at 20% O2, when the fungus had already started producing gliotoxin. The culture filtrates also contained some other as yet unidentified substances that might also to some extent contribute to the cytotoxicity. In light of these results, the authors propose that a highly aerated condition is responsible for the rapid production of gliotoxin, and that gliotoxin might play an important role in the respiratory infection by A. fumigatus, with other toxic substances acting additively or synergistically.

Substantial variation among countries has been reported regarding mortality data for COPD in industrialized countries. Differences in COPD death rates among countries have attracted considerable attention, with multiple suggested hypothesis, including smoking behaviors, air pollution, respiratory infections and genetic factors. However, the lack of standardization of death certification as well as differences among countries in diagnostic standards of COPD, could limit the interpretation of the data. No meaningful international comparisons of COPD prevalence can be possible until a GOLD initiative bring information about COPD to public health officials, the medical community, and the public throughout the world. No comparable data regarding the COPD epidemiology such as Nippon COPD Epidemiology(NICE) study, has been available in other countries than Japan. NICE study indicated that most of COPD cases(90%) are undiagnosed, and a significant attention will be required to raise awareness of COPD.

STUDY OBJECTIVES: Orexin and orexin receptors are present in the CNS. The effects of orexin peptides have been uniformly reported as excitatory, and the posterior hypothalamus containing orexin neurons has been implicated in arousal state control. Therefore, it is probable that the orexin system may have a neuromodulatory effect on arousal states. The aim of the present study was to investigate the relationship between plasma orexin-A levels and arousals from sleep in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). DESIGN: An analysis was conducted in 30 male patients with OSAHS, which had been diagnosed by polysomnography by the presence of an apnea-hypopnea index (AHI) of > 5, and 20 male age-matched and body mass index (BMI)-matched control subjects. RESULTS: Plasma orexin-A levels were higher in patients with OSAHS compared with those in control subjects (p < 0.05). Plasma orexin-A levels correlated positively, but weakly, with the arousal index (r = 0.51; p < 0.05) and the AHI (r = 0.52; p < 0.05). However, plasma orexin-A levels did not relate to age, BMI, Epworth sleepiness scale, PaO(2), PaCO(2), minimum arterial oxygen saturation (SaO(2)) during sleep, or mean SaO(2) during sleep. Plasma orexin-A levels can be a measure of both AHI and arousal index. CONCLUSION: These results suggested that the orexin system may be involved in arousal mechanisms in patients with OSAHS.

COPDの主なリスクファクターは,喫煙である.しかし喫煙者の一部にのみCOPDは発症し,遺伝的因子および環境因子の双方がその発症に関与している多因子疾患と考えられる. COPDの疾患感受性候補遺伝子は数多く挙げられているが,しばしば異なる結果が報告されており,その解釈は慎重におこなう必要がある.オランダ仮説,アデノウイルスの潜伏感染,アポトーシスなどもCOPDの発症に関与している可能性もある.

STUDY OBJECTIVES: Vascular endothelial growth factor (VEGF) signaling may be required for maintenance of the alveolar structures, and alveolar septal cell apoptosis could contribute to the pathogenesis of COPD presenting emphysematous changes; however, the common mutation at position 936 in the 3' untranslated region of the VEGF gene, a C to T substitution (the C allele was denoted as 1, and the T allele as 2), VEGF936*2, has been reported to be associated with significantly lower VEGF plasma levels. Based on these concepts, we hypothesized that VEGF936*1/2 polymorphism may be linked to the development of COPD. DESIGN: The differences in VEGF936*1/2 allele frequency were examined in 113 patients with smoking-related COPD and two control groups (101 smoker/ex-smoker control subjects and 102 population control subjects) using the polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: VEGF936*1/2 allele frequencies did not differ among the groups: 0.792/0.208 in COPD patients, 0.822/0.178 in smoker/ex-smoker control subjects, and 0.842/0.152 in population control subjects. CONCLUSION: The 936 C/T polymorphism of the VEGF gene (including both homozygous and heterozygous) was not associated with the development of COPD (odds ratio, 1.23; 95% confidence interval, 0.760 to 1.995).

An experimental model, in which exogenous gene expression in the lung is achieved, has been established. A fibroblast cell line was transfected with the lacZ gene and was administered to syngeneic mice by either intravenous or intratracheal injection. Enzyme-linked immunosorbent assay and histochemical detection of beta-galactosidase revealed efficient gene delivery to the lung by either route. Kinetic studies demonstrated that the expression peaked immediately after the injection, and this high level was maintained for 7 days by intratracheal and for 14 days by intravenous administration. This system may have potential relevance for certain experimental models requiring specific gene delivery to the lung.

OBJECTIVE: The onset of sarcoidosis may be triggered by any hereditary and/or environmental factor. Among these factors, psychosocial stress may play a critical role in the onset of sarcoidosis. The aim of the present study was to evaluate the influence of stressful life events on the onset of sarcoidosis. METHODOLOGY: The social and/or life events experienced prior to diagnosis in 55 patients with sarcoidosis, were evaluated quantitatively using the Social Readjustment Rating Scale (SRRS), the most authoritative method to quantify the magnitude of the events requiring changes in lifestyle. In addition, personality with respect to stress-reactivity was simultaneously evaluated using the Minnesota Multiphasic Personality Inventory (MMPI) alexithymia scale. Both the degree of stress, evaluated by SRRS, and stress-reactivity, evaluated by MMPI scale, of sarcoidosis patients were compared with those of 92 healthy controls. RESULTS: The magnitude of stressful life events was significantly higher in patients with sarcoidosis compared with healthy controls. In addition, capacity for coping with stress was found to be inferior in sarcoidosis patients compared with that in the control groups. CONCLUSION: These results indicated that psychosocial stress assessed on the basis of alexithymic characteristics of the self perception of stress may be partly implicated in the development of sarcoidosis.

CD40/CD40 ligand (CD40L) interaction plays an essential role in cell-mediated immune responses. We examined whether expression of CD40L in murine lung carcinoma (A11) cells could produce antitumor effects. The proliferation rate in vitro of A11 cells transfected with the murine CD40L gene (A11/CD40L) was not different from that of parent cells; however, half of the immunocompetent mice inoculated with A11/CD40L cells did not form tumors and the growth of A11/CD40L tumors developed in the rest of mice was significantly retarded compared with that of parent tumors. Protective immunity was also induced in the mice that had rejected A11/CD40L cells. In T-cell-defective nude mice, these antitumor effects were not observed. Bone-marrow-derived dendritic cells (DCs), when cultured with A11/CD40L cells, formed clusters with the tumors and showed upregulated CD86 expression. Expression of the interleukin-23 (IL-23) p19, IL-12p35, IL-18, interferon-gamma (IFN-gamma) and Mig (monokine induced by IFN-gamma) genes was induced in the DCs that were cultured with A11/CD40L but not with A11 cells, and P40, the subunit of both IL-12 and IL-23, was secreted from the cocultured DCs. These data directly showed that the expression of CD40L in tumors facilitated the interaction between DCs and the tumors, enhanced the maturation of DCs, induced secretion of cytokines, and consequently produced T-cell-dependent systemic immunity.

We studied the quality of life of obesity hypoventilation syndrome (OHS) by comparing it with age- and body mass index-matched patients without hypoventilation and age-matched obstructive sleep apnea (OSA) patients with body mass index (BMI) under 30, and the efficacy of nasal continuous positive airway pressure (CPAP) therapy for 3 to 6 months on the quality of life in these patients. Prospectively recruited patients from six sleep laboratories in Japan were administered assessments of the general health status by the Short-Form 36 Health Survey (SF-36) and subjective sleepiness by the Epworth Sleepiness Scale (ESS). Compared with matched healthy subjects, OHS and OSA patients not yet treated had worse results on the ESS scores and the SF-36 subscales for physical functioning, role limitations due to physical problems, general health perception, energy/vitality, role limitations due to emotional problems, and social functioning. The ESS scores of OHS patients were worse than those of the OSA groups including the age- and BMI-matched OSA patients. In the SF-36 subscales of OHS patients, only the subscale of social functioning showed worse results compared with that of BMI-matched OSA patients. After 3 to 6 months of treatment, ESS scores and these SF-36 subscales in all three patient groups improved to the normal level. These results suggested that the quality of life of OHS before nasal CPAP was significantly impaired and that nasal CPAP for OHS improved the quality of life associated with the improvement of daytime sleepiness to the level of the other OSA patients.

BACKGROUND: Small cell lung carcinoma (SCLC) has the propensity to grow rapidly and metastasize extensively. Detection of micro-dissemination of SCLC may have clinical relevance. For its detection, tumor-specific gene expressions were examined in peripheral blood and bone marrow aspirate from patients with SCLC. METHODS: Expression of prepro-gastrin-releasing peptide (preproGRP), neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R) were examined by reverse transcriptase polymerase chain reaction (RT-PCR) in peripheral blood and bone marrow aspirate from 40 untreated patients with SCLC. Control samples consisted of peripheral blood samples from 5 patients with nonsmall cell lung cancer (NSCLC) and 20 healthy volunteers. RESULTS: Positive rates of preproGRP, NMB-R, and GRP-R in bone marrow aspirate of patients with SCLC were 23% (9/40), 8% (3/40), and 10% (4/40), respectively. Those rates in peripheral blood were 11% (4/38), 5% (2/38), and 29% (11/38), respectively. Although GRP-R expression was detected in patients with NSCLC and in healthy volunteers, preproGRP and NMB-R expressions were not detected in patients with NSCLC and in healthy volunteers. All three gene expressions in bone marrow were more frequently observed in patients with bone marrow metastasis, accessed by biopsy, than in patients without. PreproGRP gene expression in bone marrow was also more frequent in patients with bone metastasis, accessed by bone scintigram, than in patients without, and was related to poorer survival. CONCLUSIONS: Micro-dissemination of SCLC was detectable by RT-PCR of preproGRP and NMB-R, both specific for SCLC. These gene expressions in bone marrow may be related to disease extent and prognosis.

The interaction between Fas and Fas ligand (FasL) is involved in the apoptotic death of a number of cells including lymphocytes. Forced expression of FasL in tumors can induce apoptosis of infiltrating Fas-positive T cells; accordingly, tumors can survive in the milieu of systemic immune responses. However, FasL-expressing murine lung carcinoma (A11) and melanoma (B16) cells did not develop subcutaneous tumors and FasL-expressing A11 (A11/FasL) cells produced few spontaneous lung metastatic foci in syngeneic mice. The mice that rejected A11/FasL cells were resistant to subsequent challenge of parent A11 but not irrelevant B16 cells. Vaccination of mice with UV-treated A11/FasL, but not UV-treated A11 cells, however, augmented the growth rate of A11 but not B16 tumors, both of which were subsequently inoculated. The number of lung metastatic foci of A11 cells was also increased in the mice that received UV-treated A11/FasL but not UV-treated A11 cells. Intraperitoneal injection of UV-treated A11/FasL cells resulted in the production of larger amounts of immunosuppressive TGF-beta in peritoneal exudate than that of UV-treated A11 cells. Expression of the CD80 costimulatory molecule in tissues where UV-treated A11/FasL cells were inoculated was lower than the expression at an untreated A11/FasL-injected site. Our results indicated that apoptotic FasL-expressing tumor cells could impair host immune responses against the tumors, in contrast to potent antitumor immunity generated by viable FasL-expressing tumors.

Cancer chemotherapy for haemodialysis patients has never been established. To elucidate the feasibility of cisplatin-based combination chemotherapy for haemodialysis patients with lung cancer, a dose escalation study was conducted. Five haemodialysis patients with lung cancer were treated with cisplatin and etoposide. A starting dose of 40 mg m-2 of cisplatin on day 1 and 50 mg m-2 of etoposide on days 1, 3 and 5 were administered as the first course for the first patient. Membrane haemodialysis was regularly performed three times a week and soon after the completion of therapy. By monitoring toxicity and pharmacokinetics data, the dose was escalated course by course and patient by patient. Dose escalation was completed for the first two patients resulting in full-dose chemotherapy consisting of 80 mg m-2 of cisplatin on day 1 and 100 mg m-2 of etoposide on days 1, 3 and 5. Multiple courses of the full-dose chemotherapy were administered to the other three patients. Toxicity was manageable and tolerable for all. Pharmacokinetics data were comparable to those from patients with normal renal function, except for potential long-lasting higher levels of free platinum in the renal insufficiency group. In conclusion, this standard-dose combination chemotherapy was feasible even for haemodialysis patients. © 2003 Cancer Research UK.

Background. Placement of a silicon tracheobronchial prosthesis in emergency situations has become an established therapeutic option to relieve airway stenosis due to malignant diseases. However, the alternative use of a metallic stent has never been fully evaluated. Purpose. To elucidate the clinical relevance of placing metallic stents in patients with critical airway stenosis due to malignant diseases. Patients and Methods. Thirteen patients with critical airway stenosis treated by placing metallic stents and meeting some defined conditions were retrospectively reviewed in terms of usefulness and adverse events. The stents were placed by flexible bronchoscopes under topical anesthesia in all cases. Results. Metallic stent placement was easy, quick and successful in every patient, and airway stenosis was quickly relieved after the procedure in all patients. Accordingly, dyspnea as assessed by a scoring system was improved from I day to I month after the placement. Performance status was not improved significantly by the procedure. Adverse events of serious nature were observed in 6 of the 13 patients. Conclusion. Metallic tracheobronchial stents for patients with airway stenosis and critical conditions seemed to have advantages in relieving dyspnea. Considering the adverse events, however, the choice of this option should be restricted to patients with limited expected survival.