巽 浩一郎

BACKGROUND: Obesity and craniofacial abnormalities such as small maxilla and mandible are common features of patients with obstructive sleep apnea (OSA). The authors hypothesized that anatomical imbalance between the upper airway soft-tissue volume and the craniofacial size (rather than each alone) may result in pharyngeal airway obstruction during sleep, and therefore development of OSA. METHODS: Blind measurements of tongue cross-sectional area and craniofacial dimensions were performed through lateral cephalograms in 50 adult male patients with OSA and 55 adult male non-OSA subjects with various craniofacial dimensions. RESULTS: Maxillomandibular dimensions were matched between OSA and non-OSA groups. While the tongue was significantly larger in subjects with larger maxillomandible dimensions, OSA patients had a significantly larger tongue for a given maxillomandible size than non-OSA subjects. The hypothesis was also supported in subgroups matched for both body mass index and maxillomandible dimensions. CONCLUSIONS: Upper airway anatomical imbalance is involved in the pathogenesis of OSA.

BACKGROUND: The validity of pulmonary thromboendarterectomy for treatment of relatively peripheral type of chronic thromboembolic pulmonary hypertension (CTEPH) remains uncertain. The survival and quality of life (QOL) of patients with relatively peripheral type of CTEPH was investigated at follow up. METHODS AND RESULTS: Between April 1999 and March 2006, 83 consecutive patients with CTEPH were evaluated for surgical indication and underwent computed tomography angiography. The extent of central disease was scored (ie, CD score), and a CD score of <or=1 was judged as relatively peripheral disease. Forty-three patients were excluded from surgery, and 40 patients, including 14 cases of relatively peripheral disease, underwent surgery. Long-term survival and QOL scores at follow up (1-3 years) were compared between the surgically and medically treated groups of relatively peripheral disease. Survival curves between the 2 treatment groups were not significantly different (p=0.78) because of high operative mortality (21.4%). However, improvement in physical functioning, role function (physically related), general health perception (as assessed by the Medical Outcome Study Short Form 36), and baseline dyspnea index were significantly higher in the group treated surgically compared with the medically treated group. CONCLUSIONS: Pulmonary thromboendarterectomy offers better QOL even in those patients with relatively peripheral type of CTEPH, although operative mortality must be reduced.

RATIONALE: Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP). Because PAP is rare, prior reports were based on limited patient numbers or a synthesis of historical data. OBJECTIVES: To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP. METHODS: Over 6 years, 248 patients with PAP were enrolled in a Japanese national registry, including 223 with autoimmune PAP. MEASUREMENTS AND MAIN RESULTS: Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively. The male to female ratio was 2.1:1, and the median age at diagnosis was 51 years. A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur. Dyspnea was the most common presenting symptom, occurring in 54.3%. Importantly, 31.8% of patients were asymptomatic and were identified by health screening. Intercurrent illnesses, including infections, were infrequent. A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease. CONCLUSIONS: Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses. The disease severity score and biomarkers provide novel and potentially useful outcome measures in PAP.

The antiviral effects of chloroquine (CQ) on human coronavirus 229E (HCoV-229E) infection of human fetal lung cell line, L132 are reported. CQ significantly decreased the viral replication at concentrations lower than in clinical usage. We demonstrated that CQ affects the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK). Furthermore, p38 MAPK inhibitor, SB203580, inhibits CPE induced by HCoV-229E infection and viral replication. Our findings suggest that CQ affects the activation of MAPKs, involved in the replication of HCoV-229E.

Severe combined immune deficiency (SCID) mice were more sensitive to systemic delivery of bleomycin (BLM) than the wild-type strain, and died from esophagitis. Lung injury in the SCID mice by its intratracheal injection, however, was of comparable degree but with less lymphocyte infiltration than that in the wild-type mice. Macrophages and lymphocytes increased transiently in bronchoalveolar lavage fluid of SCID mice, whereas their increase in wild-type was continuous. Unsustainable inflammation in the lung might reduce BLM-induced lung injury in BLM-sensitive SCID mice.

BACKGROUND: Respiratory syncytial virus (RSV) infection could be related to airway inflammation as well as exacerbation of chronic obstructive pulmonary disease (COPD). Tiotropium bromide decreases the frequency of exacerbation in patients with COPD; however, the mechanisms of tiotropium bromide to reduce the chances of exacerbation have not been defined. One potential mechanism could be that tiotropium bromide protects against RSV infection in epithelial cells. OBJECTIVE: To examine whether tiotropium bromide affects RSV replication in HEp-2 cells. METHODS: The supernatant titer of RSV was calculated by methylcellulose plaque assay after RSV innoculation. Intracellular RSV and ICAM-1 mRNA were measured by PCR. Syncytium formation was observed by light microscopy. Intracellular RSV fusion protein and RhoA protein were detected by Western blot analysis. Furthermore, RhoA activity, ICAM-1 expression and inflammatory cytokines in cultured supernatant were measured by binding assay, immunofluorescence staining and ELISA, respectively. RESULTS: Tiotropium bromide decreased the supernatant titer of RSV, and it inhibited syncytium formation, RhoA activation and ICAM-1 expression. Moreover, it suppressed the production of IL-6 and IL-8 after RSV infection. CONCLUSIONS: The antiviral effects of tiotropium bromide regarding RSV replication are partly due to inhibition of RhoA activity and ICAM-1 expression. Tiotropium bromide decreases RSV replication and may modulate airway inflammation by reducing the production of inflammatory cytokines.

Malignant pleural mesothelioma is relatively rare in frequency but one of the intractable diseases linked with asbestos exposure. Clinical outcomes with the present treatment modalities are unsatisfactory and no effective prevention method has been reported. Growing numbers of the patients in the Western countries with a long latent period need development of a novel therapeutic strategy. Gene therapy is a candidate for mesothelioma treatment because of its easy accessibility of a vector-mediated gene medicine into the intrapleural cavity. Several preclinical studies demonstrated that the gene medicine produced antitumor effects, suggesting the feasibility in clinical settings. In this article, we review the current status of gene therapy and clinical trials targeting mesothelioma and address possible directions to improve the efficacy.

BACKGROUND: The pathogenesis of daytime hypercapnia (Paco2 >or= 45 mm Hg) may be directly linked to the existence of obstructive sleep apnea syndrome (OSAS) per se, although only some patients with OSAS exhibit daytime hypercapnia. OBJECTIVE: To investigate the prevalence of daytime hypercapnia in patients with OSAS; the association of daytime hypercapnia and obesity, obstructive airflow limitation, restrictive lung impairment, and severity of sleep apnea; and the response to continuous positive airway pressure (CPAP) therapy in a subset of subjects. METHODS: The study involved 1,227 patients with OSAS who visited a sleep clinic and were examined using polysomnography. As for the response to CPAP therapy, the patients were considered good responders if their daytime Paco2 decreased >or= 5 mm Hg and poor responders if it decreased < 5 mm Hg. RESULTS: Fourteen percent (168 of 1,227 patients) exhibited daytime hypercapnia. These patients had significantly higher body mass index (BMI) and apnea-hypopnea index (AHI) values compared with normocapnic patients, while percentage of predicted vital capacity (%VC) and FEV(1)/FVC ratio did not differ between the two groups. Logistic regression analysis showed that only AHI was a predictor of daytime hypercapnia (p < 0.0001), while BMI (p = 0.051) and %VC (p = 0.062) were borderline predictors of daytime hypercapnia. Daytime hypercapnia was corrected in some patients (51%, 19 of 37 patients) with severe OSAS after 3 months of CPAP therapy. CONCLUSION: The pathogenesis of daytime hypercapnia may be directly linked to sleep apnea in a subgroup of patients with OSAS.

BACKGROUND: The purpose of this study was to evaluate the usefulness and safety of multidetector-row computed tomography (MDCT) pulmonary angiography and indirect venography management of acute pulmonary embolism (PE), including indication for inferior vena cava (IVC) filter. METHODS AND RESULTS: Seventy-one consecutive patients who were clinically suspected of PE and underwent 16-slice MDCT pulmonary angiography and indirect venography were enrolled. Management included indication of IVC filter for patients with extensive deep venous thrombosis (DVT) in submassive or massive PE. A right ventricular to left ventricular short-axis diameter by MDCT>1.0 was judged as submassive PE. All patients were followed for 1 year. MDCT identified 50 patients with venous thromboembolism and 47 patients had acute PE: 4 were judged as massive, 14 as submassive, and 29 as non-massive by MDCT; 3 patients had DVT alone and 7 patients had caval or iliac DVT. Only 1 patient with massive PE and DVT near the right atrium died of recurrence. No other patients died of PE. CONCLUSION: Management based on MDCT pulmonary angiography combined with indirect venography is considered to be safe and reliable in patients with suspected acute PE.

A 60-year-old man was admitted to our hospital complaining of back pain and bloody sputum. Chest CT scan showed characteristic multiple small nodules with central dense opacity and surrounding faint opacity, suggesting lesions with hemorrhage. Bone scintigram and MRI revealed multiple osteolytic lesions in pelvis and lumbar spine. Biopsy of the bone lesion established a diagnosis of angiosarcoma. Chemotherapy with paclitaxel and palliative radiotherapy for the bone were initiated. Pulmonary metastases dramatically diminished after 4 courses of paclitaxel treatment. After eight weeks, the tumor recurred. Salvage chemotherapy of weekly administration of docetaxel yielded limited effects. The patient died of cancer one year after treatment initiation.

Severe pulmonary hypertension (PH) is characterized by complex precapillary arteriolar lesions, which contain phenotypically altered smooth muscle (SM) and endothelial cells (EC). We have demonstrated that VEGF receptor blockade by SU5416 {3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin 2-one} in combination with chronic hypoxia causes severe angioproliferative PH associated with arterial occlusion in rats. We postulate that endothelial-mesenchymal transdifferentiation can take place in the occlusive lesions and that endothelium-derived mesenchymal cells can further differentiate toward a SM phenotype. To examine this hypothesis, we incubated human pulmonary microvascular endothelial cells (HPMVEC) with SU5416 and analyzed these cells utilizing quantitative-PCR, immunofluorescent staining and flow cytometry analysis. In vitro studies in HPMVEC demonstrated that SU5416 suppressed PGI2S gene expression while potently inducing COX-2, VEGF, and TGF-beta1 expression; and caused transdifferentiation of mature vascular endothelial cells (defined by Dil-ac-LDL, Lectin and Factor VIII) to SM-like (as defined by expression of alpha-SM actin) "transitional" cells, coexpressing both endothelial and SM markers. SU5416 expanded the number of CD34 and/or c-kit positive cells and caused transdifferentiation of CD34 positive cells but not negative cells. In conclusion, our data show that SU5416 generated a selection pressure that killed some EC and expanded progenitor-like cells to transdifferentiate to SM-like and neuronal-like cells.

A 30-year-old woman was admitted because of persistent and severe hemoptysis in November 2005. She had been given a diagnosis of interstitial pneumonia (IP) and pulmonary aspergilloma in 2001, and she was treated with oral prednisolone and itraconazole. However she had persistent and intractable hemoptysis. Multi-detector row computed tomography (MDCT) revealed that hemoptysis from the right upper lobe did not originate in bronchial arteries, but the abnormal branches of the right subclavian artery. Surgery was not performed because of her pulmonary function, but she was successfully treated by non-bronchial arterial coil embolization. At 10 months after the embolization, hemoptysis has not recurred. MDCT was very useful for diagnosing the cause of hemoptysis and selective nonbronchial arterial coil embolization might be helpful in treating intractable or refractory hemoptysis.

BACKGROUND: Lipoprotein lipase (LPL) might play a major role in lipid metabolism by hydrolyzing triglyceride-rich lipoproteins. Decreased LPL activity can trigger early inflammatory responses central to atherosclerosis. However, whether repeated apnea-related hypoxemia influences lipid metabolism in patients with obstructive sleep apnea syndrome (OSAS) remain undefined. This investigation determined whether circulating LPL was influenced by repeated apnea-related hypoxemia, and the effect of nasal continuous positive airway pressure (CPAP) therapy on LPL concentrations in OSAS patients. METHODS AND RESULTS: The participants of the study were 155 men with OSAS and 39 men without OSAS. Circulating LPL concentrations decreased with the severity of OSAS. They correlated negatively with serum triglyceride, and the linear regression lines between LPL concentrations and triglyceride in OSAS patients were shifted downward compared with those in non-OSAS patients, suggesting that any pathophysiological factor might decrease LPL activity in OSAS patients. Some OSAS patients were subjected to CPAP therapy for 3 months. CPAP therapy increased LPL concentrations and decreased C-reactive protein (CRP) concentrations. CONCLUSIONS: The present study suggests that repeated apnea-related hypoxemia might affect lipid metabolism and augment inflammatory responses, and CPAP therapy could be effective to decrease inflammatory responses and ameliorate lipid metabolism in patients with OSAS.

This study was designed to determine the effects of the treatment schedule on the interaction between cisplatin and radiation. Cells of a human squamous cell lung cancer cell line were treated with cisplatin and radiation using three treatment protocols: 1-h exposure to cisplatin immediately followed by irradiation (A), 4-day continuous exposure to cisplatin immediately followed by irradiation (B), and 1-h exposure to cisplatin followed by irradiation after a 4-day interval (C). The interactions were assessed by isobologram, cell cycle distribution and apoptosis. The combination resulted in a additive effect in every protocol. Cell cycle accumulation at G(2)/M phase before irradiation was observed in Protocols B and C, whereas no cell cycle shift in the limited time course was noted in Protocol A. Although a 4-day continuous exposure to cisplatin and a 1-h exposure to cisplatin followed by a 4-day interval before irradiation caused significantly increased apoptosis, an additional increase in apoptosis after irradiation was not observed in Protocols B and C, whereas Protocol A showed an additional increase. Despite a cell cycle shift favoring radiation sensitivity, the drug-radiation interactions in Protocols B and C were additive, possibly because of negative effects including induction of a durable G(2)/M-phase arrest and suppression of apoptosis by cisplatin.

Cigarette smoking is the major risk factor for COPD. However, it is likely that there are important interactions between environmental factors, such as cigarette smoking, and a genetic predisposition to COPD. Single cigarette smoking causes acute reversible airway inflammation in everyone, and only 15 % of chronic smokers may develop chronic irreversible airway inflammation, resulting in the development of COPD. Fifteen percent reason has been undefined. Multiple factors may involve the pathogenesis of COPD. Cigarette smoke may upregulate the pathways linked to lung destruction and airway inflammation, such as protease and oxidative stress, and may downregulate the pathways related to the defensive mechanism, such as antiprotease and antioxidant. Other than protease-antiprotease and oxidant-antioxidant mechanisms, multiple exposures to cigarette smoke move cells into an irreversible state of senescence, or the inability to repair lung injury. Chronic exposure to smoking may affect the VEGF signaling, resulting in apoptosis of lung cell, which may partly contribute to the pathogenesis of COPD.

The apoptosis-inducing Fas ligand (FasL) is expressed in a variety of human cancers and has been implicated in tumor immune evasion. Paradoxically, ectopic expression of FasL in experimental tumors triggers a neutrophil-mediated inflammatory response and tumor rejection. To resolve these conflicting findings, we have established B16 melanoma and P29 Lewis lung carcinoma lines expressing different levels of FasL and examined their tumorigenicity in vivo. While tumors with a high level of FasL were rapidly rejected as previously reported, those expressing a low level of FasL were not rejected but grew faster than did FasL-negative parental cells. The growth enhancement of FasL(low) tumors was not observed in T-cell-deficient nude mice, suggesting that FasL expressed in tumors at low levels counteracted against T-cell-dependent antitumor responses. In support of this notion, FasL(low) tumors were found to grow faster than parental cells in mice that had acquired tumor-specific immunity. Furthermore, histological examinations revealed apoptosis of lymphocytes in tissue sections of FasL(low) tumors. These results collectively suggest that FasL on tumors is a double-edged sword: at high levels it triggers tumor rejection whereas at low levels it facilitates tumor growth possibly by suppressing antitumor immune responses.

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.

A 33-year old woman was referred to our hospital with dyspnea on exertion. She had a history of recurrent spontaneous pneumothraxes. A giant bulla and many bullae were observed on chest computed tomography. She underwent a lung biopsy and bullectomy to obtain a definitive diagnosis and to decrease dyspnea. In pathological findings, a hematoxylin-eosin stained section of the lung biopsy showed smooth muscle proliferation at the alveolar wall and bronchiole immunohistochemical staining of HMB45 revealed the proliferation of LAM cells. After the operation, dyspnea and hemoptysis temporarily appeared. The chest X-ray and chest CT revealed ARDS. However, she improved after the administration of steroids. She underwent progesterone therapy, but her pulmonary functions have deteriorated.

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.