巽 浩一郎

慢性閉塞性肺疾患・気管支喘息などの慢性呼吸器疾患の増悪を抑制するための戦略は，1）気道炎症を可能な限り改善しておく，2）気道感染を予防する，3）心機能を保つ，に大別される．薬物療法の観点で考えると，気道感染の予防には去痰薬に分類されているカルボシステインが有用である．カルボシステインは，気道上皮細胞に対するウイルスエントリーインヒビターの役割を有しており，臨床的にも増悪抑制に有用である．

To study the role of mutant p53 in the induction and cure of tumors, we generated transgenic mice carrying mutant p53 (mp53) containing a 9 bp deletion in exon 6 in addition to wild-type p53, expressing both p53 and mp53. The mp53 cDNA was cloned from a radiation-induced mouse tumor and ligated to the chicken beta-actin promoter/CMV-IE enhancer in the expression vector. The presence of mp53 suppressed p21 expression in primary fibroblasts after ionizing irradiation, indicating the dominant-negative activity of mp53 in the mice. These mice developed fibrosarcomas after the subcutaneous injection of 3-methylcholanthrene with an incidence 1.7-fold higher than that of wild-type mice (42% excess). The tumors were then treated via a potent atelocollagen delivery system with small interfering RNA (siRNA), that targeted the promoter/enhancer of the expression vector, resulting in the suppression of tumor growth in 30% of 44 autochthonous tumors, including four cures, and their transplants, the total fraction corresponding to the tumor excess. This suppressive effect involved the induction of apoptosis. These results indicate that mp53 activity causes tumors that can be suppressed by subsequent silencing of mp53 in the presence of wild-type p53 alleles. Cancer Gene Therapy (2010) 17, 1-10; doi: 10.1038/cgt.2009.43; published online 26 June 2009

症例１は初診時39歳女性．2003年に眼所見と両側肺門リンパ節腫脹（BHL）で発症した．2009年に疼痛を伴う耳下腺と両鼠径リンパ節の腫脹が出現した．近医でミノサイクリンを使用されたが無効であり，当科に紹介されメトトレキサート（以下MTX）7.5 mg/週の単剤治療を開始したところBHLと表在リンパ節の改善が認められた．症例２は初診時51歳男性，以前より眼，皮膚，肺病変に対してプレドニゾロン（以下PSL）が投与されていた．PSLの中止後に肺病変の増悪と肺アスペルギルス症の合併を認め当科に紹介された．MTX 7.5 mg/週の単剤治療にて肺野陰影の改善が認められた．MTXはsteroid-sparing agentとして位置づけられ単剤治療での有効性を示した報告は少なく，今回２症例を報告した．

Selective right pulmonary arteriography and 3-dimensional computed tomography revealed multiple severe stenoses of the peripheral pulmonary artery associated with poststenotic aneurysms in a 65-year-old woman. She was referred to the hospital for evaluation of dry cough, gradually increasing dyspnea and multiple nodular shadows on a chest radiograph. Echocardiography and cardiac catheterization showed severe pulmonary hypertension, though other structural heart diseases or well-characterized congenital syndromes were ruled out. She was diagnosed as isolated peripheral pulmonary artery branch stenosis. Recent advances in CT technology enable a less-invasive assessment of pulmonary artery, and can be useful in the management of pulmonary arterial hypertension.

A 20-year-old female diagnosed as idiopathic pulmonary arterial hypertension at 7 years of age was referred with worsening dyspnea and chest pain. Several imaging studies and right cardiac catheterization showed multiple stenoses in the peripheral pulmonary arteries with severe pulmonary hypertension and multiple systemic arterial stenoses lacking in systemic hypertension. No evidence of inflammatory or autoimmune disease was detected. Fibromuscular dysplasia was clinically diagnosed because of the narrowed systemic and pulmonary arterial stenoses which included dilatation and aneurysms that appeared similar to a string of beads. Treatment with sildenafil yielded a temporary improvement in her disease state.

Severe pulmonary arterial hypertension, whether idiopathic or secondary, is characterized by structural alterations of microscopically small pulmonary arterioles. The vascular lesions in this group of pulmonary hypertensive diseases show actively proliferating endothelial cells without evidence of apoptosis. In this article, we review pathogenetic concepts of severe pulmonary arterial hypertension and explain the term "complex vascular lesion ", commonly named "plexiform lesion", with endothelial cell dysfunction, i.e., apoptosis, proliferation, interaction with smooth muscle cells and transdifferentiation.

本論文では漢方医学的と同時に西洋医学的観点から，気道系領域疾患の治療として，西洋薬とともにどのように漢方薬を使用するかを考察した。漢方治療では一般的に患者の体力，病態，病気の進展に合わせて薬方を決定することが重要である。喀痰がからまるという患者の病態が去痰薬，気管支拡張薬，吸入ステロイド薬，抗菌薬では十分に改善しない場合，例えば半夏厚朴湯という漢方薬は喀痰がほとんどなく，咽頭部の閉塞感を訴える場合に効果が期待できる。<br>咳嗽反射，嚥下反射の低下は誤嚥性肺炎の誘因になりうる。そのような場合，半夏厚朴湯の投与は咳嗽反射，嚥下反射を改善することにより，誤嚥性肺炎を予防しうる。<br>遷延性あるいは慢性咳嗽は鎮咳薬，抗菌薬，去痰薬，気管支拡張薬，吸入ステロイド薬などの西洋薬を使用しても，十分に改善しない場合がある。麦門冬湯，五虎湯，麻杏甘石湯，越婢加半夏湯などの漢方薬は，そのような場合に有用である可能性がある。西洋医学の薬と漢方薬の併用は，新たな効果を発揮しうると期待する。

We examined phrenic long-term facilitation (LTF) in urethane-anesthetized, vagotomized, paralyzed, and artificially ventilated orexin neuron-ablated mice and their wild-type littermates. Effect of isocapnic single hypoxic episode (SHE, for 45 s) and intermittent hypoxia (IH, 5 times of SHE separated by 5 min) on phrenic nerve activity (PNA) was measured for 1-2h. In wild-type mice, amplitude of PNA gradually increased after cessation of IH and reached 55+/-15% above the baseline (n=7, p<0.05) whereas the burst rate of PNA did not change. Qualitatively similar but significantly attenuated response (16+/-8%) was observed in orexin neuron-ablated mice. SHE did not affect amplitude nor frequency in both animals. We conclude that orexin contributes to eliciting phrenic LTF at least in part in mice. This study also showed, for the first time, phrenic LTF following IH in WT mice. Characteristics of phrenic and ventilatory LTF in mice were similar to those in rats.

A 27-year-old man experienced progressive left hypochondralgia. CT with contrast medium enhancement revealed marked splenomegaly, multiple swollen lymph nodes in the mediastinum and abdominal cavity, and multiple nodules in the spleen, liver, kidneys and lungs. Pathological examinations of the lung and liver lesions showed non-caseating granulomatous lesions, and established the diagnosis of sarcoidosis. The symptom and lesions presented by CT regressed dramatically with administration of corticosteroid (30 mg/day oral prednisolone). Symptomatic splenomegaly in a young Japanese man with sarcoidosis seems very rare especially considering that sarcoidosis lesions completely regress spontaneously within a year in 90% patients of young Japanese men with sarcoidosis.

Racemose hemangioma of the bronchial arteries is a rare abnormality and is characterized by enlarged and convoluted bronchial arteries arranged segmentally along the longitudinal axis of bronchus. Primary racemose hemangioma may arise from inborn malformation, and secondary one may develop following primary inflammatory, stenosing or deforming diseases of the bronchus, the peribronchial tissues and the surrounding lung tissues. The symptom at onset is usually hemoptysis. Although the typical treatments have not been established, various treatments, like embolization or ligation of the bronchial arteries and surgical resection of the involved area of lung, were reported. However the term 'Racemose hemangioma' seems to be used only in Japan, so it is favorable to make a consensus of its definition among countries.

BACKGROUND AND OBJECTIVE: Although lung cancer is frequently accompanied by COPD and interstitial lung disease (ILD), the precise coincidence of these diseases with lung cancer is not well understood. The objectives of this study were to determine the prevalence of abnormal CT and spirometric findings suggestive of COPD or ILD in a population of patients with untreated lung cancer, and to estimate the lung cancer risk in this population. METHODS: The study population consisted of 256 patients with untreated lung cancer and 947 subjects participating in a CT screening programme for lung cancer. Semi-quantitative analysis of low attenuation area (LAA), fibrosis and ground glass attenuation (GGA) on CT was performed by scoring. Gender- and age-matched subpopulations, with stratification by smoking status, were compared using the Mantel-Haenszel projection method. RESULTS: Inter-observer consistency was excellent for LAA, but not as good for fibrosis or GGA scores. Pooled odds ratios for lung cancer risk using LAA, fibrosis, GGA scores and reduced FEV(1)/FVC and %VC were 3.63, 5.10, 2.71, 7.17 and 4.73, respectively (P < 0.0001 for all parameters). Multivariate regression analyses confirmed these results. CONCLUSION: Abnormal CT and spirometric parameters suggestive of COPD and ILD were strong risk factors for lung cancer, even after adjusting for gender, age and smoking status.

Gender differences could exist in the respiratory functions of the upper airway, especially when they relate to sleep and possibly sleep apnea. Particular attention should be given to factors related to upper airway patency, considering the gender difference of anesthesia. The pharyngeal airway is open during wakefulness but occludes during sleep implicating a neural component dependent upon state of vigilance, although anatomical upper airway narrowing in the genesis of airway occlusion during sleep plays an important role. Respiratory disturbances, including sleep apnea syndromes, are less common in women than men until after menopause. Particularly marked is the male predominance among patients with obesity hypoventilation syndrome. While obesity increases the risk of developing sleep-disordered breathing in both sexes, women with sleep apnea syndromes are more massively obese than their male counterparts. Several factors may contribute to the protection in herento premenopausal women, including the presence of female hormones, the absence of male hormones, and the effects of gender or age unrelated to sex hormones. These factors, in turn, appear to influence airway patency and ventilatory control.

Good syndrome, characterized by hypogammaglobulinemia and acquired immunodeficiency, is a rare condition associated with thymoma. A 67-year-old woman, who 4 months previously had a thymoma resected, presented with generalized hypogammaglobulinemia with a severely decreased B cell population as demonstrated by flow cytometry. She was diagnosed as having bacterial mediastinitis associated with Good syndrome. For the subsequent 6 years, she suffered from repeated serious bacterial infections. As this paraneoplastic syndrome is not resolved by tumor removal, careful management with intensive infection-control using antibiotics and intravenous immunoglobulins is required for the long term. Serum immunoglobulin levels should be evaluated for patients with thymoma and suspected vulnerability to infection.

A 52-year-old woman with end-stage renal disease and long-term hemodialysis complained of worsening exertional dyspnea. A chest X-ray showed cardiomegaly. She was admitted to our hospital because an echocardiogram suggested pulmonary hypertension. Right heart catheterization revealed pulmonary hypertension, but pulmonary perfusion scintigraphy with Tc-99m-MAA showed no evidence of pulmonary thromboembolism. We gave her a diagnosis of pulmonary arterial hypertension associated with Sjögren syndrome on the basis of a positive serological test (SS-A. SS-B) and the findings of lip biopsy. After four months of therapy with bosentan, her 6-minute walk distance, estimated pulmonary arterial pressure and brain natriuretic peptide (BNP) improved. Bosentan is mainly cleared by hepatic elimination and its dialysis clearance is low. Bosentan for the treatment of pulmonary hypertension was safe as well as effective in this patient with end-stage renal disease and hemodialysis. In consideration of the relationship between pulmonary hypertension and end-stage renal disease, and hemodialysis, bosentan was considered to be a reasonable and effective treatment.

BACKGROUND: The predominance of chronic thromboembolic pulmonary hypertension (CTEPH) in females and association of HLA-B*5201 with CTEPH have been reported in Japan. However, the clinical characteristics of female CTEPH remain uncertain. The purpose of the present study is to clarify the clinical phenotype of female CTEPH in Japan. METHODS AND RESULTS: The 150 consecutive patients (female 103, male 47; age 52.8+/-12.4 years SD) were admitted to Chiba University Hospital, and diagnosis was confirmed using right cardiac catheterization and pulmonary angiography. Among these patients, 78 underwent pulmonary endarterectomy. Clinical characteristics, pulmonary hemodynamics, extent of central disease and surgical outcome in females were compared with those in males. The female patients were elderly and had less deep vein thrombosis, less acute embolic episodes, better cardiac function, lower arterial oxygen tension and more peripheral thrombi, and showed less improvement through surgery than males. When the patients were identified using HLA-B*5201, HLA-B*5201-positive female patients had less embolic episodes and better cardiac function with lower operative mortality. In contrast, HLA-B*5201-negative female patients had less embolic episodes, and more peripheral thrombi, resulting in less improvement by surgery. CONCLUSION: The clinical phenotype of female CTEPH differed from that of male CTEPH. Additionally, gender differences of HLA-B*5201-positive type were dissimilar to those of HLA-B*5201-negative type.

Remodeling of the lung's vascular structure is the critical abnormality in the various types of pulmonary hypertension, including pulmonary arterial hypertension. Pulmonary hypertension consists of some structural changes and an adaptation to its presence (perhaps reversible component, including vasoconstriction). However, once pulmonary hypertension is a recognizable clinical problem, its basis is structural. The research for mediators of cell injury and tissue remodeling has been one of the most active fields of biomedical study. It offers an embarrassingly wide array of candidates for the cellular events. The normal structure of the lung's vascular bed holds the key to its remodeling. The cast of cells is similar at all levels of the pulmonary vascular bed, yet the various segments have special features and different patterns of response.

Testicular involvement by sarcoidosis is a rare condition. A 23-year-old Japanese man had asymptomatic bilateral testicular lesions, which were detected by gallium scintigram, together with lesions located bilaterally in the uvea, lungs and hilar, and mediastinal lymph nodes and unilateral supraclavicular lymph nodes. Semen analysis demonstrated severely impaired spermatogenesis. Treatment with corticosteroid dramatically improved these lesions and restored spermatogenesis. This case report suggests that testicular sarcoidosis may cause male infertility.

Although mucosa-associated lymphoid tissue (MALT) lymphoma is classified as an indolent lymphoma, it frequently disseminates and recurs to make the disease difficult to cure. The present case had metachronous lesions in the skin, orbit and pleura, and all of them were diagnosed as derived from the same monoclonal tumor cell. A 65-year-old woman was admitted to our hospital because of a pleural tumor with pleural effusion. Two years before, she had undergone surgical resection for skin erythematous lesion and an ocular adnexa tumor, which were diagnosed as lymphoid hyperplasia by histological examination at that time. On admission, thoracoscopy-guided biopsy of the pleural tumor with local anesthesia established a diagnosis of MALT lymphoma. The rearranged immunoglobulin heavy chain of the skin tumor, ocular adnexa tumor, pleural tumor and lymphocytes in the pleural effusion were analyzed using a polymerase chain reaction (PCR)-based assay. This analysis revealed the metachronous MALT lymphoma originated from a distinct B-cell clone. After rituximub and CHOP therapy, complete remission was obtained. Although MALT lymphoma occurs in a wide variety of body sites, the pleural presentation of MALT lymphoma is very rare. Lifelong observation of all patients treated for MALT lymphoma is required because of the high frequency of dissemination and recurrence.

Information concerning the effects of genetic variation between different background strains on hemodynamic, morphometric, and gene expression response to hypoxia would be useful. Three strains of mice were kept in hypoxia and phenotyped followed by gene profiling analysis. Among the variables examined, hematocrit, right heart muscularization, and right ventricular systolic pressure showed a strain-specific effect. Increased gene expression of inflammatory, muscle, and angiogenesis genes were seen in all strains, though the specific genes changed varied among groups. These results suggest that different strains use different gene expression mechanisms to adapt to the challenge of chronic hypoxia, resulting in modified phenotypic changes.

BACKGROUND: Dilatation of the bronchial arteries is a well-recognized feature in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The purpose of the current study was to use computed tomography (CT) to assess the relationship between dilated bronchial arteries and the extent of thrombi, and to evaluate the predictive value of the former for surgical outcome. METHODS AND RESULTS: Fifty-nine patients with CTEPH and 16 with pulmonary arterial hypertension (PAH) were retrospectively evaluated. The total cross-sectional area of bronchial arteries was measured by CT and its relationship with the central extent of thrombi or surgical outcome was assessed. The total area of the bronchial arteries in CTEPH patients was significantly larger than that in PAH patients (median [range], 6.9 [1.7-29.5] mm(2) vs 3.2 [0.8-9.4] mm(2)), with the total area of bronchial arteries correlating with the central extent of thrombi. In patients who had undergone pulmonary thromboendarterectomy (PTE) (n=22), the change in PaO(2) after surgery had a tendency to correlate with the total area of the bronchial arteries. CONCLUSION: The total cross-sectional area of the bronchial arteries correlated with the extent of central disease in patients with CTEPH, and it might predict gas exchange improvement after PTE.

Consistent with the hypothesis that pulmonary epithelial apoptosis is the key to the acute exacerbation of idiopathic pulmonary fibrosis (IPF), we conducted serological identification of Ags by recombinant expression cloning (SEREX) analysis using type II alveolar cell carcinoma (A549) cell lines to identify disease-related Abs. In a survey of Abs to the recombinant autoantigens identified by SEREX analysis, five Abs were identified as novel candidates for the acute exacerbation of IPF. Abs to annexin 1 were detected in 47 and 53% of the sera and bronchoalveolar lavage materials from patients with acute exacerbation of IPF. Some identical TCR Vbeta genes were identified in sequential materials obtained at 1-3 mo in all 10 acute exacerbation IPF cases, suggesting that some infiltrating CD4-positive T cells sharing limited epitopes expand by Ag-driven stimulation during disease extension. The CDR3 region of these identical TCR Vbeta genes showed high homology with the N-terminal portion of annexin 1, including in the HLA-DR ligand epitopes predicted by TEPITOPE analysis. By Western blotting analysis and observation of the CD4-positive T cell responses in bronchoalveolar lavage samples, the N-terminal portion of annexin 1 was cleaved and found to induce marked proliferative responses of CD4-positive T cells in three patients. Our study demonstrates that annexin 1 is an autoantigen that raises both Ab production and T cell response in patients with acute exacerbation of IPF, and that the N-terminal portion of annexin 1 plays some role in the pathogenesis of acute exacerbation in IPF patients.

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.