田邉 信宏

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 β-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.

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.

Arterial oxygenation during sleep in Sherpa highlanders has been relatively unexplored. This study was designed to investigate arterial oxygen saturation (SaO2) and pulse rate (PR) during sleep in 61 Sherpa (29 men, 32 women) who had lived at 3450-3850 m in Nepal, from adolescence through old age, and to estimate the relative effects of aging on arterial oxygenation during sleep. The mean SaO2 during sleep (mSaO2) was found to decrease with age, and to negatively correlate with the mean PR during sleep. About one-third of subjects (n=19) exhibited a periodical fluctuation of SaO2 during sleep. The subjects who exhibited a periodical fluctuation of SaO2 during sleep were older and their mSaO2 were lower compared with those who did not exhibit a periodical fluctuation of SaO2, and the cycle of periodical fluctuation got longer with advancing years. These findings indicated that sleep desaturation occurs in high altitude residents with advancing years. © 2002 Elsevier Science B.V. All rights reserved.

Ku70 protein, cooperating with Ku80 and DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs), is involved in DNA double-strand break (DNA DSB) repair and V(D)J recombination. Recent studies have revealed increased ionizing radiosensitivity in Ku70-deficient cells. The presented study, using a human squamous cell lung carcinoma cell line, demonstrated that introduction of an antisense Ku70 nucleic acid made the cells more radio- and chemosensitive than the parental cells. Ku70 protein expression was suppressed in the cells with antisense Ku70 construct when compared to the wild-type cells. A relatively small but statistically significant increase in radiosensitivity of the cells was achieved by the introduction of the antisense Ku70. The increased radiosensitivity in vitro was accompanied by an approximately two-fold increase in α and α/β values in a linear-quadratic model. The antisense Ku70 increased the chemosensitivity of the cells to some DNA-damaging agents such as bleomycin and methyl methanesulfonate, but not to cisplatin, mitomycin C, and paclitaxel. This system provides us with partial suppression of Ku70, and will be a useful experimental model for investigating the physiological roles of the DNA DSB repair gene. © 2002 Elsevier Science B.V. All rights reserved.

The Medical Research Council (MRC) and Nocturnal Oxygen Therapy Trial (NOTT) studies performed in the late 1970s regarding effects of long-term oxygen therapy (LTOT) have revealed that LTOT improved the prognosis in patients with hypoxemic COPD and established the basis of prescription of LTOT. However, whether LTOT improved HRQoL as a secondary end point has not been clarified. Therefore we prospectively examined the effects of LTOT on HRQoL, evaluated by SF-36 and SGQR, in 43 patients with chronic lung diseases who were prescribed LTOT. HRQoL was assessed before LTOT and short- and long-term after prescription of LTOT. In this study it was demonstrated that LTOT ameliorated some physical and mental functions in patients with chronic lung diseases.

Ehlers-Danlos syndrome type IV (EDS IV) is caused by mutation within the COL3A1 gene, resulting in the disorder of type III procollagen. The diagnosis is confirmed by demonstrating the synthesis of abnormal type III procollagen molecules from cultured dermal fibroblasts or by identifying the mutation in the COL3A1 gene. The authors report a case of EDS IV caused by a novel point mutation in the COL3A1 gene in a 16-yr-old female. Recurrent haemoptysis and cavitary formation of the lung were evidence of pulmonary involvement. However, extrathoracic manifestations of EDS IV were mostly absent. To the best of the authors' knowledge, all previously reported Ehlers-Danlos syndrome IV patients with respiratory disease had the characteristic findings or histories of Ehlers-Danlos syndrome IV. In the present case, connective tissue friability was suspected due to tissue laceration observed in the biopsied lung specimen, and the diagnosis was made beginning from this pivotal finding.

Endobronchial ultrasonography (US) with 4.5-F small-caliber US probes, combined with bronchoalveolar lavage technique, was evaluated in autopsied lungs and 22 patients with various pulmonary interstitial or alveolar diseases. Several different echoic patterns were found that may reflect changes due to pathologic alteration of lung parenchyma. This technique may have potential for evaluation and diagnosis of peripheral lung diseases. © RSNA, 2002.

The pathogenesis of severe pulmonary hypertension seems to be related to inflammatory response in diseased sites. Monocyte chemoattractant protein-1 (MCP-1) has been reported to play a role in the development of congestive heart failure. In this immunological response, activation and migration of leukocytes including macrophages to the inflammatory region are important factors. We hypothesized that the severity of pulmonary hypertension may be related to MCP-1, which is thought to be upregulated by blood pressure or shear stress in pulmonary vasculature as well as by immunological and inflammatory reactions in chronic thromboembolic pulmonary hypertension (CTEPH). Circulating levels of MCP-1, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were measured by sandwich ELISA in 14 patients with CTEPH. The plasma level of MCP-1 was significantly correlated with pulmonary vascular resistance. In IL-1β and TNF-α, on the other hand, there was no correlation between cytokines and pulmonary hemodynamics. Pathological specimens obtained from the patients with CTEPH undergoing thromboendarterectomy demonstrated immunoreactivity of MCP-1 in endothelium, smooth muscle cells, and macrophages within neointima in the hypertensive large elastic pulmonary artery. We conclude that MCP-1 is upregulated in the remodeling of pulmonary arteries in close association with increased pulmonary vascular resistance in CTEPH.

Although pulmonary thromboendarterectomy is an effective modality for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), the mortality in patients with severe haemodynamic disease is still high. Recently it was reported that fractional pulse pressure (pulmonary arterial pulse pressure/mean pulmonary arterial pressure) was higher in CTEPH than in primary pulmonary hypertension (PPH). It was hypothesized that fractional pulse pressure might be low in CTEPH with inaccessible distal thrombi and/or secondary pulmonary hypertensive change, resulting to the high operative mortality. To determine the influence of fractional pulse pressure to the outcome of surgery, 32 patients with CTEPH who had thromboendarterectomy between 1985 and 1998 were studied. Pulmonary haemodynamics and fractional pulse pressure were compared between survivors (n=26) and nonsurvivors (n=6) postoperatively. Those parameters in PPH (n=18) and large vessel pulmonary arteritis (n=6) were also analysed. Fractional pulse pressure in CTEPH (1.23±0.21) was significantly higher than in PPH (0.93±0.22 p=0.0017) and lower than in pulmonary arteritis (1.69±0.32 p=0.03). Fractional pulse pressure in survivors (1.26±0.21) was significantly higher than in nonsurvivors (1.06±0.16 p=0.03). Fractional pulse pressure is a significant predictor for mortality in patients with high pulmonary vascular resistance &gt 1100 dynes·sec·cm-5. To conclude fractional pulse pressure in addition to pulmonary vascular resistance might be useful in predicting for the outcome of surgery, especially in patients with severe haemodynamic impairment.

Pulmonary capillary perfusion was analyzed from videomicroscopic recordings to determine flow switching characteristics among capillary segments in isolated, blood-perfused canine lungs. Within each alveolus, the rapid switching pattern was repetitive and was, therefore, nonrandom (fractal dimensions near 1.0). This self-similarity over time was unexpected in a network widely considered to be passive. Among adjacent alveoli, the relationship among the switching patterns was even more surprising, for there was virtually no relationship between the perfusion patterns (coefficients of determination approaching zero). These findings demonstrated that the perfusion patterns in individual alveolar walls were independent of their next-door neighbors. The lack of dependence among neighboring networks suggests an interesting characteristic: the failure of one alveolar-capillary bed would leave its neighbors relatively unaffected, a feature of a robust design.

Primary pulmonary hypertension (PPH) is a progressive disease of unknown etiology usually followed by death within 5 years after diagnosis. Although heart-lung or lung transplantation is now offered to patients with advanced PPH, adequate criteria assessing an accurate prediction of life expectancy in PPH has been difficult to establish. The aims of this study were to identify the characteristic features associated with a poor prognosis in patients with PPH, and to attempt to establish an individual prognostic index that predicts with great accuracy survival or death of PPH after one year, thereby helping to define criteria for patient selection for transplantation. In 1991, a retrospective nation-wide survey on PPH was conducted in Japan, and the clinical and cardiorespiratory variables of 223 PPH cases (female 144, male 79) in the period from 1980-1990 were obtained. The mean pulmonary arterial pressure (PPA) was 57.5 ± 17.2 mmHg (mean ± SD), and the overall median survival time was 32.5 months since the first diagnostic catheterization. The characteristic features of 61 patients who died within one year of catheterization (Nonsurvivors group) were compared to 141 patients who survived one year or more from the time of catheterization (Survivors group). Among several clinical and cardiorespiratory variables, heart rate, PPA, right atrial pressure (PRA), stroke volume index (SI), pulmonary vascular resistance, and partial pressure of carbon dioxide (PaCO2) were significantly different between the two groups. As the independent factors, PPA, PRA, SI, and PaCO2 were selected for the multiple logistic analysis. Using a 0.7 probability cut-point to separate Nonsurvivors from Survivors, 84.6% of Nonsurvivors and Survivors could be correctly predicted from this logistic regression equation. Predictive equations like the present preliminary one can be used in the future to better assess life expectancy in patients with PPH in whom transplantation will be considered.

There is little information on the distribution of acinar perfusion because it is difficult to resolve blood flow within such small regions. We hypothesized that the known heterogeneity of arteriolar blood flow and capillary blood flow would result in heterogeneous acinar perfusion. To test this hypothesis, the passage of fluorescent dye boluses through the subpleural microcirculation of isolated dog lobes was videotaped by using fluorescence microscopy. As the videotapes were replayed, dye-dilution curves were recorded from each of the tributary branches of Y-shaped venules that drained an acinus. From the dye curves, we calculated the mean appearance time of each curve. The difference in mean appearance times between venular tributary branches was small in most cases. In 43% of the observed venular branch pairs, the dye curves were essentially superimposable (the mean appearance-time difference was &lt 5%) and in another 42%, the mean appearance- time difference between curves was 5-10%. From these results, we conclude that acinar perfusion is unexpectedly homogeneous.

We evaluated arterial and mixed venous oxygen desaturation during symptom-limited exercise in patients with chronic pulmonary disease. Patients were divided into five groups according to disease: [chronic pulmonary emphysema (CPE), chronic bronchitis (CB), pulmonary tuberculosis sequalae (TB-seq), fibrosing lung disease (FLD), and pulmonary vascular disease (PVD)]. There were no significant difference in the values of arterial (PaO2) and mixed venous (Pv̄O2) oxygen tension before and at the end of exercise among the five groups, whereas absolute decreases in Pv̄O2 were significantly larger in PVD and FLD. The changes in Pv̄O2 were similar to the changes in the coefficient of oxygen delivery (COD) which is equal to oxygen transport divided by oxygen consumption. These results suggest that the relative decrease in oxygen transport during exercise due to the high ratio of oxygen extraction by tissues is an important factor to determine decreases in Pv̄O2 in pulmonary hypertensive disease and fibrosing lung disease.

We examined a relationship between tissue hypoxia and pulmonary hemodynamics or ventilatory capacity during rest and exercise in patients with tuberculosis sequelae. Nine patients performed exercise test until their symptom limit. Mean pulmonary arterial pressure (̄(PA)) during exercise was plotted against cardiac index (C.I.) from rest to maximum exercise in each patient. In most of the patients, the changes of ̄(PA) showed linear relation with the C.I., and a slope (P-F slope) was obtained from the regression equation in each patient, and it was used as an index of circulatory disability during exercise. At the same time a coefficient of oxygen delivery (COD) was calculated and mixed venous oxygen tension (P̄O2) was measured to evaluate a tissue hypoxia at rest and during exercise. The changes of COD were similar to those of P̄O2 during exercise. COD positively correlated with (P̄O2) was measured to evaluate a tissue hypoxia at rest and during exercise. The changes of COD were similar to those of P̄O2 during exercise. COD positively correlated with P~2 (R=0.873, P&lt 0.01) from rest to maximal exercise, indicating that the values of P̄O2 depended on those of COD. P-F slope negatively correlated with S.I. (R=-0.887, P&lt 0.01), oxygen transport (R=-0.780, P&lt 0.01), COD (R=-0.827, P&lt 0.01) and P̄O2 (R=-0.760, P&lt 0.01) at maximal exercise. Whereas no significant relationship between ventilatory variables and COD or P̄O2 was noted at maximal exercise. In conclusion, the patients with pulmonary tuberculosis sequelae who had a steep P-F slope showed low mixed venous oxygen tension during exercise as a result of limited oxygen transport in consequence of low stroke volume.

Seventy-two patients with chronic obstructive pulmonary disease (COPD) underwent right heart catheterization when they were clinically stable and the relationship between length of survival and acute pulmonary vascular response to 100% oxygen inhalation was studied. Oxygen inhalation significantly reduced mean pulmonary arterial pressure (P̄PA), cardiac index (CI), and pulmonary arteriolar resistance (PAR). The percent change in PAR (%ΔPAR) was used as an index of the acute pulmonary vascular response to 100% oxygen inhalation. Each patient was classified as a responder (%Δ PAR≤15%) or a nonresponder (%Δ PAR&lt 15%). The cumulative survival rates of these two groups were compared. Responders survived significantly longer than did nonresponders (mean survival times were 2571 days and 1432 days, respectively). The two groups did not differ significantly in anthropometic data, pulmonary hemodynamics, or blood gas data measured at base line during air inhalation. However, FEV1 and VC were significantly lower in nonresponders than in responders. The %Δ PAR was not significantly related to age, P̄PA, PAR on air inhalation, FEV1, FEV1%, VC, or %VC. We conclude that the pulmonary vascular response to oxygen inhalation (%Δ PAR) may be an independent prognostic factor in patients with COPD.

A 38-year-old woman was referred to our hospital for severe pulmonary hypertension (pulmonary arterial pressure 63/36 mmHg). Digital subtraction angiography showed complete obstruction of the right main pulmonary artery and severe stenosis of the left main pulmonary artery. Although there were no symptoms or signs of systemic arterial lesions, the initial diagnosis was aortitis syndrome with pulmonary arterial involvement, and prednisolone therapy was started (60 mg/day). Pulmonary arterial pressure decreased to 53/12 mmHg. At a dosage of 20 mg/day, however, multiple nodular shadows were present on the X-ray film of the chest, but they disappeared after the dosage was increased. The level of anti-myeloperoxidase antibodies in her serum changed at almost the same time as multiple nodular shadows appeared on the chest X-ray film. Because anti-MPO antibodies have been never detected in patients with aortitis syndrome, polyangitis overlap syndrome was suspected. However, we found no evidence of systemic vasculitis that is, vasculitis in other organs, including the kidney and the skin. Therefore, we made a diagnosis of idiopathic pulmonary arteritis with positive anti-MPO antibodies.

Twenty-eight COPD patients underwent right heart catherterization while in clinically stable condition. Pulmonary vascular response to oxygen was evaluated by the percent change in pulmonary arteriolar resistance after 100% oxygen inhalation (%ΔPAR), and its relation to the pressure-flow relationship during incremental exercise was assessed. Mean pulmonary arterial pressure (P̄(PA)) during exercise was plotted against the cardiac index (C.I.) from rest to maximal exercise in each patient. In most of the patients, the changes in P̄(PA) were nearly linear to the C.I. Therefore, a slope could be obtained from the regression equation in each patient. Patients were divided into two groups according to whether their %ΔPAR was greater than 20 defined as a respender (RES), or less than five defined as a non-responder (N-RES). Seven out of 28 patients were RES, nine were N-RES, RES showed a higher %FEV1.0 level, C.I. and stroke volume index (S.I.) at maximal exercise, and a lower level of RV/TLC as well as slope. The slope correlated significantly with %DLco (r=-0.724, p&lt 0.01), baseline PAR (r=0.562, p&lt 0.01) and %ΔPAR (r=-0.522, p&lt 0.01). These results suggest that the diminished pulmonary vascular bed, and the distensibility of pulmonary vessels, appear to contribute to the steepness of the slope and reduced %ΔPAR in patients with COPD.

健常者5例および胸部疾患患者35例に対し, 心電図同期スピン・エコー法により Magnetic Resonance Imaging を施行し右主肺動脈内腔の血流信号を観察した. 疾患例では, 右心カテーテル検査成績とも比較し, その臨床的意義を検討した. 心拡張期には, 健常者, 疾患例ともに殆どの例で有意な血流信号が認められたが, 収縮期には疾患例の一部にのみ認められた. 疾患例において, 収縮期に有意な信号が認められた群と認められない群とでは, 平均肺動脈圧, 肺小動脈抵抗, 心係数のそれぞれの平均値の間に有意な差が認められ, 前者の群で増悪していた. また血流信号の強度と平均肺動脈圧とは有意な相関がなかったのに対し, 肺小動脈抵抗とは正の, 心係数とは負の有意な相関がみられた. 肺動脈内血流信号は, 心拍出量の低下がもたらす血流速度の減少に伴って増強すると推定され, 胸部疾患患者における右心不全評価の臨床的指標の一つとして有用であると考えられる.

A 72-year-old female was admitted to our hospital because of bronchorrhea and diffuse infiltrative shadows on chest x-ray. The TBLB specimens suggested adenocarcinoma with a bronchiolo-alveolar pattern. This case was clinically diagnosed as bronchiolo-alveolar cell carcinoma. Corticosteroids were not effective and she died of respiratory failure about 3 months after the admission. Autopsy findings showed a 5 X 4 x 2cm mass at the tail of the pancreas. The specimens obtained from the lung tissue showed tumor cells growing as a single layer along alveolar walls. The features of the lesion in the lung were pathologically similar to those of the lesion in the tail of the pancreas. Further examination revealed metastatic pulmonary adenocarcinoma of pancreatic origin. Comparative analyses of biochemical components in sputum in this case and previous reports showed that levels of fucose, albumin, and DNA were low in this case. It was suggested that this excessive production of sputum was due to abnormal secretion of tumor cells rather than exudation of plasma constituents and inflammatory change in the airways. © 1991, The Japan Lung Cancer Society. All rights reserved.

In an open, prospective, multicenter trial the clinical efficacy of imipenem/cilastatin sodium (IPM/CS) for the treatment of 14 cases with aspiration pneumonia was investigated. The mean age was 75.4 years old. Diseases of central nervous system were present in 11 cases, cardiovascular diseases, pulmonary diseases and diabetes mellitus in 2 cases each respectively. Seven cases were community-acquired and another seven were hospital-acquired. Six cases were moderate and 8 cases were severe. Causative organisms were determined in 9 cases (64.3%),multiple causative organisms were isolated in 3 cases. Isolated organisms were Staphylococcus aureus (4),Pseudomonas aeruginosa (3), Klebsiella pneumoniae (3), Escherichia coli (1), Acinetobacter calcoaceticus (1). Detection of anaerobes was not attempted. Clinical effects of IPM/CS were excellent in 3, good in 8, fair in 2, poor in 1, the efficacy rate was thus 78.6%. P. aeruginosa was isolated from 2 out of 3 cases in which therapy with IPM/CS failed. Monotherapy with IPM/CS appears to be highly effective for cases of aspiration pneumonia, but the disease due to IPM-resistant P. aeruginosa is an exception. © 1990, Japan Antibiotics Research Association. All rights reserved.

In an open, prospective, multicenter trial we investigated the clinical efficacy of Imipenem/cilastatin sodium (IPM/CS) for the treatment of pulmonary infection. Out of 129 cases collected, 103 could be evaluated for utility of IPM/CS: 83 with pneumonia (49 moderate and 34 severe cases), 6 with lung abscess, 5 with empyema, 9 with chronic bronchial infection caused by Pseudomonas aeruginosa. In 83 cases of pneumonia, the mean age was 67.6 years old, significant underlying diseases were present in 87.9%, and 21 cases (25.3%) were hospital-acquired. Causative organisms were determined in 36 cases (43.4%), and multiple causative organisms were isolated in 5 cases. The principal pathogens were Streptococcus pneumoniae (8), Staphylococcus aureus (8), P. aeruginosa (8), Haemophilus influenzae (6), Klebsiella pneumonia (6). The efficacy rate of the cases of pneumonia in monotherapy with IPM/CS was 84.6%: moderate 87.2%, severe 80.6%, community-acquired 91.7%, and hospital-acquired 61.1%. Monotherapy with IPM/CS was highly effective in cases of aspiration pneumonia. The efficacy rate in cases in which the causative organism was P. aeruginosa was low (50.0%). The efficacy rate of the cases of lung abscess was 100% and of empyema was 50.0%. Of 9 cases of chronic bronchial infection due to P. aeruginosa, in 5 cases treated with IPM/CS combined with tobramycin and I case treated combined with amikacin, the efficacy rate was 66.6% and the eradication rate 33.3%. We consider monotherapy with IPM/CS to be highly effective in cases of moderate and severe pneumonia, with the exception of disease due to imipenem-resistant P. aeruginosa. © 1990, Japanese Society of Chemotherapy. All rights reserved.