[Two cases of Churg-Strauss syndrome with impaired prognosis].

We report two cases of Churg-Strauss syndrome with impaired prognosis. Case 1: A 58-year-old woman started to complain of progressive dysesthesia and muscle weakness of the lower extremities on February 6, 1992 and was admitted to our hospital eight days later. The eosinophil count was 1, 170/microliters and chest X-ray on admission revealed bilateral diffuse interstitial shadows. Necrosis of muscle fibers and significant infiltration of eosinophils into vessel walls were histopathologically demonstrated. Case 2: A 69-year-old woman was admitted to our hospital with productive cough and back pain. An expiratory wheeze was audible in all lung fields and bronchial asthma was diagnosed. Laboratory findings showed eosinophilia (8, 550/microliters), an IgE level of 16, 266 IU/ml and no positive data for allergic bronchopulmonary aspergillosis. A biopsy of subcutaneous nodules in the lower extremity revealed significant edema of vessel walls and infiltration eosinophils and lymphocytes. Churg-Strauss syndrome was diagnosed in both cases, and corticosteroid therapy was successful in alleviating eosinophilia. However, symptoms of vasculitis in case 1, including mononeuritis multiplex, did not improve, and cardiomyopathy in case 2 progressively worsened. Particularly in elderly patients, it is very important to make an early diagnosis and to initiate therapy that does not disturb quality of life, even for diseases generally regarded as having a good or fair prognosis.

1 alpha, 25-dihydroxyvitamin D3 and all-trans-retinoic acid inhibit the growth of a lung cancer cell line.

The secosteroid 1 alpha, 25-dihydroxyvitamin D3 (calcitriol) and retinoic acid are the major biologically active metabolites of vitamins D and A, respectively. Their antitumor activity has been observed in several cancer cells in vitro apart from lung cancer cells. The purpose of this study was to examine the possible effects of the agents on lung cancer cell lines. The responses of five lung cancer cell lines to calcitriol or all-transretinoic acid (RA) were assessed by a colorimetric MTT assay. Calcitriol inhibited growth in one of the tested cell lines, i.e. EBC-1 squamous cell carcinoma, dose dependently. RA also exhibited the same effect in EBC-1 cells. However neither agent affected the growth of other lung cancer cell lines. Subsequently we examined the mRNA expression of vitamin D receptor (VDR) and retinoic acid receptor (RAR alpha) in these lung cancer cells by quantitative RT-PCR. EBC-1 cells expressed high levels of mRNA for both VDR and RAR alpha, while other cell lines expressed much lower mRNA levels for the receptors. These data suggest that the growth inhibitory effects of the vitamins are associated with mRNA expression for VDR and RAR alpha.

Stimulatory effect of 1 alpha,25-dihydroxyvitamin D3 on mouse alveolar macrophage tumor necrosis factor-alpha production in vitro: involvement of protein kinase C and Ca2+/calmodulin-dependent kinase.

1 alpha,25-Dihydroxyvitamin D3 [1 alpha,25(OH)2D3, calcitriol] has been shown to modulate the immune function of peripheral monocytes and peritoneal macrophages. However, its effect on alveolar macrophage (AM) cytokine secretion has not been reported. We therefore investigated the influence of calcitriol on tumor necrosis factor (TNF-alpha) production by murine AMs and attempted to elucidate changes in the signal transduction system involved in such effects. Calcitriol significantly enhanced TNF-alpha secretion by AM stimulated with either lipopolysaccharide (LPS; 10 micrograms/ml; p < 0.005) or phorbol 12-myristate 13-acetate (PMA; 100 ng/ml; p < 0.05) at low doses (between 10(-11) and 10(-9) M). However the protein kinase C (PKC) inhibitor, H7 (10 microM), and the Ca2+/calmodulin inhibitor, W7 (25 microM), reversed such calcitriol effects. Calcitriol increased the total PKC activity of AMs. These findings indicate that calcitriol enhances both LPS- and PMA-stimulated TNF-alpha secretion through PKC- or Ca2+/calmodulin-dependent pathways.

[Influence of age on mouse pulmonary alveolar macrophage clonal growth].

Although monocyte influx has been suggested as the primary source of pulmonary alveolar macrophages (AM), increasing evidence from recent studies has indicated that AM may be sustained through a self-renewal mechanism. We evaluated the age-related changes of the clonal growth (colony formation) of AM in mice (C57BL/6N mice and senescence accelerated mice). The colony forming unit (CFU) of AM of 24 month old C57BL/6N mice was lower than that of AM of 4-month-old mice (p < 0.05). In SAMP6 (senescence accelerated mice), CFU of AM was decreased with aging (p < 0.05). In SAMR1 (controls for SAMP6), CFU of AM was decreased with aging (p < 0.001). In SAMR1, CFU of bone marrow (BM) adherent cells of 12-month-old mice was similar to that of 4-month-old mice. In SAMP6, CFU of BM adherent cells of 12-month-old mice was larger than that of 4-month-old mice (P < 0.005). It was concluded that the CFU of AM declined with aging, but the CFU of the BM adherent cells did not. The decline of the AM CFU may be partly responsible for the defect of the immune response of the alveolar space in the elderly.

Effect of aging on plasma 1,5-anhydroglucitol levels in humans and rats.

Since normal reference values change with age in some clinical parameters, we measured the plasma levels of 1,5-anhydroglucitol (AG), a new marker of glycemic control in diabetes mellitus, in healthy subjects and in rats. Our results showed a significantly negative correlation of the marker with age in humans and that the plasma AG levels of older rats were markedly lower than those of younger counterparts. This remarkable reduction of AG in the older rat group can be partially explained by our finding that aged animals excreted AG more rapidly in the urine than younger ones, besides a decrease in food intake. We therefore suggest that normal clinical reference values for plasma AG levels should be modified according to age.

Effect of ageing on erythrocyte aldose reductase and sorbitol dehydrogenase activity.

We measured erythrocyte aldose reductase and sorbitol dehydrogenase activity in erythrocytes in healthy individuals aged from 16 to 91 years to determine the mechanism of age-dependent sorbitol accumulation. Erythrocyte aldose reductase activity increased significantly with age but ageing had no effect on sorbitol dehydrogenase activity. Age and the aldose reductase/sorbitol dehydrogenase ratio were positively correlated. These findings suggest that an increase in the ratio of aldose reductase to sorbitol dehydrogenase may contribute to the tissue accumulation of sorbitol in the elderly and may be a mechanism of a disease that is common in elderly individuals.

Treatment of malignant tracheobronchial stenosis by Dacron mesh-covered Z-stents.

Z-stents partially covered with an expandable Dacron mesh into which epinephrine and thrombin were infiltrated, were used to reopen both mainstem bronchi, stenosed by bronchogenic carcinoma and to deliver hemostatic agents to the lesion. On follow-up 4 and 6 weeks later, airway patency was retained, the tumor surface was compressed, and the glossy surface of the stent suggested that it was covered with mucosa. For treatment of airway stenosis due to cancer invasion, a stent covered with a Dacron mesh sheet is thought to be effective in compressing the tumor and preventing tumor ingrowth into the stent.

Pharmacokinetic re-evaluation and phase I study of high dose epirubicin in advanced non-small cell lung cancer.

We performed a phase I trial to evaluate the toxicity and the maximum tolerated dose of high dose epirubicin on a three-consecutive-day schedule on Japanese patients with advanced non-small cell lung cancer. Fourteen patients were entered in the study. At least three patients were assigned to each different dose level. Epirubicin was given intravenously daily for three day by bolus injection. The dose was started at 60 mg/m2/course and escalated by 30 mg/m2/course. Granulocytopenia was found to be the dose limiting toxicity with a maximum tolerated dose of 150 mg/m2/course. Thrombocytopenia and non-hematological toxicities were mild and well tolerated. The maximum tolerated dose was lower than that in Europe and Canada. Partial responses were observed in two out of five patients on 150 mg/m2/course. The recommended phase II dose for high dose epirubicin was demonstrated to be 120 mg/m2/course. A further dose-escalating study of epirubicin in conjunction with the administration of granulocyte colony stimulating factor is scheduled for the determination of its antitumor activity in non-small cell lung cancer.

[Effects of aerosol oxitropium bromide and fenoterol on maximal exercise capacity in chronic obstructive pulmonary disease and their correlation with air flow during exercise and with parameters of maximal exercise].

To examine the effects of bronchodilators on maximal exercise capacity and their correlation with airflow during exercise in patients with chronic obstructive pulmonary disease (COPD), we conducted a double-blind, randomized comparison between inhaled fenoterol (beta 2-agonist) and oxitropium bromide (anticholinergic agent) in 8 patients with stable COPD (mean age 73 years, mean FEV1 1.1 L, mean FEV1% 50%). Only oxitropium bromide resulted in statistically significant improvement in FEV1 40 min after inhalation. On maximal exercise, fenoterol did not affect oxygen uptake (VO2 max), minute ventilation (VEmax), respiratory frequency (Rfmax), ventilatory efficacy (VEmax/VO2 max), peak expiratory flow during exercise (PEFmax), heart rate (HRmax) and dyspnea (Borg Scale Slope). After oxitropium bromide, dyspnea during exercise and HRmax decreased significantly, but PEFmax and other parameters did not change significantly compared with control. There was no correlation between changes in dyspnea during exercise and changes in FEV1 and PEFmax after oxitropium bromide inhalation. We conclude that inhaled oxitropium bromide, an anticholinergic agent, reduces dyspnea during exercise in patients with COPD. This favorable effect was not due to change of airflow limitation during exercise, and other factors can thus influence reduction of dyspnea during exercise in these patients.

[A case of pulmonary embolism probably induced by long term use of oral contraceptive].

We present a 53-year-old female with pulmonary embolism (PE), who had been taking oral contraceptive for 13 years. She was admitted to our hospital with upper abdominal pain and was found to be in shock. The diagnosis of PE was made from chest X-ray examination, electrocardiogram and pulmonary angiography. Pulmonary hypertension was observed on right heart catheterization, and an anticoagulant was administered. Multiple defects of the right pulmonary artery were detected on lung perfusion scan, and there were no significant findings on leg phlebogram. Home oxygen therapy was effective for the treatment of pulmonary hypertension and chronic hypoxemia which still persisted after her recovery from the acute stage. We are concerned that wide spread use of oral contraceptives will increase the incidence of PE in the near future in this country. We conclude that contraceptive users should be warned of their higher risk of PE, and that they should visit a clinic for examination.

[A case of Wegener's granulomatosis complicated by hypopituitarism].

A 71-year-old male complaining of chest pain was admitted to our hospital. A single cavitary mass shadow was observed on chest X-ray films. Urinalysis revealed microscopic hematuria. CT examination demonstrated a tumorous shadow in the maxillary sinus. The diagnosis of Wegener's granulomatosis was histologically established by biopsy specimens from the nasal mucosa which showed necrotizing vasculitis and granuloma with fibrinoid degeneration. He was treated with combination therapy of prednisolone and cyclophosphamide. The abnormal shadows on chest X-ray and in the maxillary sinus on CT improved rapidly, but the patient developed progressive weight loss and complained of cold intolerance, weakness and dysphagia. Serum T3, T4 and TSH were found to be reduced. Anterior pituitary function tests showed reduction of TSH, GH and ACTH responses, which was probably due to irreversible vasculitis.

Idiopathic acute eosinophilic pneumonia.

A previously healthy young man presented with acute respiratory distress, high fever and bilateral ground-glass appearance on chest radiograph. Bronchoalveolar lavage analysis demonstrated significant eosinophilia (72%) with no evidence of infection. The transbronchial lung biopsy showed that the walls of bronchioli and alveolar septa were markedly infiltrated with eosinophils. The patient rapidly improved with corticosteroid therapy. This case exemplifies the recently described idiopathic acute eosinophilic pneumonia. Similar cases published in the Japanese literature were reviewed and discussed.

[A case of primary intrapulmonary benign schwannoma].

A case of primary intrapulmonary schwannoma was described. A 72-year-old man was admitted to our hospital because of dry cough. A chest radiograph showed partial atelectasis of the middle lobe, but computed tomogram of the chest revealed no tumor shadow. Bronchoscopy disclosed a pale-yellow uneven endobronchial wall of the right middle lobe bronchus. Transbronchial biopsy revealed benign schwannoma. Primary intrapulmonary schwannoma has been rarely reported.

[Quantitative assessment of dyspnea by introducing new indices based on the Borg scale during exercise test and the correlation with parameters of pulmonary functions at rest].

Incremental exercise test with a bicycle ergometer was performed on thirty eight patients (11 patients with chronic obstructive pulmonary disease, 6 patients with interstitial lung disease, 21 patients with preoperative check up for respiratory disease). In 34 patients except four patients with interstitial lung disease, there was a close correlation between dyspnea expressed on the Borg scale (BS) and oxygen consumption (VO2) (r = 0.778-0.998). To evaluate dyspnea in more quantitative manner, we introduced three parameters by the BS-VO2 regression line. The Borg scale slope (BSS) represents the slope of the regression line, threshold load of dyspnea (TLD) represents the onset of dyspnea on the regression line, and the breakpoint load of dyspnea (BLD) represents the maximum oxygen consumption before the subject interrupted exercise. BSS had significant negative correlations with VC, %VC, FEV1.0, TLC, DLco, and %DLco. TLD and BLD had significant positive correlations with VC, FEV1.0, DLco, and %DLco. No correlation was found between dyspnea evaluated by the Hugh-Jones classification and the parameters of pulmonary functions (VC, FEV1.0, DLco) at rest. From these findings, we conclude that the degree of dyspnea sensation on exercise correlated with parameters of pulmonary function at rest, and that these newly introduced parameters using the Borg scale were useful for a quantitative assessment of dyspnea in health and disease.

Effect of endothelin-1 on pulmonary resistance in rats.

We examined the effect of endothelin-1 (ET-1), a novel 21-residue vasoconstrictor peptide, on pulmonary resistance (RL) in Wistar rats. The lung volume, tracheal flow, and transpulmonary pressure of tracheotomized and paralyzed rats were measured with a fluid-filled esophageal catheter and a pressure-sensitive body plethysmograph. RL was calculated by the method of von Neergaard. The femoral artery was cannulated to measure the mean arterial blood pressure. Intravenous bolus administration of synthetic ET-1 provoked a dose-dependent increase in RL in rats. The bronchoconstricting effect reached maximum at 500 pmol/kg. This bronchoconstriction was observed in less than 5 min, increased up to 15 min, and was sustained for 60 min. ET-1 increased the mean arterial blood pressure in a dose-dependent manner. We conclude that ET-1 is a hitherto unknown potent bronchoconstrictor that has a sustained effect in vivo. The potential physiological and pathophysiological role of this new peptide in the development of respiratory disease warrants further investigation.

[The influence of cigarette smoke on metabolism of eicosanoids in rat lung in terms of variation of 15-hydroxyeicosatetraenoic acid and 11-dehydrothromboxane B2].

We investigated the effects of cigarette smoking on metabolism of two eicosanoids, 15-hydroxyeicosatetraenoic acid (15-HETE) and 11-dehydrothromboxane B2 (11-dehydro-TXB2) in the lung. Twelve female Wistar rats aged between 5 and 6 weeks were chosen and the smoking group (SG, n = 6) was compared to the control group (CG, n = 6). Cigarette smoke exposure was performed using a Hamburg-II inhalation apparatus and the dose was 10 cigarettes in 30 min. Bronchoalveolar lavage (BAL) was conducted 30 min after smoking exposure and the recovered BAL fluid was centrifuged at 3000 rpm for 10 min. The levels of 15-HETE and 11-dehydro-TXB2 of the supernatant were measured by radioimmunoassay in each sample. Recovered 15-HETE significantly increased in SG (SG: 490 +/- 109 pg, CG: 191 +/- 63 pg, p less than 0.05), while there was no significant difference in recovered protein (SG: 2.64 +/- 0.50 mg, CG: 2.23 +/- 0.10 mg), 11-dehydro-TXB2 (SG: 128 +/- 13 pg, CG: 156 +/- 7 pg). We conclude that acute cigarette smoke exposure increases recovered BAL fluid 15-HETE, a potent inflammatory mediator and that 15-HETE in BAL fluid may indicate lung injury induced by smoking.

[Immunologic evaluation in patients with lung cancer with special regard to peripheral blood natural killer cell activity and interleukin-2 productivity].

Thirteen patients with lung cancer and 62 age-matched control subjects were investigated in this study (68.5 +/- 2.7 y.o. and 70.5 +/- 1.1 y.o. respectively). The peripheral blood natural killer (NK) cell activity of patients with lung cancer and control subjects was 59.3 +/- 4.4% and 69.3 +/- 1.8%, respectively. The NK cell activity in these patients was significantly lower than the NK activity of control subjects (p less than 0.05). The Interleukin-2 (IL-2) productivity of stimulated peripheral lymphocytes from patients with lung cancer was 4.96 +/- 0.99 unit, and from control subjects was 12.31 +/- 1.51 unit. When compared with control subjects, the IL-2 productivity in the patients with lung cancer was significantly lower (p less than 0.05). There were no differences in values of OKT series or OKT4/OKT8 ratio between these patients and control subjects. Ten of the 13 patients received schizophyllan intramuscularly once a week (40 mg/week). The NK cell activity was significantly increased on the second day after the second injection of schizophyllan, but there was no change in IL-2 productivity. We conclude that the peripheral blood NK cell activity and IL-2 productivity of patients with lung cancer was decreased. The antitumor polysaccharide, schizophyllan, temporarily raised the NK cell activity of these patients.

[Cisplatin combination chemotherapy in advanced lung cancer in the aged].

Eleven aged patients over 65 years of age with advanced lung cancer (mean age = 70.8 +/- 1.4, non-small cell:small cell = 9:2, stage III:IV = 5:6) were treated with combination chemotherapy consisting of cisplatin (50 or 80 mg/m2) and vincaloids (vindesine 3 mg/m2 or etoposide 80 mg/m2). To evaluate this cisplatin combination therapy, the aged group was compared with a young group consisting of eleven patients (mean age = 53.3 +/- 1.7, non-small cell:small cell = 9:2, stage III:IV = 5:6) matched for cell type, stage and dose regimen. The mean dose of cisplatin was 58.2 mg/m2 in the aged and 63.6 mg/m2 in the younger group. A notable reduction in tumor size was observed in 9.1% of the aged and 27.3% of the young, while one-year survival rate was 63.6% in the aged and 72.7% in the young. The common side effects were nausea and vomiting, while diarrhea was seen in 18.2% of the aged. Neutropenia, anemia and thrombocytopenia were found in both groups and the time course of myelosuppression in the aged (18.2 +/- 0.8 days) was significantly shorter than that in the younger patients (22.0 +/- 1.4 days, p less than 0.05). With regard to nephrotoxicity, creatinine clearance rate in the aged decreased remarkably from 56.9 to 38.9 ml/min, while there was no significant change in BUN, serum creatinine and urine NAG between the aged and the young. Disorders of electrolytes such as hypokalemia and hyponatremia were seen in 45.5% of the aged. We conclude that advanced lung cancer in the aged was effectively treated with cisplatin combination therapy with tolerable nephrotoxicity and myelosuppression.