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(Chest. 2004;125:2160-2168.)
© 2004 American College of Chest Physicians

Increased Arteriovenous Carboxyhemoglobin Differences in Patients With Inflammatory Pulmonary Diseases*

Hiroyasu Yasuda, MD; Takahiko Sasaki, MD; Mutsuo Yamaya, MD; Satoru Ebihara, MD; Masahiro Maruyama, MD; Akio Kanda, MD and Hidetada Sasaki, MD, FCCP

* From the Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Japan.

Correspondence to: Hidetada Sasaki, MD, Professor and Chairman, Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan; e-mail: dept{at}geriat.med.tohoku.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Purpose: Exhaled carbon monoxide and arterial blood carboxyhemoglobin concentrations increase in inflammatory pulmonary diseases. The present study was undertaken to elucidate whether arteriovenous carboxyhemoglobin (a-vHb-CO) concentration differences are also useful to define the site of inflammation, either in the lung or organs other than the lung.

Materials and methods: We examined concentrations of carboxyhemoglobin in both arterial and peripheral venous blood and exhaled carbon monoxide in patients with acute pulmonary inflammation including bronchial asthma (n = 18) and pneumonia (n = 33), and those in patients with extrapulmonary inflammatory diseases, including acute pyelonephritis (n = 28) and active rheumatoid arthritis (n = 16).

Results: The values of carboxyhemoglobin in both arterial and peripheral venous blood were significantly higher in patients with pulmonary and extrapulmonary inflammation compared with those in control subjects (n = 22). Furthermore, a-vHb-CO differences in patients with inflammatory pulmonary diseases were higher than those in patients with acute pyelonephritis and patients with rheumatoid arthritis, and than those in control subjects. The a-vHb-CO differences correlated with the WBC count of peripheral venous blood in patients with pneumonia. In patients with bronchial asthma, the a-vHb-CO differences inversely correlated with FEV1, although they did not correlate with WBC count of peripheral venous blood. The a-vHb-CO differences in patients with acute pyelonephritis were higher than those in patients with active rheumatoid arthritis.

Conclusion: The present study suggests that a-vHb-CO differences may be a useful means to define the site of inflammation, either in the lung or organs other than the lung, in patients with a fever of unknown origin. The large a-vHb-CO differences may be caused by carbon monoxide production in pulmonary inflammation.

Key Words: carboxyhemoglobin • heme oxygenase • inflammatory pulmonary disease


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Carbon monoxide is produced endogenously by the class of enzymes known collectively as heme oxygenase (HO).1 HO-1, the inducible form of HO, is produced by various stimuli including proinflammatory cytokines and nitric oxide.1 Carbon monoxide is known to be present in measurable quantities in the exhaled air of normal subjects.23 Exhaled carbon monoxide is increased in patients with inflammatory pulmonary diseases such as bronchial asthma, bronchiectasis, upper respiratory tract infections, and seasonal allergic rhinitis.34567 Treatments with inhaled and oral corticosteroids, which have been shown to reduce airway inflammation, are associated with a reduction in the exhaled levels of carbon monoxide in asthma.38 Furthermore, exhaled carbon monoxide is increased in the exacerbations of bronchial asthma induced by respiratory viruses infections.8

Based on these findings, it has been proposed that measurements of exhaled carbon monoxide may serve as an indirect marker of airway inflammation.345678 However, exhaled carbon monoxide concentration is reported to correlate closely with blood carboxyhemoglobin concentrations over the range of values encountered in smokers and in nonsmokers.2 Furthermore, we demonstrated that carboxyhemoglobin concentration in arterial blood increases in patients with inflammatory pulmonary diseases.9 These findings suggest that the peripheral venous blood carboxyhemoglobin concentration may also increase in patients with inflammatory pulmonary diseases. Meyer et al10 showed increases in blood carboxyhemoglobin from both arteries and central veins in patients treated in an ICU. However, the peripheral venous blood carboxyhemoglobin concentration in inflammatory pulmonary diseases has not been studied.

Carbon monoxide in the arterial blood is consumed in the tissues, in part, via the distribution to extravascular space in the liver.1112 This carbon monoxide consumption may relate to the arteriovenous carboxyhemoglobin (a-vHb-CO) concentration differences in normal subjects and critically ill patients.10 HO-1 expression is increased in alveolar macrophages in patients with bronchial asthma,4 and increased in airway and lung epithelial cells in response to proinflammatory cytokines and oxidant stress.1314 Therefore, carbon monoxide production in the pulmonary inflammation may increase the carboxyhemoglobin concentration in the arterial blood, and high a-vHb-CO concentration differences may be another indirect marker of pulmonary inflammation. However, a-vHb-CO differences have not been studied in patients with inflammatory pulmonary diseases. In the present study, we determined whether the carboxyhemoglobin concentration in the peripheral vein blood and the a-vHb-CO differences are increased in patients with inflammatory pulmonary diseases including bronchial asthma and pneumonia, compared with those in patients with extrapulmonary inflammation and control subjects.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
We studied 22 normal control subjects (mean ± SE age, 62.2 ± 3.9 years), 18 patients with bronchial asthma (61.8 ± 4.2 years), 33 patients with acute pneumonia (71.2 ± 2.6 years), 28 patients with acute pyelonephritis (67.7 ± 3.5 years), and 16 patients with active rheumatoid arthritis (57.2 ± 4.9 years). In 22 control subjects, there was no history of respiratory or cardiovascular diseases. None of these control subjects were receiving long-term medication. Asthma was defined as a clinical history of intermittent wheeze, cough, chest tightness, or dyspnea, and a documented reversible airflow limitation either spontaneously or with treatment during the preceding year.15 All patients had been treated with an inhaled corticosteroid (beclomethasone dipropionate, 400 to 1,200 µg/d). An oral bronchodilator (procaterol hydrochloride, 50 to 100 µg/d) was administered to 8 of 18 patients with bronchial asthma. Furthermore, inhaled ß-agonist (fenoterol hydrobromide, 200 µg/puff, or procaterol hydrochloride, 10 µg/puff) were also used on demand to relieve wheezing in another 10 of 18 patients with bronchial asthma. All 18 patients with bronchial asthma had a clinical history of these symptoms and a reversible airflow limitation. Pneumonia was defined as a pulmonary infiltrate shown on a chest radiograph, cough, and a temperature > 38.0°C, or subjective dyspnea.16 All 33 patients with pneumonia had the features of pulmonary infiltrate shown on a chest radiograph, and cough and a temperature > 38.0°C. Acute pyelonephritis was defined as pyuria, flank pain, and/or costovertebral angle tenderness, and a temperature > 38.0°C.17 Rheumatoid arthritis was defined according to the American College of Rheumatology classification criteria including morning stiffness, arthritis of three or more joint areas, arthritis of hand joints, symmetric arthritis, rheumatoid nodules, serum rheumatoid factor, and radiographic changes typical of rheumatoid arthritis.18 All the subjects lived uptown in Sendai City in Miyagi Prefecture with the same environment. We excluded patients with pleuropulmonary diseases such as interstitial pneumonitis and pleuritis secondary due to systemic rheumatoid arthritis, because they had not only peripheral inflammation in the extremities but also active intrapulmonary inflammation. Fourteen of 22 control subjects, 13 of 18 patients with bronchial asthma, 11 of 33 patients with pneumonia, 11 of 28 patients with acute pyelonephritis, and 10 of 16 patients with rheumatoid arthritis were nonsmokers, while other control subjects and patients were ex-smokers who stopped smoking for at least 3 months before this study. To exclude current smokers, we measured urinary cotinine concentrations with high-performance liquid chromatography as described previously.19 The concentrations of urinary cotinine were expressed as nanograms per milliliter. To adjust for urinary dilution, urinary cotinine concentrations were standardized to urinary creatinine concentrations and expressed as cotinine/creatinine ratios.20 These urinary cotinine/creatinine ratios were calculated by dividing the urinary cotinine concentration by the urinary nicotine concentration.20 Because urinary nicotine concentrations were expressed as milligrams per milliliter, the cotinine/creatinine ratios were expressed as nanograms per milligram.20 The study was approved by the Tohoku University Ethics Committee, and informed consent was obtained from each subject.

Measurement of Carboxyhemoglobin and Exhaled Carbon Monoxide
We took arterial blood from the radial artery, and peripheral venous blood from the median forearm, basilic, or cepharic vein, in order to measure the carboxyhemoglobin concentration with a spectrophotometer (ASL System; Radiometer; Copenhagen, Denmark) as previously described.2921 We measured the carboxyhemoglobin concentration three times using the same blood sample, and calculated the mean value. The differences in the arterial blood concentrations and in the peripheral venous blood carboxyhemoglobin concentrations among three measurements of the same blood samples were within 0.1%, suggesting no significant variability of the carboxyhemoglobin concentrations (data not shown). Furthermore, in the preliminary study in a patient, we found that the differences in the arterial blood carboxyhemoglobin concentrations and the peripheral venous blood carboxyhemoglobin concentrations among the blood samples obtained three times with 5-min intervals were also within 0.1% (data not shown). The calibration of the spectrophotometer was performed by zero-point calibration according to the instruction manual. Exhaled carbon monoxide was measured on a portable Bedfont EC50 analyzer (Bedfont Technical Instruments; Sittingbourne, UK) as previously described.23678 It has been shown that exhaled carbon monoxide can be a reflection of passive smoking in children, suggesting the influence of ambient carbon monoxide on the values of exhaled carbon monoxide.20 Therefore, in the present study, we determined the exhaled carbon monoxide by subtracting the background levels from the observed reading as described previously.3678 Furthermore, the estimation of carboxyhemoglobin from exhaled carbon monoxide measurements can be inaccurate in patients with severe airflow obstruction.22 Therefore, we excluded patients in whom the FEV1/FVC ratio was < 45%.22

Study Protocol
In all patients with bronchial asthma, the carboxyhemoglobin concentration was measured on admission to hospital due to exacerbations. Likewise, carboxyhemoglobin concentration was measured in all patients with pneumonia, all patients with acute pyelonephritis, and all patients with rheumatoid arthritis at the onset of illness. To examine the relationship between carboxyhemoglobin and exhaled carbon monoxide concentration, exhaled carbon monoxide concentration was also measured in all 51 patients with inflammatory pulmonary diseases, in all 28 patients with acute pyelonephritis, and in all 16 patients with rheumatoid arthritis.

Statistical Analysis
The age, carboxyhemoglobin concentrations, a-vHb-CO differences, and exhaled carbon monoxide concentrations in each group are reported as mean ± SE. Statistical analysis of these data were performed by one-way analysis of variance and followed by the Newman-Keuls test. Linear regression analysis was performed using the method of least squares, to compare the relationship between the exhaled carbon monoxide and carboxyhemoglobin concentrations, between the arterial carboxyhemoglobin concentrations and FEV1, and between the a-vHb-CO differences and either the WBC count or FEV1. Significance was accepted at p < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Subjects
In control subjects, the arterial blood carboxyhemoglobin concentrations in ex-smokers (n = 8) did not differ from those in nonsmokers (n = 14). Furthermore, urinary cotinine concentrations of all control subjects and patients were < 30 ng of the cotinine per milligram creatinine ratio, the level used to categorize subjects as exposed and unexposed to cigarette smoking,20 showing that the ex-smokers in control subjects and patients were not current smokers. Therefore, we analyzed the data including those from nonsmokers and ex-smokers together, in control subjects, and patients.

Carboxyhemoglobin Concentrations
The values of carboxyhemoglobin in both arterial blood (Fig 1 , top, A) and peripheral venous blood (Fig 1, bottom, B) were significantly higher in patients with bronchial asthma and pneumonia, and those in patients with acute pyelonephritis, and in patients with active rheumatoid arthritis compared with those in control subjects (n = 22). Furthermore, a-vHb-CO concentration differences in patients with bronchial asthma and with pneumonia were significantly higher than those in patients with acute pyelonephritis and in patients with active rheumatoid arthritis, and those in control subjects (Fig 2 ). a-vHb-CO concentration differences in patients with acute pyelonephritis were also significantly higher than those in patients with active rheumatoid arthritis. In contrast, a-vHb-CO concentration differences in patients with acute pyelonephritis did not differ from those in control subjects (Fig 2).



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  		Figure 1.. Arterial blood carboxyhemoglobin (a Hb-CO) [top, A] and peripheral venous blood carboxyhemoglobin (v Hb-CO) [bottom, B] concentrations in control subjects (n = 22), and patients with bronchial asthma (n = 18), pneumonia (n = 33), acute pyelonephritis, (n = 28), and active rheumatoid arthritis (Active RA, n = 16). Mean values are indicated by horizontal bars.

 


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  		Figure 2.. a-v Hb-CO concentration differences in control subjects (n = 22), and patients with bronchial asthma (n = 18), pneumonia (n = 33), acute pyelonephritis (n = 28), and active rheumatoid arthritis (n = 16). Mean values are indicated by horizontal bars. N.S. = not significant. See Figure 1 legend for expansion of abbreviation.

 
Exhaled Carbon Monoxide and Carboxyhemoglobin Concentrations
Exhaled carbon monoxide concentrations were significantly correlated with the carboxyhemoglobin concentrations in both arterial blood and peripheral venous blood in patients with inflammatory pulmonary diseases, including bronchial asthma and pneumonia (n = 51, r = 0.63, p < 0.0001 in arterial blood carboxyhemoglobin; r = 0.46 and p < 0.001 in peripheral venous blood carboxyhemoglobin), and in patients with extrapulmonary inflammatory diseases including acute pyelonephritis and active rheumatoid arthritis (n = 44, r = 0.81, p < 0.0001 in arterial blood carboxyhemoglobin; r = 0.46 and p < 0.01 in peripheral venous blood carboxyhemoglobin).

WBC Count, FEV1, and a-vHb-CO Concentration Differences
The WBC count of peripheral venous blood in patients with bronchial asthma (n = 18, 6,728 ± 386/µL, p < 0.001), in patients with pneumonia (n = 33, 11,201 ± 400/µL, p < 0.0001), in patients with acute pyelonephritis (n = 28, 8,252 ± 626/µL, p < 0.0001), and in patients with active rheumatoid arthritis (n = 16, 7,628 ± 389/µL, p < 0.0001) was significantly higher than that in control subjects (n = 22, 5,178 ± 212/µL). The WBC count of peripheral venous blood correlated with arterial blood carboxyhemoglobin concentrations (Fig 3 , top left, A) and a-v Hb-CO concentration differences (Fig 3, top right, B) in patients with pneumonia. In contrast, the WBC count of peripheral venous blood did not correlate with arterial blood carboxyhemoglobin concentrations (Fig 3, top center left, C) and a-vHb-CO concentration differences (Fig 3, top center right, D) in patients with bronchial asthma. In patients with pyelonephritis, the WBC count of peripheral venous blood correlated with arterial blood carboxyhemoglobin concentrations (Fig 3, bottom center left, E), but did not correlate with a-vHb-CO concentration differences (Fig 3, bottom center right, F). In contrast, in patients with rheumatoid arthritis, the WBC count of peripheral venous blood did not correlate with arterial blood carboxyhemoglobin concentrations and a-vHb-CO concentration differences (Fig 3, bottom left, G, and bottom right, H). In patients with bronchial asthma, FEV1 inversely correlated with arterial blood carboxyhemoglobin concentrations (Fig 4 , top, A) and a-vHb-CO concentration differences (Fig 4, bottom, B), at the visit to the hospital due to exacerbations.



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  		Figure 3.. Relationship between the WBC count of peripheral venous blood and either the aHb-CO concentrations (left panels) or the a-vHb-CO concentration differences (right panels) in patients with pneumonia (n = 33, top left, A, and top right, B), with bronchial asthma (n = 18, top center left, C, and top center right, D), with acute pyelonephritis (n = 28, bottom center left, E, and bottom center right, F), or with rheumatoid arthritis (n = 16, bottom left, G, and bottom right, H). See Figures 1 and 2 legends for expansion of abbreviations.

 


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  		Figure 4.. Relation between FEV1 and either the aHb-CO concentrations (top, A) or the a-vHb-CO concentration differences (bottom, B) in patients with bronchial asthma (n = 18) at the visit to the hospital due to exacerbations. See Figure 1 legend for expansion of abbreviation.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study suggests that the a-vHb-CO concentration differences may be a useful means of monitoring pulmonary inflammation. These conclusions are based on several observations. First, blood carboxyhemoglobin concentrations from arteries and peripheral veins increased in patients with inflammatory pulmonary diseases including bronchial asthma and pneumonia, and in patients with extrapulmonary inflammatory diseases including acute pyelonephritis and rheumatoid arthritis. The increased carboxyhemoglobin concentrations in arterial and venous blood in the patients with inflammation are consistent with those reported previously in critically ill patients.10 The increased carboxyhemoglobin concentrations in arterial blood in patients with inflammatory pulmonary diseases are also consistent with those reported by us.9 Furthermore, the values of a-vHb-CO concentration differences in patients with inflammatory pulmonary diseases were significantly higher than those in patients with extrapulmonary inflammatory diseases including acute pyelonephritis and rheumatoid arthritis, and those in the control subjects. In patients with inflammatory pulmonary diseases, the values of exhaled carbon monoxide concentrations correlated with those of carboxyhemoglobin concentrations in arterial blood as reported previously.9 The a-vHb-CO concentration differences correlated with the WBC count of peripheral venous blood in patients with pneumonia. In patients with bronchial asthma, the a-vHb-CO concentration differences inversely correlated with forced expiratory volume in one second, although they did not correlate with the WBC count of peripheral venous blood. Because exhaled carbon monoxide is increased in patients with inflammatory airway and pulmonary diseases,345678923 it has been proposed that measurements of exhaled carbon monoxide may serve as an indirect marker of airway inflammation. High a-vHb-CO concentration differences in patients with inflammatory pulmonary diseases may also reflect inflammations in the airway and lung.

In control subjects, arterial carboxyhemoglobin levels in ex-smokers did not differ from those in nonsmokers. Urinary cotinine concentrations of all control subjects and patients, including both ex-smokers and nonsmokers, were less than the 30 ng of the cotinine per milligram creatinine ratio, the level used to categorize subjects as exposed and unexposed to cigarette smoking.20 Because we studied many elderly subjects, a relatively high proportion of ex-smokers were recruited in the present study, although we excluded current smokers. These findings suggest that the ex-smokers in control subjects, patients with bronchial asthma and pneumonia, and patients with extrapulmonary inflammatory diseases might not be current smokers in the present study. Therefore, carbon monoxide bound to arterial and venous blood hemoglobin, as carboxyhemoglobin and exhaled carbon monoxide appears to be derived from an endogenous source in the present study. Although the source of the carbon monoxide in carboxyhemoglobin and exhaled carbon monoxide is uncertain, HO-1, the inducible form of HO, is likely to be expressed in airway epithelial cells,13 endothelial cells,24 and alveolar macrophages.4

Positive a-vHb-CO concentration differences in both patients with inflammation and control subjects suggested the loss of carbon monoxide during passage through the systemic vascular bed. Minimal systemic consumption of carbon monoxide was estimated to be 60 mL/h/m2 of body surface area, which is far more than the physiologic production of 0.4 mL/h previously calculated.11 Although the mechanisms of carbon monoxide consumption in the peripheral tissue and cells are still uncertain, the distribution of exogenous radioactive carbon monoxide has suggested the transfer of carbon monoxide to extravascular spaces including the liver.12 Carbon monoxide binds to mitochondrial cytochrome oxidase25 and heme proteins,26 although a significant conversion of carbon monoxide to carbon dioxide has not been detected.12

In patients with extrapulmonary inflammatory diseases, carboxyhemoglobin may be produced in peripheral organs or tissue, such as kidneys in acute pyelonephritis and peripheral joints in rheumatoid arthritis. Carboxyhemoglobin in peripheral veins may be mixed in the right atrium through central veins, and carbon monoxide may be then partly excreted into the lung alveoli. In patients with rheumatoid arthritis, venous blood contains a high concentration of carboxyhemoglobin produced in the inflated joints. In contrast, in patients with acute pyelonephritis, a high concentration of carboxyhemoglobin may be delivered to the right atrium through the inferior central vein. Peripheral venous blood in the forearm contains low concentrations of carboxyhemoglobin after carbon monoxide consumption in the peripheral tissue other than the kidneys. These differences in the delivery route and site of carboxyhemoglobin production might cause the a-vHb-CO concentration difference between patients with acute pyelonephritis and rheumatoid arthritis. However, carbon monoxide produced in the airway and alveoli may increase carboxyhemoglobin levels in patients with inflammatory pulmonary diseases, and may increase a-vHb-CO concentration differences compared with those in patients with extrapulmonary inflammatory diseases.

The present study shows the first evidence that a-vHb-CO concentration differences in patients with inflammatory pulmonary diseases including bronchial asthma and pneumonia are significantly higher than that in control subjects and that in patients with extrapulmonary inflammatory diseases. Many cytokines are involved in asthmatic inflammation, including interleukin-1, interleukin-6, and tumor necrosis factor, which can up-regulate HO-1 activity in animal and human tissues.27 Furthermore, asthmatic airways produce high levels of nitric oxide,28 and nitric oxide is shown to decrease cytochrome P450 and microsomal heme through increases in the activity of HO-1.29 Therefore, high levels of the a-vHb-CO concentration differences may reflect inflammation of the asthmatic lung.

Likewise, histologic examinations reveal neutrophil accumulation and infiltration in the lung in bacterial pneumonia.30 Increased levels of reactive oxygen species in neutrophils and BAL fluid were demonstrated in inflammatory pulmonary diseases such as cystic fibrosis and ARDS.31 Reactive oxygen species including superoxide anions and hydrogen peroxide up-regulate HO-1 production.14 Proinflammatory cytokines and nitric oxide are also increased in experimental pneumonia in rats.3233 Furthermore, the reactive oxygen species and proinflammatory cytokines are suggested to increase the exhaled carbon monoxide in patients with bronchiectasis and cystic fibrosis.523 These factors may induce HO-1 production142729 in the bacterial infection of the lung, thereby resulting in the increased a-vHb-CO concentration differences in patients with pneu-monia.

Increased blood carboxyhemoglobin concentrations in both arteries and peripheral veins in the present study were consistent with those observed in critical care patients.10 HO-1 up-regulation by inflammatory cytokines and reactive oxygen species1 might also relate to the increased carboxyhemoglobin concentrations in patients with extrapulmonary diseases including acute pyelonephritis and rheumatoid arthritis.

The a-vHb-CO concentration differences correlated with WBC count of peripheral venous blood, which is associated with the severity of pneumonia,34 in patients with pneumonia. Furthermore, in patients with bronchial asthma, the a-vHb-CO concentration differences inversely correlated with FEV1, which is associated with airway narrowing, although they did not correlate with the WBC count of peripheral venous blood. Therefore, the a-vHb-CO concentration differences may also be associated with the severity of patients with pneumonia and patients with bronchial asthma.

In summary, we have demonstrated large a-vHb-CO concentration differences in patients with inflammatory pulmonary diseases including bronchial asthma and pneumonia, compared with the differences in patients with extrapulmonary inflammatory diseases, especially in patients with rheumatoid arthritis. Although both the arterial and peripheral venous blood carboxyhemoglobin concentrations rose in patients with inflammatory pulmonary diseases and extrapulmonary inflammatory diseases, measurement of a-vHb-CO concentration differences could be a simple and valuable marker to define the site of inflammation, either in the lung or organs other than the lung, in patients with a fever of unknown origin.


   Acknowledgements
 
The authors thank Grant Crittenden for the English correction and Dr. Mitsutoshi Shinkawa for samples.


   Footnotes
 
Abbreviations: a-vHb-CO = arteriovenous carboxyhemoglobin; HO = heme oxygenase

Received for publication October 2, 2003. Accepted for publication January 6, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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S. Permutt and D. B. Pearse
Blood Carbon Monoxide Will Increase from a Decline in Pulmonary Function Alone
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H. Yasuda, M. Yamaya, K. Nakayama, S. Ebihara, T. Sasaki, S. Okinaga, D. Inoue, M. Asada, M. Nemoto, and H. Sasaki
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