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ABSTRACT |
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INTRODUCTION
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An exaggerated hypoxic pulmonary vasoconstriction is essential
for development of high-altitude pulmonary edema (HAPE). We hypothesized that susceptibility to HAPE may be related to decreased production of nitric oxide (NO), an endogenous modulator of pulmonary vascular resistance, and that a decrease in exhaled NO could be detected during hypoxic exposure. Therefore,
we investigated respiratory tract NO excretion by chemiluminescence and pulmonary artery systolic pressure (Ppa,s) by echocardiography in nine HAPE-susceptible mountaineers and nine HAPE-resistant control subjects during normoxia and acute hypoxia
(fraction of inspired oxygen [FIO2] = 0.12). The subjects performed
oral breathing. Nasally excreted NO was separated from respiratory gas by suction via a nasal mask. In HAPE-susceptible subjects,
NO excretion in expired gas significantly decreased (p < 0.05)
during hypoxia of 2 h in comparison with normoxia (28 ± 4 versus
21 ± 2 nl/min, mean ± SEM). In contrast, the NO excretion rate of
control subjects remained unchanged (31 ± 6 versus 33 ± 6 nl/
min, NS). Nasal NO excretion did not differ significantly between
groups during normoxia (HAPE-susceptible group, 183 ± 16 nl/
min; control subjects, 297 ± 55 nl/min, NS) and was not influenced by hypoxia. The changes in Ppa,s with hypoxia correlated
with the percent changes in lower respiratory tract NO excretion
(R = 
0.49, p = 0.04). Our data provide the first evidence of decreased pulmonary NO production in HAPE-susceptible subjects
during acute hypoxia that may contribute among other factors to
their enhanced hypoxic pulmonary vascular response.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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High-altitude pulmonary edema (HAPE) (1, 2) is a form of noncardiogenic pulmonary edema that develops in approximately 10% of randomly selected mountaineers within 24 h after rapid ascent to altitudes above 4,000 m (3). An even higher incidence rate of about 60% has been demonstrated in subjects who are susceptible to HAPE as documented by previous occurrence of the disease (3). HAPE can be effectively prevented by prophylactic use of nifedipine (4) or slow ascent. Nevertheless, it remains the most common cause of death related to high-altitude exposure during trekking or mountaineering (5). The mortality rate in Himalayan mountaineers was estimated to be 50% if immediate treatment with supplemental oxygen or rapid descent was impossible (6).
Although knowledge of the factors influencing the development of HAPE is still incomplete, there is experimental evidence that an exaggerated hypoxic pulmonary vasoconstriction (HPV) plays an important role. An excessive rise in pulmonary artery pressure has been demonstrated by invasive (7, 8) and noninvasive (4, 9) measurements at high altitude in individuals with HAPE. This rise precedes edema formation (4). Subjects who are susceptible to the disease demonstrate an increased pulmonary vascular response even during a brief hypoxia exposure at low altitude (8, 10, 11). The underlying pathophysiological mechanism for this exaggerated HPV is still unknown. There is, however, evidence that the endogenous vasodilator nitric oxide (NO) (12, 13) modulates hypoxic vascular reactivity. Thus, in healthy human volunteers, administration of the NO synthase antagonist NG-monomethyl-L-arginine (L-NMMA) during hypoxia increases pulmonary artery pressure and vascular resistance (14). Furthermore, it has been demonstrated that the exogenous administration of 40 ppm NO in hypoxic subjects prone to HAPE evokes a decrease in pulmonary artery pressure three times larger than the decrease in HAPE-resistant subjects (9). These findings suggest that reduced endogenous NO synthesis in HAPE-susceptible individuals may contribute to their heightened hypoxic pulmonary vascular response.
NO is produced endogenously within the upper and lower respiratory tract and can be measured in exhaled gas by chemiluminescence analysis (15). We hypothesized that HAPE susceptibility may be related to a decreased release of NO in the respiratory tract. To test this hypothesis, we measured NO excretion in exhaled gas together with pulmonary artery pressure in normoxia and during acute hypoxia of 4 h in HAPE-susceptible and in HAPE-resistant mountaineers.
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INTRODUCTION
METHODS
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DISCUSSION
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Study Population
With written informed consent, we investigated 18 healthy male mountaineers, whose susceptibility or resistance toward HAPE was known from previous studies at an altitude of 4,559 m (3, 4, 9). All volunteers were nonsmoking natives of low altitude, free of airway infections, and receiving no medication. Cardiac and pulmonary diseases were ruled out by clinical examination and blood gas analysis. None of the subjects had resided above 2,000 m within the last 2 wk before the measurements, which were carried out in Heidelberg, Germany, at an altitude of 100 m above sea level. The group of HAPE-susceptible individuals consisted of nine mountaineers (mean age, 45 ± 3 yr; weight, 79 ± 3 kg, height, 172 ± 1 cm) who had developed at least one case of radiographically documented pulmonary edema at an altitude of 4,559 m within the last 4 yr. Nine mountaineers (mean age, 37 ± 4 yr; weight, 81 ± 3 kg; height 181 ± 3 cm) who did not develop pulmonary edema during repeated exposure at the same altitude were included in the control group. The study was carried out according to the principles of the Helsinki Declaration of 1983, and approved by the Ethics Committee of the University of Heidelberg.
General Procedures
The subjects were investigated in the supine position while breathing synthetic gas mixtures consisting of 21 or 12% oxygen mixed in N2. The hypoxic gas mixture corresponded to an altitude exposure of 4,500 m. Inhalation was performed via a loose-fitting face mask except for the time of NO measurements, which required oral breathing via a mouthpiece. Heart rate and oxygen saturation were continuously monitored with a fingertip pulse oximeter (Biox 3700; Datex-Ohmeda, Louisville, CO). Nitric oxide measurements were performed during normoxia and at 90-110 and 245-260 min of hypoxia. Further hemodynamic and gas exchange parameters (arterial blood pressure, arterial blood gases, and pulmonary artery pressure) were measured after the determination of exhaled nitric oxide.
Measurement of Arterial Blood Pressure, Arterial Blood Gases, and Pulmonary Artery Pressure
Systemic arterial pressure and heart rate were measured with a blood pressure monitor (Finapress; Ohmeda). Arterial blood samples were taken from a radial artery, using a Microsampler (Biomedical Industrade, Graz, Austria), and analyzed with an 845 blood gas CO oximeter (Chiron Diagnostics, Fernwald, Germany). Systolic pulmonary artery pressure (Ppa,s) was determined echocardiographically. Two-dimensional Doppler recordings were obtained with 2.5-Mhz Duplex probes and conventional equipment (SSD-2200; Aloka, Tokyo, Japan). Ppa,s was estimated according to the equation: Ppa,s = 4(V)2 + 5 mm Hg, where V is the peak velocity (in meters per second) of the tricuspid valve regurgitant jet, and 5 mm Hg is the estimated right arterial pressure (16).
Measurement of NO
NO from the lower respiratory tract was measured in mixed orally exhaled gas during continuous removal of nasally released NO. Gases for inhalation were purified from NO (NO concentration < 0.2 ppb), using a zero air generator (PAG003; ECO PHYSICS, Duernten, Switzerland) and were provided via a tube system connected to a reservoir. Spontaneous breathing was performed exclusively through a mouthpiece connected to a nonrebreathing flutter valve (opening pressure < 1 cm H2O; Intersurgical, St. Augustin, Germany). Exhaled gas was directed continuously through a heated (37° C) 3-L mixing chamber that was distally occluded by a flap valve to prevent retrograde contamination with ambient air. A pneumotachograph (PT36; Jaeger, Wuerzburg, Germany) allowed monitoring of the respiratory gas flow. NO concentration in orally expired gas was measured at the mixing chamber.
To remove nasally released NO, a suction flow of 1.3 L/min was applied continuously via a tightly fitting nasal mask covering both nostrils (Respironics, Murrysville, PA). The resulting gas flow was directed through the open velum palatinum and the nasal cavity and out of the nose. The flow rate for the nasal aspiration was produced with a pump and maintained at 1.3 L/min, using a mass flow controller (CAL 601; ECO PHYSICS). Nasally released NO was measured in the non-pressurized gas behind the pump.
The measurement of NO concentrations was accomplished by chemiluminescence analysis, in which NO is converted to NO2 in the presence of an excess of ozone. This chemical reaction is associated with the production of infrared radiation, whose intensity is a measure of the NO concentration (17). We used a chemiluminescence analyzer of the CLD 780 TR type (ECO PHYSICS). It possesses a rise time of 0.3 s for NO signals between 0.5 and 500 ppb, and a lower detection limit of less than 0.05 ppb if the signal is integrated over a time of 1 min. The gas used for adjustment of the zero level is produced internally from ambient air, whereby NO is completely converted to NO2 by reaction with ozone. The scale was calibrated with a test gas containing 480 ppb NO.
All measured concentration and flow values were stored continuously, using a computerized data acquisition system, for later analysis. Values of respiratory gas flow and mixed orally exhaled NO concentration were time shifted by 20 s against each other in order to account for the retardation due to the gas transit through the mixing chamber. An offset of 22 ml/s was added to the expiratory flow data to compensate for the loss due to nasal suction. Flow and NO values were then averaged separately over time intervals of 90 s before multiplication to obtain pulmonary NO excretion rates. Nasal NO excretion rates were calculated by averaging the NO concentration in nasally aspirated gas over 90 s, followed by multiplication with the constant suction flow rate of 1.3 L/min.
Statistical Analysis
To determine the significance of the results, three types of statistical tests were used. In the investigation of the intraindividual changes during hypoxia versus normoxia, analysis of variance (ANOVA) for repeated measures with post hoc tests according to Bonferroni was applied. The differences between HAPE-susceptible subjects and control subjects were examined using the t test for unpaired samples. Correlation analysis of exhaled NO and Ppa,s pressure changes was performed with the Spearman rank correlation coefficient (SPSS statistical software, version 7.5.2; SPSS, Chicago, IL). Results with p values of less than 0.05 were regarded as significantly different. Data in text and tables are expressed as means ± SEM.
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RESULTS |
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Hemodynamics and Gas Exchange
The measured values are summarized in Table 1 and in Figure 1. Arterial blood gases in normoxia were not significantly different between HAPE-susceptible and control subjects. In both groups, acute hypoxia significantly lowered arterial oxygen tension and saturation when compared with normoxia. Pulmonary artery pressure was determined in all subjects except one HAPE-susceptible individual, in whom no adequate Doppler signals could be obtained. Prolonged hypoxia caused a significant increase in systolic pulmonary artery pressure in both groups (Figure 1). Although pulmonary artery systolic pressure (Ppa,s) values were comparable during normoxia for both groups (HAPE-susceptible subjects, 29 ± 2 mm Hg; control subjects, 26 ± 1 mm Hg; NS), they became significantly different between HAPE-susceptible subjects and control subjects during hypoxia (HAPE-susceptible subjects, 54 ± 3 mm Hg; control subjects, 38 ± 1 mm Hg; p < 0.05, values at 4 h of hypoxia). Hypoxia caused an increase in heart rate in both groups, but arterial blood pressure did not change significantly in either group.
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Nitric Oxide Excretion During Normoxia and Hypoxia
Results of the NO measurements are given in Table 2. During normoxia, NO concentrations in gas aspirated from the nose were not significantly different between HAPE-susceptible subjects and control subjects, but there was a trend toward lower values in HAPE-susceptible subjects (140 ± 12 ppb versus 229 ± 43 ppb, NS, p = 0.06). The nasal NO excretion rate of 183 ± 16 nl/min in HAPE-susceptible subjects was also not significantly different compared with the value of 297 ± 55 nl/ min obtained in control subjects (p = 0.06). Normoxic NO concentrations in exhaled gas from the lower respiratory tract, which were measured during maintenance of nasal suction, were comparable between both groups (HAPE-susceptible subjects, 3.1 ± 0.3 ppb; control subjects, 3.4 ± 0.5 ppb; NS, Table 2). There was also no significant difference in minute ventilation (HAPE-susceptible subjects, 9.1 ± 0.8 L/min; control subjects, 9.3 ± 0.6 L/min; NS, Table 2) and in pulmonary NO excretion rates (HAPE-susceptible subjects, 28 ± 4 nl/min; control subjects, 31 ± 6 nl/min). Acute hypoxia of 2 and 4 h in duration did not influence nasal NO release in either group. This is demonstrated both by the NO concentrations in nasally aspirated gas (Table 2) and the corresponding nasal NO excretion rates (Figure 2A). As already noted in normoxia, there was a trend toward a lower nasal NO concentration in HAPE-susceptible subjects when compared with control subjects, which persisted even at 2 and 4 h of hypoxia (Table 2; p = 0.11 at 2 h, p = 0.06 at 4 h, respectively). During hypoxia, NO excretion from the lower respiratory tract in control subjects did not differ significantly from its normoxic baseline value. In contrast to the control subjects, HAPE-susceptible subjects had a statistically significant decrease in exhaled NO concentration during hypoxia when compared with normoxia (2.3 ± 0.5 ppb at 2 h and 2.3 ± 0.5 ppb at 4 h of hypoxia versus 3.1 ± 0.3 at normoxia; p < 0.05; Table 2), which yielded a significant reduction in the NO excretion rate of 23 ± 6 and 27 ± 8%, at 2 and 4 h, respectively (Figure 2B).
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Relationship between Exhaled NO and Pulmonary Artery Pressure Changes with Hypoxia
Figure 3 is a plot of the individual percent changes in exhaled
NO excretion against the measured rise in Ppa,s with 2 h of hypoxia. It shows that there is a negative correlation between the changes in exhaled NO and the strength of the hypoxic
pulmonary vascular response, with a correlation coefficient of
0.49 (p = 0.04). There was no correlation within subgroups.
Corresponding analysis for the 4-h values yielded a smaller
correlation coefficient of 0.32 and did not reach statistical
significance (p > 0.05). Using mean values that were averaged
over 2 and 4 h resulted in a correlation coefficient comparable
to that obtained for the 2-h values, which just failed to reach
significance (R = 0.46, p = 0.06). Similar results were obtained for the correlation between absolute values of Ppa,s
and NO rates (R = 0.45, p = 0.07) when both values were
averaged over 2 and 4 h.
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DISCUSSION |
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METHODS
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DISCUSSION
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To investigate whether susceptibility to HAPE may be related to decreased release of NO in the respiratory tract, we separately measured upper and lower respiratory tract-exhaled NO together with hemodynamic and gas exchange parameters during normoxia and acute hypoxia of 4-h duration. Hypoxia caused no changes in nasal NO excretion in either HAPE-susceptible subjects or control subjects. We found that healthy HAPE-susceptible subjects, in contrast to healthy control subjects, had a significant decrease in NO excretion from the lower respiratory tract during hypoxia. The decrease in pulmonary NO excretion during acute hypoxia was accompanied by sustained and significantly greater pulmonary artery pressure elevation in HAPE-susceptible subjects than in control subjects.
The interpretation of our data is based on the assumption
that NO measured in exhaled gas is pulmonary and not nasal
in origin, and that the hypoxic vasoconstriction is comparable
to that caused by high altitude, which we mimicked by 4 h of
breathing 12% oxygen. Successful separation of pulmonary
and nasal NO by nasal aspiration is evidenced by the low magnitude of NO levels in exhaled gas. The expiratory NO concentrations are about 80 times less than those in nasally aspirated gas. Furthermore, they are in the same range as the
values reported in subjects with orotracheal intubation, and
with balloon occlusion of the posterior oropharynx (18). In addition, it has been reported that nasal suction at a suction flow rate of 0.7 L/min exerted to each nostril results in a
complete removal of nasally released NO (21). The greater
increase in pulmonary artery pressure with hypoxia in HAPE-susceptible subjects compared with control subjects is consistent with results of previous studies using right heart catheterization (8, 10) and Doppler echocardiography (11). In contrast
to the previous assumption from short-term animal studies of
5- to 10-min hypoxic challenges, in which pulmonary artery
pressure (
) pressures appear to attain a plateau, it has been
demonstrated that in humans there is a slower, second phase
of hypoxic pulmonary vasoconstriction that reaches a maximum at 2 h of isocapnic hypoxia (22). Our 4-h protocol was
chosen with the recognition of this slower time course. In addition, our measured values of arterial blood gases are in good
agreement with those reported during previous investigations at the Capanna Regina Margherita in the Swiss-Italian Alps
(2). Thus, our experimental design of breathing hypoxic gas
evoked hemodynamic and arterial blood gas changes similar
to those generated at an altitude exposure of 4,600 m.
There remain uncertainties regarding the exact origin of NO arising from the lower respiratory tract. Thus it may be questioned whether and how well the changes in exhaled NO we measured reflect events at the pulmonary vascular level. Studies using selective inhibitors of the NO synthase isoenzymes reveal that almost all exhaled NO from the healthy lower respiratory tract is synthesized by endothelial NO synthase found both in the airways and vessels whose activity is influenced by intracellular Ca2+ concentration (23, 24). Although the anatomic source of the exhaled NO is not clear, studies of the effects of the NO synthase antagonist L-NMMA in humans during inhalation and infusion (25) suggest that less than 10% of the NO excretion from the lower respiratory tract arises from the vascular endothelium while the majority is released by the surface epithelium of lower airways and alveoli. In spite of the predominant contribution of the airway/alveolar epithelial production to exhaled NO, we have shown in the isolated perfused rabbit lung that controlled changes in vascular perfusion and pressure do alter exhaled NO excretion by 8-20% in a manner and direction consistent with flow and stretch-mediated actions on lung vessels, if these changes do not alter blood volume and hence NO scavenging by red cells in the pulmonary capillaries (26). These values are in the same range as the measured reduction in exhaled NO in HAPE-susceptible subjects during hypoxia.
If there were a direct relationship between NO production
at the vascular endothelial level and exhaled NO, then we
should have observed a strong correlation between hypoxic
Ppa,s responses and changes in exhaled NO. In the present
study we found only a modest correlation that at 2 h was significant at the conventional p = 0.05 threshold, but not at 4 h.
When the 2- and 4-h data for each subject were averaged, the
p value was 0.06, just short of conventional significance. Owing to the small number of subjects, estimates of significance
can be sensitive to uncertainties in single data points. The certainty of our interpretation of a definite correlation is further
strengthened by the data of Duplain and coworkers (27), who
found that HAPE-susceptible mountaineers showed a sustained decrease of 30% in exhaled NO over 48 h after reaching 4,559 m when compared with HAPE-resistant climbers. In fact, the correlation (R = 0.51) these authors found between exhaled NO and Ppa,s was similar to that we found in the first 4 h of acute hypoxia.
There are several reasons for the modest correlation, which can only explain 25% of the variability found in the hypoxic Ppa,s response. First, hypoxic pulmonary vasoconstriction is not directly mediated by suppression of nitric oxide, and as discussed above, changes in exhaled NO may only imperfectly reflect changes in vascular NO production. Furthermore, differences in the response of cardiac output, pulmonary capillary blood volume, and circulating catecholamines may be important because these factors also alter NO production and/or scavenging (26). Last, hypoxia alters other modulators of pulmonary vascular tone such as endothelin, adrenomedullin, natriuretic peptides, and prostacyclin, such that individual differences in the release of these vasoactive substances will further reduce any correlation of exhaled NO changes to Ppa,s. These considerations notwithstanding, we believe that our data support the concept of a key difference in lung endothelial NO production in the hypoxic vascular responses of HAPE-susceptible and HAPE-resistant mountaineers, that contributes among other factors to the enhanced hypoxic pulmonary vasoconstriction in HAPE-susceptible individuals.
Healthy control subjects breathing 12% oxygen have no significant change in nasal and pulmonary NO excretion. With respect to the NO excretion from the lower airways our finding is in agreement with the results of Tjusino and coworkers (28), who investigated healthy human volunteers during a short-term exposure to hypoxia (10% oxygen for 6-8 min). On the basis of animal experiments that revealed a decrease in pulmonary artery endothelial NO synthesis (29), they expected a decrease in exhaled NO and concluded that the duration of the hypoxic phase in their study was insufficient. In contrast, our results suggest an unchanged NO excretion in the respiratory tract of healthy subjects even during prolonged hypoxic breathing. The apparent contradiction to animal results cited above may be resolved, if the degree of hypoxia is taken into account. In cultured pulmonary endothelial cells only severe but not moderate hypoxia (PaO2, 15 versus 42 mm Hg) reduces NO activity (32). Similar dose responses have been obtained in the isolated perfused rabbit lung (33, 34) on exhaled nitric oxide. Thus, the unchanged NO excretion in healthy control subjects in our study at mean PaO2 values of 41 ± 2 and 45 ± 3 mm Hg does not appear to be surprising, and confirms that at this level of inspired hypoxia, oxygen is not substrate limiting for NO synthesis in healthy humans.
In contrast to the significant fall in lower respiratory tract NO excretion with hypoxia, we found no corresponding changes in nasal NO excretion in the HAPE-susceptible subjects. This dissociation in the hypoxic responses between upper and lower respiratory tract NO excretion is not readily explicable, but may be related to the presence of different isoforms of NO synthases in these areas. Thus, it has been demonstrated that nasal NO is almost exclusively produced by an enzyme sharing mRNA sequence homology with human hepatocyte inducible NO synthase whose activity is not Ca2+ controlled (35). Autoinhalation of nasal NO has been hypothesized to participate in pulmonary vascular control (18) and was demonstrated in postoperative patients by Settergren and coworkers (36), who found that nasal breathing compared with oral breathing decreased the pulmonary vascular resistance index by about 10%. Although our data suggest that hypoxia caused no changes in the autoinhaled amount of nasal NO in HAPE-susceptible subjects, we found a tendency for reduced nasal NO release compared with control subjects that was already present at normoxia. During hypoxia, the effects of reduced NO autoinhalation from upper and lower airways may be additive. Whether this may be of importance for the increased hypoxic pulmonary vasoconstriction in HAPE-susceptible subjects remains speculative and should be clarified in future investigations.
In conclusion, we have found that HAPE-susceptible individuals demonstrate a reduction in pulmonary NO excretion with hypoxia while their nasal NO release remains unchanged. The reduced NO production in the lower respiratory tract may contribute among other factors to the enhanced hypoxic pulmonary vasoconstriction that is central to the development of HAPE. It remains to be discovered exactly how hypoxia of the magnitude studied here and experienced at high altitude uniquely depresses pulmonary NO synthesis in the HAPE-susceptible individual, but the answer may offer novel preventive and therapeutic possibilities.
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Footnotes |
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Correspondence and requests for reprints should be addressed to T. Busch, Ph.D., Klinik für Anaesthesiologie und Operative Intensivmedizin, Charité, Campus Virchow-Klinikum, Humboldt-Universität zu Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
(Received in original form January 31, 2000 and in revised form June 20, 2000).
Presented in part at the ERS Annual Congress, Geneva, Switzerland, September 19-23, 1998.Acknowledgments: The authors thank the volunteers for participating in this study; M. Schuster for excellent technical assistance; and R. Mohnhaupt for providing the data acquisition system.
Supported by Deutsche Forschungsgemeinschaft (DFG Fa139/4-3).
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References |
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METHODS
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DISCUSSION
REFERENCES
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