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HIGHLIGHTED TOPIC
Physiological Imaging of the Lung
Departments of 1Radiology, 4Radiation Oncology, and 7Physics, University of Virginia, Charlottesville, Virginia; 2University of Pennsylvania and 3Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; 5Department of Environmental Health Sciences, School of Public Health, Johns Hopkins University, Baltimore, Maryland; and 6Department of Medicine, Duke University, Durham, North Carolina
Submitted 7 April 2006 ; accepted in final form 3 November 2006
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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hyperpolarized gas magnetic resonance imaging; elastase
1-antitrypsin deficiency who were treated with 1-antitrypsin, whereas no significant change was seen with spirometry (20). Thus CT has been proposed as a potential biomarker for emphysema (3). Because of the tissue destruction that occurs in emphysema, emphysematous regions of the lung have less lung tissue per unit volume than normal lung, so they exhibit lower attenuation on CT. However, other processes in the lung can reduce CT attenuation, including reduced perfusion and air trapping (23). Furthermore, the relatively high radiation dose of a chest CT scan may limit its use for repeated scans in longitudinal studies and clinical trials (4). Hyperpolarized 3He and 129Xe are gaseous contrast agents for MR imaging (MRI) that provide new ways to evaluate the lungs in vivo. With conventional proton MR, the nuclear spins of hydrogen nuclei are brought into alignment by the strong magnetic field of the MR scanner, resulting in a nuclear polarization on the order of 10–6. With hyperpolarized gases, the nuclear spins of the 3He or 129Xe atoms are brought into alignment outside the MR scanner using the laser-based spin-exchange or metastability-exchange process, and a nuclear polarization on the order of 0.1 can be achieved (9). This high nuclear polarization provides a strong MR signal, despite the low physical density of the gas. When inhaled, these gases provide MRIs of the ventilated air spaces of the lung with high temporal and spatial resolution.
Diffusion-weighted imaging is commonly used in proton MRI of the brain to assess for acute stroke (10). By modification of the parameters of a diffusion MRI pulse sequence for the rapid rate of diffusion of the hyperpolarized gas atoms, it is possible to measure the apparent diffusion coefficient (ADC) of the 3He or 129Xe atoms in the lung (5, 6). Compared with the free diffusion coefficients of 3He or 129Xe, the measured ADCs in the lung are significantly reduced, because the diffusion of the gas atoms is restricted by the walls of the distal air spaces. Thus the ADCs measured with hyperpolarized 3He and 129Xe are thought to be a measure of the morphology of the microstructure of the lung. The ADC of 3He in the normal lung is approximately a factor of 4 less than the free diffusion coefficient of 3He in air (6). With alveolar enlargement, such as from emphysema, the inhaled gas atoms are less restricted, and so the measured ADC would be expected to be increased relative to values in normal lung. Indeed, in patients with emphysema, the ADC of 3He has been found to be significantly elevated relative to that in normal subjects, approaching the free diffusion coefficient in some areas (17, 18, 21, 24).
Prior attempts to correlate the 3He ADC with histology in animal models of emphysema have been only moderately successful. In a rat model of emphysema, an elevation of the 3He ADC was found in the emphysematous animals, but only when imaging was done at end expiration, and the changes were not significant for imaging during a breath hold at full inspiration (5). In the same study, a correlation between histology and the ADC data could not be established, possibly because of differences in the lung volumes used for fixation and in vivo imaging. Peces-Barba et al. (16) showed moderate correlations between the 3He ADC and the histological alveolar internal area and mean linear intercept in a rat model of mild emphysema, but the ADC measurements were done postmortem. Woods et al. (25) showed a relation between the 3He ADC and the surface-area-to-volume ratio, but their study was limited to three dogs, and no correlation was drawn. In human subjects with emphysema, a correlation between the 3He ADC and clinical measures of disease severity has been demonstrated (18). Thus hyperpolarized 3He-MR appears to detect the structural changes that occur in emphysema; however, the relation between the 3He ADC and histology has yet to be definitively established.
129Xe is naturally quite abundant on Earth, in contrast to 3He, and for this reason has been proposed as an alternative to 3He should hyperpolarized gas MRI become widely used. However, the different properties of 129Xe, including a 43 times higher atomic weight and 6 times lower diffusivity in air, will alter the ADCs measured in the lung compared with ADCs measured with 3He. To our knowledge, the evaluation of diffusion MRI based on hyperpolarized 129Xe has not been reported in diseased lungs, and there have been only limited reports of results in healthy individuals (15).
The purpose of this study was to compare the sensitivities and trends of 3He and 129Xe ADCs with lung histology in a rabbit model of elastase-induced emphysema. Secondary aims of the study were to evaluate the repeatability of the ADCs and to assess the ability of 3He and 129Xe diffusion MRI to detect changes in the degree of emphysema over time, as would be required for a human clinical trial of a treatment for emphysema.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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2, 4, 6, and 8 wk after the induction of emphysema. Because of technical problems, it was not possible to image all rabbits with 129Xe during weeks 4 and 6; therefore 129Xe results are not reported for weeks 4 and 6. At all other time points, a single acquisition for each set of MR parameters was performed in each of the control (rabbits 1–3) and emphysema (rabbits 4–10) animals. At the end of the experiment, the three control and seven emphysema rabbits were euthanized, and their lungs were examined histologically. To assess the repeatability of the measurements, eight rabbits were imaged twice, in separate breath holds, at the same time point using identical MRI parameter values. For 3He imaging, the repeat runs were done at baseline (rabbits 7 and 10) and at week 8 (rabbits 4 and 6) in animals from the emphysema group. For 129Xe imaging, the repeatability data were obtained from four healthy rabbits (rabbits 11–14); these rabbits were not part of the control group.
For each imaging time point and at the time of emphysema induction, the animals were weighed, anesthetized with an intramuscular injection of ketamine (50 mg/kg) and xylazine (5 mg/kg), and intubated. Additional anesthetic was administered as needed. All procedures were carried out with approval of the local Institutional Animal Care and Use Committee and in compliance with all local and federal guidelines.
Emphysema induction. Under fluoroscopic guidance, six rabbits (rabbits 4–9) received a single endotracheal instillation of porcine elastase (Worthington Labs, Lakewood, NJ) via a high-pressure microsprayer (PennCentury, Philadelphia, PA), creating a plume of liquid aerosol that was carried deep into the lungs by spontaneous breathing. Three rabbits (rabbits 1–3) received a single instillation of normal saline via the same device. One rabbit (rabbit 10) received a single unilateral instillation of elastase in the right main bronchus, rather than in the trachea, in an attempt to create a model of unilateral emphysema. Two elastase doses were used: 30 U of elastase diluted with saline for a total volume of 1.2 ml (moderate emphysema group, n = 3 bilateral and n = 1 unilateral) and 5 U of elastase diluted to a total volume of 0.2 ml (mild emphysema group, n = 3 bilateral). The control group received 1.2 ml of saline.
MRI.
The 3He and 129Xe gases were polarized in a commercial system (model IGI 9600, MITI, Durham, NC) via the spin-exchange method, with rubidium vapor used as the alkali metal, as described previously (7, 13). 3He polarization levels were 30–40%, whereas 129Xe (isotopically enriched to 83%) polarization levels were 8–20%. Since 3He and 129Xe were polarized using the same laser system and, thus, could not be prepared on the same day, it was necessary to perform imaging at each time point during two different sessions, separated by 
5 days. All studies were performed on a 1.5-T whole body MR scanner (Magnetom Sonata, Siemens Medical Solutions, Malvern, PA) that was modified with a broadband amplifier to allow operation at the 3He and 129Xe resonant frequencies. A flexible radio-frequency coil (IGC Medical Advances, Milwaukee, WI) was used for 3He imaging, and a rigid birdcage radio-frequency coil (IGC Medical Advances) was used for 129Xe imaging.
All MR studies were performed using gradient-echo-based pulse sequences that included a bipolar gradient waveform in the slice-selection direction for diffusion sensitization. Contiguous coronal images covering the entire lung volume were acquired with a matrix size of 64 x 128, an in-plane voxel size of 2.2 x 2.2 mm2 (3He) or 2.7 x 2.7 mm2 (129Xe), and TR/TE = 12/6.8 ms (3He) or 16/11 ms (129Xe). The number and thickness of slices varied depending on the degree of polarization achieved on a particular day and ranged from three (20-mm-thick) to four (15-mm-thick) contiguous slices for 3He gas and one (60-mm-thick) to two (30-mm-thick) slices for 129Xe gas.
Before imaging, the animals were anesthetized and intubated but were breathing spontaneously. The animals were scanned in a supine position, and the images were acquired within 15 min of positioning. The phase of respiration was assessed by visual inspection of the animal. For each MR acquisition, 50 ml of undiluted hyperpolarized gas were administered at the end of spontaneous expiration from a syringe attached to the endotracheal tube. The endotracheal tube was then clamped for the duration of the MR acquisition (2–6 s) to achieve a breath hold.
At each slice position, two images were acquired corresponding to two different b values, designated bL and bH. The b value is a measure of the amount of diffusion sensitization provided by the bipolar gradient waveform in the pulse sequence. A higher b value corresponds to greater diffusion sensitization and, therefore, greater attenuation of the signal due to diffusion. The b value is calculated from the waveform shape of the diffusion-sensitization gradient and its duration and amplitude. To minimize signal attenuation from T1 decay and radio-frequency pulses, the phase-encoding lines corresponding to bL and bH were acquired before incrementation of the phase-encoding gradient strength to its next value. To assess the effect of the b value on the sensitivity of the ADC measurements to structural changes in the lung, we evaluated four different b-value pairs: 0 and 1.6 s/cm2 and 0 and 4.0 s/cm2 with 3He and 0 and 5.0 s/cm2 and 0 and 10.0 s/cm2 with 129Xe. The b-value pair 0 and 1.6 s/cm2 has been used in prior studies of the 3He ADC in humans (18). To compensate for the lower diffusivity and, hence, lower diffusion-induced signal attenuation of 129Xe than 3He, we used higher b values and longer diffusion times for 129Xe. The trapezoidal bipolar waveforms used for diffusion sensitization had ramp-up and ramp-down times of 300 µs and the following parameter values for bH = 1.6, 4.0, 5.0, and 10.0 s/cm2: flat-top times of 980, 980, 3,000, and 3,000 µs and maximum gradient strengths of 14.3, 22.7, 18.3, and 25.9 mT/m, respectively.
MRI analysis.
The MRIs were postprocessed using routines written in MATLAB (MathWorks, Natick, MA) by a reviewer who was blinded to all clinical information about the rabbits and the results of the histological analysis. For each slice position and b-value pair, ADCs were calculated on a pixel-by-pixel basis using the images corresponding to bL and bH. For the ADC calculation, a monoexponential attenuation due to diffusion was assumed, and ADC was calculated according to
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For each animal at each time point and each b-value pair, ADC maps for each slice were calculated, and the whole lung ADC histogram was plotted. The mean (SD) of the ADCs for the entire lung volume were calculated without segmenting out the major airways. In addition, the means (SD) of the ADCs were calculated in regions of interest, placed manually for each acquisition, in the upper, middle anterior, middle posterior, and lower lung regions. The regions of interest placed in the upper portion of the lung did not include pixels corresponding to the trachea. Lung volumes were also calculated on the basis of the images obtained with bL = 0 by multiplication of the voxel volume by the number of voxels with signal intensities above the threshold. The signal-to-noise ratio (SNR) of each bL = 0 image was also determined by division of the mean signal intensity of the pixels with values above the threshold by the SD of the noise.
Histology.
After MRI at week 8, the animals were euthanized and their lungs and trachea were harvested in a single block through an anterior midline incision parallel to the sternum. The heart was removed, and the lungs were inflated with air at a constant pressure of 30 cmH2O for 48 h. Once the tissue was fully dried, 10 x 20 x 0.5 mm samples from four different regions (upper, middle posterior, middle anterior, and lower) of the right lung were carefully excised. Each tissue sample was then washed 10 times, in successive baths of ethanol and xylene, before being embedded in paraffin and sliced with a microtome (Biocut 2035, Leica Microsystems, Wetzlar, Germany) into 5-µm-thick sections. The sections were stained with hematoxylin-eosin.
A reviewer who was blinded to the clinical status of the rabbits and to the MRI results evaluated each section and selected three regions that appeared representative and free of major airways and blood vessels to be digitally photographed (resolution = 1,360 x 1,024 pixels) at x4 magnification using a 12.5-megapixel digital camera (model DP70, Olympus, Melville, NY) attached to a microscope (model BX-51, Olympus). The digital images of the lung histological sections were analyzed using Image J (Wayne Rasband, NIH, Bethesda, MD) with an algorithm based on the method described by Lum et al. (11). Only areas of the lung that did not contain large airways were analyzed. Briefly, the images were converted from 32-bit color images to an 8-bit gray-scale format (Fig. 1A). A grid of parallel lines (1 pixel thick and 10 pixels apart) was added to the images, and the intersections of lung tissue and grid lines were automatically identified (Fig. 1B). The lengths of the resulting grid-line chords were measured automatically. Any chord <10 µm or with at least one end at the border of the image was thought to be unreliable and discarded (Fig. 1C). The mean chord length (MCL) and the SD of the chord lengths were computed. The MCL results from the three images acquired from the same tissue sample were averaged, and these average values were used for regional correlation with the ADC from the respective area (upper, middle posterior, middle anterior, and lower) of the lung (Fig. 2).
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The pair-wise percent differences and the mean (SD) of these values for each b-value pair were calculated for the repeatability measurements. The values are presented as the absolute percent differences.
Pearson correlation coefficients were calculated for 1) the whole lung mean ADC and whole lung MCL, 2) regional mean ADCs and regional MCLs, 3) the whole lung mean ADC and animal weight at baseline, 4) SNR and whole lung mean ADC, and 5) SNR and lung volume.
For all statistical comparisons, the threshold for significance was set to P = 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Temporal evolution. The mean (SD) of the whole lung ADCs at baseline and the percent change in mean ADC from baseline are shown for the control and emphysema groups in Table 1. The average change in mean 3He ADC for the bH = 1.6 cm2/s acquisition from baseline to week 8 was 15.3% for the moderate emphysema group, 7.8% for the mild emphysema group, and 4.3% for the control group. The mean ADC was significantly higher at week 8 than at baseline for the rabbits with induced emphysema (P = 0.03). Similar but more modest changes were found with the other b-value pairs used (Table 1). Representative 3He ADC maps at baseline and week 8 are shown in Fig. 2 for rabbits from the control and emphysema groups. All rabbits had homogeneously low ADC values at baseline. At week 8, the control rabbits showed little change from baseline (Fig. 2, left). For the rabbits with bilateral emphysema, diffuse elevation of the ADC throughout the lungs was observed at week 8 (Fig. 2, right). For the rabbit with unilateral emphysema, elevation of the ADC values was heterogeneous in the right lung, and the left lung appeared normal (Fig. 2, middle).
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The mean lung volume measured at baseline was 0.15 liter (SD 0.02) and 0.14 liter (SD 0.01) for 3He with bH = 1.6 and 4.0 s/cm2, respectively, and 0.13 liter (SD 0.04) and 0.13 liter (SD 0.04) for 129Xe with bH = 5.0 and 10.0 s/cm2, respectively. At week 8, the mean lung volumes for all b-value pairs increased by 5% (P = 0.31). At baseline, the mean SNRs of the bL images were 32.0 (SD 3.0) and 29.7 (SD 3.7) for 3He with bH = 1.6 and 4 s/cm2, respectively, and 27.6 (SD 3.2) and 26.3 (SD 3.3) for 129Xe with bH = 5.0 and 10.0 s/cm2, respectively. At week 8 the SNRs were 7% lower (P = 0.02), possibly because of the increased lung volume. These small changes in lung volume and SNR suggest that they are not significant confounding factors in our results.
Repeatability. The absolute percent differences between repeated measurements of the whole lung mean ADC, lung volume, and SNR from the eight rabbits that were scanned twice at a single time point with identical MR parameter values are listed in Table 2. For 3He and 129Xe ADC, the pair-wise differences in mean ADCs were quite low, with >5% variation (range 0.26–7.6%, mean 1.7%) in only 1 of 16 paired runs. The repeatability of the SNR was generally very good, with >5% variability in only 2 of 16 paired runs. Lung volume, as measured by MR, had the greatest variability, with >5% variation in 6 of 16 paired runs. Interestingly, the variation in SNR was poorly correlated with the variation in mean ADC (r = –0.21, P = 0.15) but was moderately correlated with the variation in lung volume (r = 0.62, P = 0.03), likely because lower SNR images had a lower number of lung voxels that exceeded the threshold, yielding a lower lung volume as measured by MR. However, the variation in lung volume was poorly correlated with the variation in mean ADC (r = 0.37, P = 0.15), suggesting that the mean ADC is relatively robust to slight variations in lung volume as measured by MR, at least for the range of values in this study. Representative ADC maps from repeated acquisitions showed a striking similarity in appearance (Fig. 3).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Prior studies of hyperpolarized 3He ADC vs. lung histology in animal models of emphysema found correlations nearly as strong as those established in this study (5, 16). The strongest correlation found previously was r = 0.71 (16), whereas the strongest correlation found in this study was r = 0.80. In our study, the animal model of bilateral emphysema appeared to have a more homogeneous distribution of disease than shown in prior studies. Similar to prior studies, the histology results were based on a relatively small number of samples from the lung, but with a heterogeneous model of emphysema, sampling may introduce significant variability to the histology results, an effect that can be minimized by using an animal model with a homogeneous distribution of emphysema or by using more histology samples. Furthermore, in our study, particular attention was paid to technique during administration of the hyperpolarized gas to the animals and during harvesting and drying of the lungs, which may have helped minimize variability in the degree of inflation of the lungs between the in vivo and histological evaluations.
The excellent repeatability of the 3He mean ADC is concordant with a prior study in human subjects (14). We found the 129Xe mean ADC to be highly repeatable as well. MCLs from the animals in the control group are consistent with those in the literature for rabbits (12).
For a highly complex and restricted medium such as the rabbit lung, the signal attenuation from the diffusion of the gas atoms does not follow a monoexponential function (26); therefore, ADCs calculated on the basis of the measurement of only two b values depend on the b values used. The measured 3He ADCs for bH = 4 s/cm2 were slightly smaller than those for bH = 1.6 s/cm2, and the measured 129Xe ADCs for bH = 10 s/cm2 were slightly smaller than those for bH = 5 s/cm2, a result that is consistent with prior studies (6, 26). ADCs for 129Xe were approximately six times smaller than those for 3He, which is likely due to the factor of 6 difference in the free diffusivities of the two gases in air. The change in mean ADC after the induction of emphysema was greatest with 3He and bH = 1.6 s/cm2, suggesting that of the four sets of parameters tested, this may be the most sensitive to emphysematous change in rabbits. Also, the strongest correlation with regional histology was with 3He and bH = 1.6 s/cm2. The SD of the ADC was lower with bH = 4 s/cm2 than with bH = 1.6 s/cm2, which may be due to the greater diffusion sensitization for the higher b value.
One unexpected finding was that the mean ADC in the animals with elastase-induced emphysema decreased slightly, but not significantly, from week 2 to week 8 after induction of emphysema when imaged with 3He, but not when imaged with 129Xe. With 129Xe, there was a small upward trend from week 2 to week 8. The reason for this disparity is unknown, but this result suggests that 3He and 129Xe may be sensitive to different aspects of lung structural change. One possible explanation for the ADC decrease with 3He could be an increase in the overall lung volume associated with the progression of the disease or animal growth. The smaller voxel volume for 3He than for 129Xe might also have contributed to the apparently lower sensitivity for 129Xe due to differences in the degree of partial-volume averaging between the 3He and 129Xe measurements.
Despite the limitation of a relatively low number of animals in the study, we were able to detect a strong correlation between global and regional mean ADC and MCL from histology. A larger number of animals would permit the death of animals at each time point, which might be useful for elucidating the etiology of the disparity between 3He and 129Xe trends in the mean ADC with time. A second limitation of the study concerns the choice of the imaging parameters for 129Xe. Because very few in vivo 129Xe ADC studies have been performed, there is little guidance regarding the choice of optimal parameters. Thus the lower sensitivity of 129Xe to the structural changes of emphysema found in this study may have been due to the choice of imaging parameters, rather than an intrinsic limitation of the technique. At least in theory, it would seem that 129Xe might be more sensitive to early structural changes because of its lower diffusivity. The optimization of the 129Xe imaging parameters for the detection of emphysematous change in the lung appears to be a promising area for future research. A basic limitation of the diffusion-imaging technique is that the ADC can only be measured in ventilated regions of the lung, which is a disadvantage compared with CT. This was not a limitation in our study, since the elastase-induced emphysema did not result in unventilated regions of the lung, but it is a limitation for the extension of this technique to human patients with COPD, in which regions of poor ventilation are common (8). Furthermore, although the microstructural (<500 µm) detail may be greater than that of CT, the macrostructural (>1 mm) detail is much lower. Finally, noble gas polarizers are available at only a limited number of academic medical centers. Although there are no fundamental technological barriers to impede the more widespread use of this technology, the corporation that licenses the patent for the in vivo use of hyperpolarized gases has yet to announce plans to commercialize this technology.
In summary, in an animal model of emphysema, we found a strong correlation between the global and regional ADCs measured by hyperpolarized gas MRI and alveolar size as measured by MCL on lung histology, providing further validation that diffusion-weighted hyperpolarized gas MRI detects the structural changes of emphysema in the lung. Furthermore, diffusion-weighted hyperpolarized gas MRI was found to possess many of the characteristics required of a biomarker for emphysema.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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1-antitrypsin deficiency. Eur Respir J 25: 23–30, 2005.This article has been cited by other articles:
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  D. A. Yablonskiy, A. L. Sukstanskii, J. C. Woods, D. S. Gierada, J. D. Quirk, J. C. Hogg, J. D. Cooper, and M. S. Conradi Quantification of lung microstructure with hyperpolarized 3He diffusion MRI J Appl Physiol, October 1, 2009; 107(4): 1258 - 1265. [Abstract] [Full Text] [PDF]
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 M. Plotkowiak, K. Burrowes, J. Wolber, C. Buckley, R. Davies, F. Gleeson, D. Gavaghan, and V. Grau Relationship between structural changes and hyperpolarized gas magnetic resonance imaging in chronic obstructive pulmonary disease using computational simulations with realistic alveolar geometry Phil Trans R Soc A, June 13, 2009; 367(1896): 2347 - 2369. [Abstract] [Full Text] [PDF]
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I. A. Greaves, C. C. W. Hsia, D. M. Hyde, M. Ochs, E. R. Weibel, J. H. T. Bates, H. B. Rossiter, E. C. Breen, H. Parameswaran, A. Majumdar, et al. Commentaries on viewpoint: use of mean airspace chord length to assess emphysema. To be or not to be-accurate. J Appl Physiol, December 1, 2008; 105(6): 1982 - 1983. [Full Text] [PDF]
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Last Word on Viewpoint: Use of mean airspace chord length to assess emphysema J Appl Physiol, December 1, 2008; 105(6): 1986 - 1987. [Full Text] [PDF]
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W. Mitzner Use of mean airspace chord length to assess emphysema J Appl Physiol, December 1, 2008; 105(6): 1980 - 1981. [Full Text] [PDF]
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R. E. Jacob, K. R. Minard, G. Laicher, and C. Timchalk 3D 3He diffusion MRI as a local in vivo morphometric tool to evaluate emphysematous rat lungs J Appl Physiol, October 1, 2008; 105(4): 1291 - 1300. [Abstract] [Full Text] [PDF]
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