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J Appl Physiol 103: 1326-1331, 2007. First published July 19, 2007; doi:10.1152/japplphysiol.01191.2006 Free Article
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Frontal cortical oxygenation changes during gravity-induced loss of consciousness in humans: a near-infrared spatially resolved spectroscopic study

Koichi Kurihara,1 Azusa Kikukawa,2 Asao Kobayashi,2 and Toshio Nakadate1

1Department of Hygiene and Preventitive Medicine, Showa University School of Medicine, Shinagawa-ku, and 2Aeromedical Laboratory, Japan Air Self-Defense Force, Tachikawa-shi, Tokyo, Japan

Submitted 10 February 2006 ; accepted in final form 13 July 2007


    ABSTRACT
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Gravity (G)-induced loss of consciousness (G-LOC), which is presumably caused by a reduction of cerebral blood flow resulting in a decreased oxygen supply to the brain, is a major threat to pilots of high-performance fighter aircraft. The application of cerebral near-infrared spectroscopy (NIRS) to monitor gravity-induced cerebral oxygenation debt has generated concern over potential sources of extracranial contamination. The recently developed NIR spatially resolved spectroscopy (SRS-NIRS) has been confirmed to provide frontal cortical tissue hemoglobin saturation [tissue oxygenation index (TOI)]. In this study, we monitored the TOI and the standard NIRS measured chromophore concentration changes of oxygenated hemoglobin and deoxygenated hemoglobin in 141 healthy male pilots during various levels of +Gz (head-to-foot inertial forces) exposure to identify the differences between subjects who lose consciousness and those who do not during high +Gz exposure. Subjects were exposed to seven centrifuge profiles, with +Gz levels from 4 to 8 Gz and an onset rate from 0.1 to 6.0 Gz/s. The SRS-NIRS revealed an ~15% decrease in the TOI in G-LOC. The present study also demonstrated the TOI to be a useful variable to evaluate the effect of the anti-G protection system. However, there was no significant difference found between conditions with and without G-LOC in subjects with terminated G exposure. Further studies that elucidate the mechanism(s) behind the wide variety of individual differences may be needed for a method of G-LOC prediction to be effectively realized.

hypergravity; loss of consciousness; near-infrared spectroscopy; cerebral oxygenation; oxygenated hemoglobin; deoxygenated hemoglobin


PILOTS OF HIGH-PERFORMANCE fighter aircraft are frequently exposed to high, sustained levels of headward +Gz accelerations [expressed as a multiple of the acceleration due to Earth's gravity (G)] during quick turns or recovery from dives. The inertial forces, which are in opposition to such acceleration, may produce physiological changes in the human body, such as distortion of tissues and organs and alteration in the flow and distribution of blood and body fluids. The progressive reduction in retinal blood flow causes various degrees of gray-out: complete cessation of the flow causes loss of vision (blackout) (5). Exposure to +Gz somewhat greater than that required to produce loss of vision results in a protracted loss of consciousness (G-LOC), which is presumably caused by a reduction of cerebral blood flow resulting in decreased oxygen supply to the brain (5, 11, 33). G-LOC has been identified as responsible for military aircraft accidents since this phenomenon was first described as "fainting in the air" during World War I (4, 13, 22). There have been numerous efforts to develop G protection methods against it, including muscle tensing, anti-G straining maneuvers, and anti-G suits (5, 11).

The reduction in cerebral oxygenation levels during +Gz exposure has been successfully monitored by an optical technique known as near-infrared spectroscopy (NIRS) in both human centrifuge (10, 18, 26, 30, 31) and operational in-flight studies (19, 20). NIRS is based on the transparency of tissue to near-infrared light (700–900 nm) and on oxygenation-dependent changes in absorption in cerebral tissue caused by oxy- and deoxyhemoglobin (O2Hb and HHb, respectively) (6, 16). The NIRS devices used in most studies have a light source and detector that are placed a few centimeters apart on the same side of the head, and these measure chromophore (O2Hb and HHb) concentration changes from an arbitrary starting point using a modified Beer-Lambert (MBL) method (6). Several human centrifuge studies using MBL-NIRS have reported that when the frontal cortical oxygen saturation falls to a certain level, G-LOC occurs (28, 35). However, clinical studies have suggested a confounding effect of extracranial tissue on MBL-NIRS measurements, which to date cannot be completely eliminated (9, 21). In an animal study using rhesus monkeys equipped with NIRS sensors fixed onto the cranial bone, Tran et al. (30) showed that cerebral hypoxemia was not sufficient to induce G-LOC defined as the disappearance of electrocorticogram activity (centrifuged up to 12 Gz). Thus they concluded that total hemoglobin (Hb) decrease or cerebral ischemia is the main mechanism for the occurrence of G-LOC. However, this theory has not been evaluated in the human G-LOC that occurs at +5–+6 Gz without any protection.

To overcome the extracranial contamination, another type of tissue oxygenation monitor has been developed which measures the absolute tissue hemoglobin saturation [tissue oxygen index (TOI)] utilizing NIR spatially resolved spectroscopy (SRS) (24, 29). In SRS, the slope of light attenuation vs. the distance is measured at a distant point from the light input, from which the TOI is calculated using photon diffusion theory (24). Al-Rawi et al. (2, 3) concluded that extracranial blood flow changes did not affect SRS-determined TOI in the brain of adult patients undergoing endarterectomy.

The purpose of the present study was to measure frontal cerebral oxygenation using both MBL and SRS during various levels of +Gz exposure to identify the differences between subjects who lose consciousness and those who do not during high +Gz exposure.


    METHODS
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects.   There were 141 healthy male pilots of the Japan Air Self-Defense Force (JASDF) who participated in JASDF centrifuge training and volunteered for the study, and an informed consent was signed by each. The subjects' average age was 25.3 ± 2.2 yr, height 172.0 ± 5.9 cm, and weight 68.9 ± 6.4 kg. Approval for this study was obtained from the Aeromedical Laboratory, the JASDF Human Ethics Committee.

Facilities and +Gz profiles.   The JASDF Aeromedical Laboratory Centrifuge (radius of 7.6 m) at Iruma Air Base, Saitama, Japan was used for the centrifuge training. The centrifuge was configured with an upright (13°seat back angle) seat.

Subjects were exposed to seven centrifuge profilings on 4 consecutive training days. The profiles include gradual-onset run [(GOR); onset rate of 0.1 Gz/s] with a maximum of up to +8 Gz; short-term repeated and sustained exposures with Gz levels from +4 to +8 Gz; a plateau from 8 to 30 s; and an onset rate from 1.0 to 6.0 Gz/s [rapid onset run (ROR)]. Table 1 shows the Gz level of each profile. There was a 1-min rest plateau of +1.4 Gz between G pulses in the case of the repeated-exposure profiles (Fig. 1). The subjects wore a custom-fitted standard JG-5A anti-G suit, which has bladders over the abdomen, thighs, and calves. The anti-G suit inflates to a uniform pressure through a flexible hose connected to the anti-G system, which supplies pressure with a schedule of ~10.3 kPa/G. The GOR and one of two short-term repeated-exposure profiles were performed without anti-G suit inflation. During GOR, subjects remained relaxed until they experienced gray-out, and then they initiated muscle and respiratory straining (an anti-G straining maneuver), which is a forced exhalation effort against a closed glottis while tensing the leg, arm, and abdominal muscles to maintain vision and consciousness. The subjects knew the profiles in advance and were given a 10-s countdown to onset.


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Table 1. Gz exposures in 7 profiles

 

Figure 1
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Fig. 1. Graphic display of near-infrared spectroscopy from a subject who experienced gravity (G)-induced loss of consciousness (G-LOC) during +6-Gz (head-to-foot inertial forces) exposure in a repeated-G exposure profile. The x-axis represents the time (min). From top to bottom; recordings show oxyhemoglobin (O2Hb), deoxyhemoglobin (HHb), total hemoglobin (cHb) concentration changes (µmol/l), +Gz (mV), and tissue oxygen index (TOI; %).

 
Criteria for terminating the +Gz exposures were the following: subjects' inability to proceed further; subjects' near loss of vision; G-LOC (slumping of head and trunk, and eyes closure); and completion of each profile.

Measurements.   During the Gz exposures, the cerebral O2Hb, HHb, TOI and +Gz levels were recorded using a custom-built NIRO-300G near-infrared spectrophotometer based on a commercially available bedside monitor (model NIRO-300, Hamamatsu Photonics, K. K. Hamamatsu, Japan). The NIRO-300G was adapted to withstand sustained high +Gz environment under field conditions. The optodes (light source and light detector) were set at a constant distance of 4 cm in a specialized rubber holder. Two sets of the optodes' rubber holder were placed on both sides of the forehead, just below the hairline but avoiding the area of the temporal muscle regions and sinuses. The rubber holders were secured to the skin with a double-sided adhesive sheet and an elastic bandage (19).

Using three wavelengths (775, 810, and 850 nm), the chromophore concentration changes (in µmol/l) in O2Hb and HHb can be calculated from an arbitrary starting point using MBL-NIRS: {Delta}C = {Delta}OD/{alpha}·L·B, where {Delta}C is the concentration change, {Delta}OD is the attenuation of light expressed as changes in optical density, {alpha} is the extinction coefficient of the chromophore (mmol/cm), L is the distance between the light source and the detector, and B is a pathlength factor that takes into account the scattering of light in the tissue (5.93) (32). Three wavelengths of lights are delivered by three pulsed photodiodes, and scattered light is detected by three closely placed photodiodes. The Hb concentration changes are measured by the middle photodiode, while the TOI is measured by means of all three. The sampling time was set at 0.5 s, and the pathlength of 24 cm (= probe distance x pathlength factor = 23.7) was used in the present study. An error message was recorded at each data point of each variable when the receiving light levels were out of the optimal working range. The data point with the error message was excluded from analysis. Gz levels were monitored with a low-capacity acceleration transducer (model AS10GB, Kyowa Electronic Instruments, Tokyo, Japan).

Data analysis.   NIRS variables from the right side of the forehead were analyzed at each G exposure. Baseline values for O2Hb, HHb, and TOI were taken as an average over 30 s before +Gz exposure in each profile. During this period, subjects were still and quiet on the seat in the centrifuge gondola waiting to run. The baseline duration was relatively brief to avoid the movement artifacts observed in some subjects, although stable baseline data were recorded for ~2–3 min in most of them. The maximum concentration changes of Hb ({Delta}O2Hb and {Delta}HHb) and TOI (%{Delta}TOI) from the baseline were calculated for each +Gz exposure.

Group averages of {Delta}O2Hb, {Delta}HHb, TOI, and %{Delta}TOI were calculated for three groups of subjects: those who completed exposure, those who terminated with G-LOC, and those who terminated without G-LOC in GOR (profile 1) as well as in the short-term repeated exposure with ROR (profiles 2 and 3).

The complete left-side data were used in the case of a lack of right-side data during +Gz exposure. In our laboratory's previous +Gz exposure studies using the NIRO300G, no significant difference has been observed in NIRS variables between the sides of the forehead (20).

Statistics.   NIRS variables in three groups were compared by using one-way ANOVA with Tukey's post hoc tests for multiple comparisons. When examining the anti-G suit effect, comparison of the TOI between profile 2 (without the G suit) and profile 3 (with the G suit) for each plateau +Gz (4, 5, 6, and 7 Gz) was performed in the completing subjects using repeated-measures ANOVA. A P value of <0.05 was taken to be significant.

A receiver operating characteristic (ROC) curve was plotted to determine the sensitivity and specificity of the TOI values to predict G-LOC using Stat Flex version 5.0 software (Artec, Osaka, Japan). Optimum cutoff values with the best combination of sensitivity and specificity were calculated. Overall accuracy of the diagnosis was expressed by the area under the curve, ranging from 0.5 to 1. A value of 1 implies perfect sensitivity and specificity, whereas a value of 0.5 implies that the model's accuracy is not better than chance.


    RESULTS
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
In some of the measurements, the errors of the receiving NIR light levels were recorded on the right side during sustained high +Gz exposure over +6 Gz. Thus 34% of the MBL-NIRS-derived data and 29% of the SRS-NIRS-derived data were taken from the left side. Figure 1 shows representative NIRS recordings in a G-LOC case during repeated short-term Gz exposure without anti-G suit inflation. The subject completed +4- and +5-Gz exposures while performing the anti-G straining maneuver, but he lost consciousness during +6-Gz exposure. The subject awoke and responded to the operator during the recovery of oxygenation levels to the baseline level with decreasing +Gz. O2Hb and TOI decreased with increasing +Gz, whereas HHb was slightly increased during +Gz exposure. A larger HHb increase was observed during the recovery to the ground level.

Figure 2 shows the mean values of NIRS variables in the three groups in the GOR profile. There was no significant difference among the number completed (n = 31), terminated with G-LOC (n = 12), and terminated without G-LOC (n = 91) in O2Hb or HHb. In TOI, no significant difference was observed among the number completed (n = 31), the number terminated with G-LOC (n = 12), and the number terminated without G-LOC (n = 79).


Figure 2
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Fig. 2. Near-infrared spectroscopy variables in the completed and terminated groups during the gradual-onset run profile. Top: maximum concentration changes ({Delta})of O2Hb and HHb. Bottom: minimum TOI.

 
The TOI in the short-term repeated-exposure profiles (profiles 2 and 3) significantly differed among groups (P = 0.00035; Fig. 3, bottom). TOI was significantly lower in the terminating subjects both with (n = 30; P < 0.01) and without G-LOC (n = 36; P < 0.05) compared with the completed subjects (n = 37). %{Delta}TOI was also significantly lower in the terminating groups than that in the completed subjects in the case of short-term repeated exposure with ROR (Table 2). In contrast to TOI, there was no significant difference among the completed (n = 47), terminated with G-LOC (n = 42), and terminated without G-LOC (n = 51) in O2Hb or HHb (Fig. 3, top).


Figure 3
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Fig. 3. NIRS variables in the completed and terminated groups during the short-term repeated-G exposure with rapid-onset rate profiles (profiles 2 and 3). Top: maximum concentration changes of O2Hb and HHb. Bottom: minimum TOI. The TOI in the terminated group both with and without G-LOC were significantly different from that in the completed group (*P < 0.05, **P < 0.01).

 

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Table 2. Maximum percent change in TOI in both GOR and repeated +Gz exposure with ROR

 
Table 3 shows the Hb and TOI in the G-LOC subjects in both the GOR and short-term repeated exposure with ROR profiles. There was no significant difference in the NIRS variables between ROR and GOR. In %{Delta}TOI, no significant difference was observed between them (Table 2).


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Table 3. NIRS variables in G-LOC during +Gz exposure with GOR and repeated +Gz exposure ROR

 
A significant anti-G suit effect was observed in the TOI in 30 subjects who completed two short-term repeated-exposure profiles (P < 0.05; Fig. 4). TOI was significantly higher with anti-G suit inflation than without inflation in +Gz exposures over 5 Gz (P < 0.05; Fig. 4).


Figure 4
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Fig. 4. Effect of the anti-G suit on the G-induced cerebral oxygenation decrease. Baseline and minimum TOI in the completed subjects during short-term repeated Gz exposures (profiles 2 and 3) are shown. There were significant differences between the conditions with ({circ}) and without (bullet) the anti-G suit (*P < 0.05, **P < 0.01).

 
Figure 5 (top) shows the TOI histograms for the baseline (866 data) and G-LOC (65 data) obtained from all subjects. The area under the ROC curve (Fig. 5, bottom) that used TOI to predict G-LOC was 0.972 (95% confidence interval 0.959–0.985), which indicates a sufficient accuracy to distinguish between G-LOC and baseline. Table 4 shows the discriminatory power of several TOI cutoff levels for predicting G-LOC. TOI levels yielded a sensitivity of 0.631 and a specificity of 0.991, with the optimum cutoff value of 58% equal to the %{Delta}TOI of –13 (Table 4), which was identified as the threshold level for ischemia in the adult brain in the study of patients undergoing carotid endarterectomy (3).


Figure 5
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Fig. 5. Top: TOI histogram for baseline (866 data points) and G-LOC (65 data points) obtained from 141 subjects. Bottom: receiver operating characteristic curve showing the sensitivity and specificity of different TOI values to predict G-LOC. The area under the receiver operating characteristic curve for TOI was 0.972 (95% confidence interval 0.959–0.985).

 

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Table 4. Discriminatory power of potential TOI cutoff values for predicting G-LOC

 

    DISCUSSION
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Without sufficient blood flow to the brain, the oxygen supply to the brain tissues is diminished and the brain cells do not maintain the metabolism necessary for consciousness. It is generally believed that G-LOC occurs following the critical reduction of cerebral blood flow that occurs due to increased acceleration. Although the G-LOC cases in the present study demonstrated this critical cerebral oxygenation level, there was scant difference in the oxygenation variables between those with and without G-LOC. We also found that the oxygenation variables decreased to the same levels in subjects with G-LOC and in subjects who completed a GOR up to +8Gz. The reason for the large variability in the individual susceptibility to reductions in cerebral oxygenation induced by GOR +Gz exposure is unclear.

Methodology.   During high +Gz exposure the NIRS apparatus generated error messages in ~30% of the recordings from the right side, although no visible displacement of the sensor probes occurred. +Gz as well as the anti-G straining maneuver may have induced skin movement on the forehead (5, 11) and higher tension on the right side optical fiber connecting with the main body on the higher shelf in the gondola. MBL-NIRS measurements may be considerably influenced by contamination from extracranial tissue (2, 9, 23). Germon et al. (9) have confirmed that the source-detector distance increases sensitivity to cerebral oxygenation while decreasing sensitivity to extracerebral oxygenation. Although the source-detector distance used in the present study (4 cm) is shorter than the demonstrated optimal distance (4.8–5.5 cm) for minimizing the effect of an extracranial change, it has been shown to be sensitive to hypoxia deep in the scalp (9). In our laboratory's preliminary study, probe separations over 4 cm induced a higher number of errors during high +Gz exposure.

Compared with the MBL-NIRS-determined chromophore concentration changes ({Delta}O2Hb and {Delta}HHb), the TOI determined by SRS-NIRS is less prone to contamination from extracranial tissue, because it takes into account the spatial variation of the intensity of retro-reflected light as a function of the distance from the light source with large source-detector spacing (24, 29). Al-Rawi et al. (2) demonstrated that TOI from the frontal region decreased with chromophore changes during internal carotid artery clamping but not with the changes induced by external carotid artery clamping. They also showed that TOI changes were closely related to changes in transcranial Doppler mean flow velocity of the ipsilateral middle cerebral artery but not with changes in frontal cutaneous laser-Doppler flowmetry. Taken together, these data indicate that TOI reflects oxygenation changes of intracranial tissue (2).

In the present study, both O2Hb and TOI decreased with increasing +Gz exposure. However, the minimum O2Hb value was not consistent with the TOI in short-term repeated exposure. The TOI was significantly higher in subjects who completed the profile than those who terminated, whereas no significant group difference was observed in O2Hb (Fig. 3, Table 2). Together with the finding of a gradual increment of HHb and the total Hb during recovery from +Gz exposure (Fig. 1), the discrepancy between O2Hb and TOI may indicate a higher contribution of extracranial tissue, such as skin blood flow, to the MBL-NIRS signal (2).

In addition to these technical limitations, effects of +Gz exposure on the skin and cerebrospinal fluid are other potential sources of error. The high pressure differences across the walls of the capillaries in the skin of dependent parts produced by exposure to +Gz acceleration gives rise to transudation of fluid (11). Cerebrospinal fluid pressure also falls in parallel with the reduction of arterial and venous vascular pressure in the head during +Gz exposure (11). Thus, during +Gz acceleration, changes in tissue fluid and the cerebrospinal fluid layer are likely to influence the scattering of light and in turn the NIRS measurement of chromophore change. It is difficult to evaluate the quantitative effects of these fluid changes, but the fact that Gz induced gradual TOI changes suggested that they are of minor importance as indicated by a cerebral ischemia study (2, 3).

Cerebral oxygenation and loss of consciousness.   The present study demonstrated cortical oxygenation levels at G-LOC that were not related to the Gz onset rate. Based on hydrostatic column theory, it has been proposed that during G exposure a lower perfusion pressure is produced at the top of the brain compared with the base (34). However, no consistent pattern of the vertical distribution of flow has been found by either animal (33) or human in-flight studies (27). In-flight measurement of cerebral blood flow with single-photon-emission computed tomography study revealed no significant regional differences during +6 Gz between 33 cerebral regions (27). These studies suggest that the NIRS-determined decrease in cortical oxygenation may be taken to reflect similar oxygenation changes in deeper parts of the brain. Al-Rawi and Kirkpatrick (3) identified a quantifiable TOI threshold for ischemia in the adult brain in the study of patients undergoing carotid endarterectomy. A threshold for %{Delta}TOI of –13 was identified, above which no patients exhibited any evidence of ischemia on clamping in their study (sensitivity, 1.0, specificity, 0.932) (3). In the present study, the mean %{Delta}TOI of G-LOC was –14.33 for GOR and –15.01 for ROR (Table 2). ROC analysis revealed good discriminatory accuracy between normal and G-LOC by measurement of the TOI. The area under the ROC curve was >0.8, implying good predictive power (36). ROC analysis also showed that the TOI threshold for ischemia identified in the previous clinical study was the optimal cutoff value for G-LOC (sensitivity of 0.631 and a specificity of 0.991). Another important finding of the study was that the +Gz-induced TOI decrements were effectively prevented by the standard anti-G suit which induces peripheral vascular resistance and a reduction of venous pooling in the lower limbs (12). These results suggest that cerebral oxygenation debt is one of the important factors in G-LOC. However, no significant difference was observed in the NIRS variables in the terminated cases with and without G-LOC. Although the relation between cerebral oxygenation debt and the fading of consciousness is recognized, other factors may be involved that are not assessed by NIRS, e.g., loss of cortical connectivity and/or particular blood flow changes in brain stem regions (15, 17, 23, 25, 28). Subtle microvascular perfusion changes, which respond to second-by-second changes in local metabolic demand, are one of the possible factors for maintaining the cerebral metabolism required for consciousness. Recent studies have revealed the red blood cells themselves actually contribute to the local vasodilation process, with hemoglobin acting as the hypoxic sensor that couples decreasing oxygen tension to increased blood flow (1, 7, 8, 14). A relatively higher HHb concentration may contribute to local vasodilation in subjects tolerant to GOR +8-Gz exposure (+8 Gz, 7.45 µmol/l; G-LOC, 5.69 µmol/l).

Conclusions.   SRS-NIRS spectroscopy revealed a decrease of ~15% in the TOI of frontal cortical oxygen saturation in acceleration-induced loss of consciousness in fighter pilots, and it also demonstrated that TOI is useful to evaluate the effect of anti-G protection systems. However, because of the large variability in susceptibility to reductions in cerebral oxygenation, changes in frontal cortical TOI and O2Hb did not allow a prediction of G-LOC.


    ACKNOWLEDGMENTS
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
The authors thank the JASDF pilots who enthusiastically served as subjects for this study. They are also grateful to the staff of the centrifuge training section of the Aeromedical Laboratory for assistance with data collection and to the Aeromedical Laboratory physicians for assistance with medical monitoring.

Portions of the data were presented at the 75th Annual Scientific Meeting of the Aerospace Medical Association, Anchorage, Alaska, May 2–6, 2004.

Pacific Edit reviewed the manuscript before submission. Dr. Rudolph Richichi, Statistical Analysis and Measurement Consultants, Inc., reviewed the summary statistics of the manuscript before submission.


    FOOTNOTES
 

Address for reprint requests and other correspondence: A. Kobayashi, Pharmacochemistry Sec. of Aeromedical Laboratory, Japan Air Self-Defense Force, 1-2-10 Sakae-cho, Tachikawa-shi, Tokyo 190-8585, Japan (e-mail: asaokobayashi{at}jcom.home.ne.jp)

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.


    REFERENCES
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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