Endocrine relationships during human spaceflight

T. P. Stein1, M. D. Schluter1, and L. L. Moldawer2

1 Department of Surgery, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, New Jersey 08084; and 2 Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Human spaceflight is associated with a chronic loss of protein from muscle. The objective of this study was to determine whether changes in urinary hormone excretion could identify a hormonal role for this loss. Urine samples were collected from the crews of two Life Sciences Space Shuttle missions before and during spaceflight. Data are means ± SE with the number of subjects in parentheses. The first value is the mean preflight measurement, and the second value is the mean inflight measurement. Adrenocorticotropic hormone (ACTH) [27.7 ± 4.4 (9) vs. 25.1 ± 3.4 (9) ng/day], growth hormone [724 ± 251 (9) vs. 710 ± 206 (9) ng/day], insulin-like growth factor I [6.81 ± 0.62 vs. 6.04 ± 0.51 (8) nM/day], and C-peptide [44.9 ± 8.3 (9) vs. 50.7 ± 10.3 (9) µg/day] were unchanged with spaceflight. In contrast, free 3,5,3'-triiodothyronine [791 ± 159 (9) vs. 371 ± 41 (9) pg/day, P < 0.05], prostaglandin E2 (PGE2) [1,064 ± 391 (8) vs. 465 ± 146 (8) ng/day, P < 0.05], and its metabolite PGE-M [1,015 ± 98 (9) vs. 678 ± 105 (9) ng/day, P < 0.05] were decreased inflight. The urinary excretion of most hormones returned to their preflight levels during the postflight period, with the exception of ACTH [47.5 ± 10.3 (9) ng/day], PGE2 [1,433 ± 327 (8) ng/day], PGF2alpha , [2,786 ± 313 (8) ng/day], and its metabolite PGF-M [4,814 ± 402 (9) ng/day], which were all increased compared with the preflight measurement (P < 0.05). There was a trend for urinary cortisol to be elevated inflight [55.3 ± 5.9 (9) vs. 72.5 ± 11.1 µg/day, P = 0.27] and postflight [82.7 ± 8.6 (8) µg/day, P = 0.13]. The inflight human data support ground-based in vitro work showing that prostaglandins have a major role in modulating the changes in muscle protein content in response to tension or the lack thereof.

cortisol; shuttle; urinary hormone excretion

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

MICROGRAVITY PERTURBS the homeostasis of the body because of the loss of hydrostatic pressure, conflicting inputs into the neurovestibular system, and lack of physical tension on the musculoskeletal system. The fluid shifts and the neurovestibular disorientation generally resolve within the first day or two in microgravity, but the effects on the musculoskeletal system are chronic. Specifically, there is a continued loss of protein from muscles and calcium from bones with antigravity functions, particularly in the trunk and legs (12, 22, 37, 48).

In a previous report, we described the metabolic response to spaceflight by humans as consisting of two components, a fixed obligatory component and a variable component, depending on whether the astronauts were in energy balance. The latter is subject and mission dependent; the former is not (37). The obligatory response consists of an initial metabolic stress response combined with the chronic loss of protein from muscle and calcium from bone. The metabolic stress response diminishes within the first few days, whereas the bone and muscle losses continue (37). In this report, we describe the urinary hormone excretion profile during spaceflight on the shuttle. The objective of the study was to determine whether changes in the urinary hormone excretion could be used to identify a hormonal role in the obligatory losses of protein from muscle.

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Informed consent for these studies was obtained in accordance with the procedures of the National Aeronautics and Space Administration and the University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine.

The shuttle data presented here are from two recent Life Sciences Missions (SLS1 and SLS2) that were flown in 1991 and 1993, respectively (36, 37). The SLS1 mission lasted 9.5 days and the SLS2 mission 15 days. Dietary intake and urine output were monitored for 10 days preflight, during the inflight period, and for 7 days postflight. Details of sample collection and nitrogen balance determination have been reported previously (37).

Biochemical analyses. Urine samples were kept frozen until analyzed. After thawing, 24-h urine pools were made by the fractional aliquot method. All hormonal analyses were done in duplicate on the urine samples with commercially available reagents. Enzyme-linked immunosorbent (ELISA) kits (Quantikine HS) for interleukin (IL)-6 and IL-10 were obtained from R & D Systems (Minneapolis, MN); kits for C-peptide, cortisol, adrenocorticotropic hormone (ACTH), free 3,5,3'-triiodothyronine (T3), and insulin-like growth factor I (IGF-I) were purchased from Incstar (Stillwater, MN), and a human growth hormone (GH) Radioimmunoassay kit was purchased from Kallestad Diagnostics (Chaska, MN). The GH assay was specific for total GH. Enzyme immunoassay (EIA) kits for prostaglandin E2 (PGE2), its metabolite 13,14-dihydro-15-keto-PGE2 (PGE-M), and PGF2alpha were obtained from Cayman Chemicals (Ann Arbor MI). The reagents for the EIA assay of PGF2alpha metabolite 13,14-dihydro-15-keto-PGF2alpha (PGF-M) were also purchased from Cayman Chemicals. The epinephrine and norepinephrine data and some of the cortisol data were supplied by National Aeronautics and Space Administration (NASA) as part of the SLS1/2 investigators' data-sharing agreement. The cortisol analyses for the two subjects for whom values were not provided by NASA were determined with an RIA kit from Incstar.

Statistical analyses. The database was divided into four periods, preflight, flight day 1 (FD1), flight days 2-12 (FD2-FD12), and the 7 postflight days (R0-R7). Because dietary intake was significantly reduced on FD1 (Ref. 37, Table 1), data for FD1 were evaluated separately from the other inflight days. Means were computed for each period, and a repeated-measures analysis of variance (RMANOVA) was performed with the SAS program (SAS Institute, Cary, NC). Significance was accepted at P < 0.05. If significance was found during the inflight period FD2-FD12, the period was further divided into flight days 2-7 (FD2-FD7) and flight days 8-12 (FD8-FD12) with the objective of determining whether the observed difference in the total inflight value was attributable to either the early or late inflight periods or both. Paired t-tests were used and significance was accepted at P < 0.05. Values in the text, tables, and figures are means ± SE, and the number of subjects is in parentheses.

                              
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Table 1.   Summary of body weight, dietary intake, and nitrogen balance data

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

The data are given as the composite means of the SLS1 (n = 3) and SLS2 (n = 6) missions with inflight points beyond flight day 10 being from SLS2 only. The hormonal data have not been normalized to body weight because body weight and composition may change with spaceflight.

Table 1 summarizes the previously reported anthropometric and dietary data for these astronauts (37). On FD1 dietary intake was reduced by ~55% because of space motion sickness. After the first day, however, dietary intake was stable at ~80% of the preflight level for the remainder of the time in orbit (Table 1, Ref. 37). The nitrogen balance values are estimates because they are derived from urinary nitrogen alone and do not include fecal nitrogen losses. Nitrogen retention was decreased during the inflight period and returned to the preflight levels after landing (Table 1).

Table 2 summarizes the urinary excretion measurements, and the figures demonstrate how selected parameters changed with time in space. Entry into microgravity was associated with increases in IL-6 (P < 0.05), IL-10 (P < 0.05), and cortisol excretion (Fig. 1) and decreases in C-peptide (P < 0.05), norepinephrine (P < 0.05), GH (P < 0.05), and ACTH (P < 0.05, Table 2). The RMANOVA for cortisol approached but failed to achieve statistical significance (P = 0.0597). If it is accepted that this overall P value indicates significance, cortisol was increased on FD1 (P < 0.05). Urinary creatinine was reduced on FD1 (Table 1) possibly because of some incomplete collections in the period immediately after launch. Normalizing the FD1 data to creatinine renders the decreases in GH and ACTH no longer significant, but the increase in cortisol becomes significant.

                              
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Table 2.   Urinary hormone excretion data before and during mission


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Fig. 1.   Change in urinary cortisol excretion for 9 subjects during and after spaceflight. Data are means ± SE and are given as percentage of preflight mean value. Except for flight day 1 (FD1) and FD12, data points are means of 2 24-h pools.

With the possible exception of cortisol, the urinary excretion of the hormones discussed above returned to preflight values and was unchanged for the remainder of time in orbit. There was a weak trend for cortisol to be elevated for the period FD2-FD12 (P = 0.27, Table 2, Fig. 1). In contrast, T3 (P < 0.05, Fig. 2), norepinephrine (P < 0.05, Table 2) (20), PGE2 (P = 0.05, Fig. 3), and PGE-M excretion (P < 0.05, Fig. 4) were all decreased inflight. The decreases in T3, norepinephrine, PGE2, and PGE-M excretion were statistically significant for both the early (FD2-FD7) and late (FD8-FD12) phases of the mission (Table 2).


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Fig. 2.   Change in urinary free 3,5,3'-triiodothyronine (T3) excretion for 8 subjects during and after spaceflight. Data are means ± SE and are given as percentage of preflight mean value. Except for FD1 and FD12, data points are means of 2 24-h pools.


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Fig. 3.   Change in urinary prostaglandin E2 (PGE2) excretion for 8 subjects during and after spaceflight. Data are means ± SE are given as percentage of preflight mean value. Except for FD1 and FD12, data points are means of 2 24-h pools.


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Fig. 4.   Change in urinary metabolite of prostaglandin E2 (PGE-M) excretion for 9 subjects during and after spaceflight. Data are means ± SE and are given as percentage of preflight mean value. Except for FD1 and FD12, data points are means of 2 24-h pools.

After landing, dietary intake and nitrogen balance returned to preflight levels (Table 1) as did the urinary excretion of T3 (Fig. 2), norepinephrine, PGE2 (Fig. 3), and PGE-M (Fig. 4). PGF2alpha (Fig. 5) and PGF-M (Fig. 6), which showed only weak trends toward decreases inflight (P = 0.14 and P = 0.13, respectively), were significantly increased above their preflight values postflight (P = 0.02 and P = 0.01). PGE2 (P < 0.006) but not PGE-M excretion (P = 0.23) was also increased during the postflight period. The trend for cortisol excretion to be elevated persisted into the postflight measurement period (Fig. 1, P = 0.12) and was paralleled by an increase in ACTH excretion (Table 2, P < 0.05).


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Fig. 5.   Change in urinary PGF2alpha excretion for 8 subjects during and after spaceflight. Data are means ± SE and are given as percentage of preflight mean value. Except for FD1 and FD12, data points are means of 2 24-h pools.


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Fig. 6.   Change in urinary metabolite of PGF2alpha (PGF-M) excretion for 9 subjects during and after spaceflight. Data are means ± SE and are given as percentage of preflight mean value. Except for FD1 and FD12, data points are means of 2 24-h pools.

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

As with other spaceflight missions, the astronauts on SLS1 and SLS2 lost body protein (22, 37, 48). Details of the changes in nitrogen balance studies on these astronauts have been discussed in Ref. 37. The observations are in agreement with the report by LeBlanc et al. (22), who used dual-beam X-ray absorptiometry to document the loss of lower body and back muscle protein after shuttle flights. The astronauts on these missions also lost calcium from bone. Urinary calcium and deoxypyridinoline excretion were increased by 19 (P < 0.02) and 23% (P < 0.01), respectively, inflight (1).

The database. The studies reported here have relied on 24-h urinary excretion measurements to document the daily production of several hormones and inflammatory mediators. The use of urine instead of blood to assess total production has both disadvantages and advantages. The two principal disadvantages are as follows. 1) Urine-derived data could be affected by abnormal renal function. This is not a likely possibility because there is no evidence that renal function is generally altered by spaceflight (20). There was an early increase in the glomerular filtration rate on these missions, but these changes did not persist beyond the first week in orbit (20, 33). 2) Urinary measurements are further removed from the sites of synthesis and action of a hormone than plasma. However, neither urine nor plasma actually reflects the situation at the site of tissue production or action.

An advantage of urinary excretion measurements is that changes can sometimes be detected in urine when they cannot be detected in the plasma. This is because plasma samples represent single spot values, and plasma hormone levels can fluctuate very rapidly with time. In contrast, urine measurements give an integrated value over time, depending on the biological half-life of the molecule. This is particularly advantageous in situations where anticipated changes are small, when the hormone is released in a pulsatile manner, and when sampling opportunities are limited.

In analyzing the data, we have made two assumptions. First, as discussed above, urine excretion data are a valid measure of 24-h whole body production.

The second assumption is that the data are not complicated by an inflight energy deficit. Actual energy balance data are not available for any of these astronauts, but it is highly likely that they were either in or close to energy balance. Energy expenditure as measured by the doubly labeled water method for four subjects on a similar mission, the 1996 Life and Microgravity Sciences mission (LMS), was 40.8 ± 0.6 kcal · kg-1 · day-1 (39). Physical activity was greater on the LMS mission because there were required exercise regimens. There was no mandatory exercising on SLS1/2 because of time constraints (37). Energy expenditure on the LMS mission was greater than the dietary intake of the subjects on SLS1/2 (40.8 ± 0.6 vs. 31.1 ± 1.8 kcal · kg-1 · day-1) (37). The difference can be explained by the difference in activity between the two missions.

There is considerable experimental evidence to suggest that energy expenditure is reduced during spaceflight. Energy expenditure was reduced during spaceflight on the LMS mission (39). Energy expenditure was also reduced by chair-adapted Rhesus monkeys flown as part of the U.S.-Russian Bion biosatellite program (37). A reduction in energy expenditure can account for the reduced urinary excretion of T3 found in this study (Fig. 2).

Catecholamines. Decreases in urinary norepinephrine secretion have been consistently documented in many spaceflight and bed rest studies (3, 11, 20, 21), and the same result was found in these two flights (20). The reduction in norepinephrine and the unchanged epinephrine excretion have been attributed to inhibition of sympathoneural outputs secondary to increased cardiac filling from the head-directed fluid shifts (11). Urinary catecholamine excretion was elevated on the day of reentry, and a trend toward an increase persisted for the remainder of the recovery period. The postflight catecholamine data are for the most part uninterpretable because of fluid loading with some of the subjects before landing and electrolyte replacement for other subjects after landing (20).

Insulin. Potentially, alterations in insulin production and responsiveness could be a major factor in the protein loss, because insulin resistance does occur in stress states, and we have previously shown that entry into orbit is associated with a metabolic stress response (37). The current data, however, show that no major changes were found with insulin production. There was a small increase in C-peptide excretion with time in orbit (37), but the changes were modest compared with some of the other hormones.

Cortisol and the hypothalamic-pituitary-adrenal axis. With the exception of cortisol, which was increased on FD1 and marginally increased during spaceflight (P = 0.27), spaceflight had little discernible effect on the urinary excretion of the hypothalamic-pituitary-adrenal (HPA) axis hormones. The urinary GH findings agree with the analyses on blood samples collected during the Skylab missions by Leach et al. (20). On Skylab, GH was unchanged except for a transient increase on flight days 3 and 4 (20). The absence of a decrease in GH inflight is paralleled by the absence of any increase during the postflight period. These findings argue against a primary role for the HPA axis and GH in particular on the regulation of muscle protein content inflight. This conclusion is supported by animal data. Inflight replacement of GH in rats was without any effect on skeletal muscle mass (15). HPA axis hormones act systemically and lack specificity on individual muscle groups. In contrast, spaceflight-induced muscle atrophy is limited primarily to muscles with antigravity functions (12, 40).

There was however a weak trend for cortisol excretion to be increased during (P = 0.27) and after spaceflight (P = 0.12, Fig. 1). Urinary cortisol levels were persistently elevated in six of the nine subjects (178 ± 21% of the mean preflight value). Seven of the nine subjects were the same as studied by Leach et al. (20). For these seven subjects, the increase in urinary cortisol was statistically significant (20). On Skylab, urinary cortisol was elevated for the duration of the mission for all nine subjects (28-84 days). It is therefore reasonable to believe that cortisol production is increased during spaceflight. However, there are a number of arguments against cortisol being a major factor in the muscle loss.

1) On the ground, infusion of cortisol results only in a transient increase in protein degradation, and the increased degradation is primarily seen in myofibrillar proteins as evidenced by increased 3-methylhistidine excretion (4, 16, 27). In contrast, there was no evidence that myofibrillar protein breakdown was increased on these two missions. Urinary 3-methylhistidine excretion was unchanged with spaceflight (38).

2) The spaceflight-induced increase in cortisol excretion differs from that found with a metabolic stress response in which an increase in plasma cortisol is associated with an increase in ACTH. This relationship is not found during human spaceflight, but it was found postflight when both cortisol and ACTH excretion were increased. As with other missions, ACTH excretion was unchanged in these astronauts. Both U.S. and Russian investigators have observed and commented on this apparent anomaly (12, 20, 41). Leach et al. (20) suggested that this was due in some way to cortisol lagging behind ACTH secretion because blood was not sampled until some time after any increase in ACTH secretion may have occurred (20). This explanation is inconsistent with our data because the urine measurements are integrated over time, and the trend for an increase in cortisol persisted for the duration of the mission. An alternate explanation is that the elevated cortisol excretion found after the initial adaptation period is not due to a metabolic stress response but may be a consequence of the emotional stress that is associated with spaceflight (41, 45, 46).

3) Increased cortisol has only been found with some but not all bed rest studies (6, 10, 41, 45, 46), whereas bed rest is invariably associated with muscle atrophy.

4) An increase in cortisol production is a systemic response and so cannot by itself account for the specificity of the load-bearing muscle and bone losses that are found.

5) With spaceflight, slow-twitch fibers (type I) atrophy more rapidly than fast-twitch fibers (type II, Ref. 5), whereas with cortisol the effect is predominantly on fast-twitch fibers (9).

Prostaglandins. Plasma PGE2 and PGF2alpha are unstable and so are measured as their metabolites PGE-M and PGF-M. PGE-M and PGF-M are the major metabolites of the E and F prostaglandins, respectively (2, 13, 26). They are excreted unchanged in the urine and are generally taken to reflect whole body as opposed to renal plus systemic prostaglandin production (2, 7, 8, 25, 32).

Both PGE-M (P = 0.005, Fig. 4) and PGF-M excretion values (P = 0.13, Fig. 6) were decreased inflight compared with their preflight values, but the decrease in PGE-M was much greater (30%) and statistically significant. Postflight, the pattern of prostaglandin excretion was reversed. There was a ~30% increase in PGF-M (P = 0.001) and a return to the preflight value for PGE-M.

Much of the urinary PGE2 and PGF2alpha is renal in origin, and therefore urinary measurements will reflect an unknown mixture of systemic and renal prostaglandin metabolism (2, 31). Even so, the changes in PGE2 and PGF2alpha excretion paralleled the PGE-M and PGF-M profiles, suggesting that the changes found with PGE2 and PGF2alpha reflected systemic rather than renal production of PGE2 and PGF2alpha .

As with any whole body study, unambiguous assignment of the source of the decreased prostaglandin production cannot be made. It is, however, reasonable to assume that the site(s) is/are ones that is/are known to be affected by spaceflight. In the present case, these are muscle and bone. Both muscle and bone release prostaglandins in response to mechanical stress (17, 24, 34, 43, 47). We suggest that muscle is likely to be the major site of the decreased prostaglandin production because there is considerably more muscle than there is of bone, and muscle is a more metabolically active tissue. A study on unweighted rats by Ku and Thomason (19) reported that skeletal muscle continuously adjusts its protein synthesis rate to accommodate workload. It would be expected, therefore, that the associated mediators would also respond rapidly to alterations in muscle tension, and this is what was found with prostaglandins in this experiment (Figs. 4 and 6).

Although cortisol can inhibit prostaglandin release, this is not a likely explanation for the inflight decrease in prostaglandin production. Cortisol functioning alone cannot confer the specificity of the inflight response. Second, PGF-M excretion was increased postflight at a time when cortisol excretion was also increased. Cortisol was essentially unchanged for the flight and recovery periods, i.e., it was marginally elevated throughout (Fig. 1). It is improbable that similar increases in cortisol during and after flight can have an inhibitory effect on prostaglandin production inflight and a stimulatory effect postflight.

PGE2 and PGF2alpha stimulate muscle protein degradation and synthesis, respectively (30, 42). Of particular relevance to the spaceflight-induced muscle atrophy is that, in vitro, PGE2 and PGF2alpha function as autocrine second messengers in regulating stretch-induced changes in muscle protein synthesis and breakdown (28, 43). Furthermore, cell culture studies by Vandenburgh and colleagues (43, 44) demonstrated that muscle cells release PGE2 and PGF2alpha into the medium, and the amount released varies with the tension applied to the cells. Prostaglandin release decreases as tension is decreased. In rats, the PGE2 secreted by muscle acts synergistically with NO to dilate the microcapillaries in the muscle (18). Conversely, a decrease in PGE2 release leads to constriction of the blood vessels. Histological examination of human quadriceps muscle biopsies taken immediately after landing showed a decrease in the number of capillaries per muscle fiber (5).

A possible consequence of decreased blood flow is a decrease in nutrient availability, which thereby initiates a localized starvation response in the muscle. Without adequate oxygen and substrate delivery, muscle cells adapt by conserving energy, decreasing protein synthesis, and remodeling. The process is one of adaptation; the decrease in cell protein content and distribution can be selective, with the possibility of strength being conserved at the expense of some other property, for example, increased fatigability (5). As soon as the resting muscles experience tension, prostaglandin release occurs, resulting in the dilation of the capillaries and increasing nutrient availability for the replacement of lost muscle proteins.

Whereas we believe our measurements relate primarily to muscle loss, similar prostaglandin mechanisms may also be involved in the spaceflight-induced loss of calcium from bone. Both PGE2 and PGF2alpha are powerful stimulators of bone resorption. The prostaglandins produced by osteoblasts and osteoclasts in response to mechanical stress are involved in the local regulation of bone metabolism (24, 29). The resultant prostaglandins promote angiogenesis by stimulating the release of vascular endothelial factor by osteoblasts (14). Conversely, decreased prostaglandin release will lead to microcapillary constriction.

In summary, the principal findings from this study are that 1) T3 and prostaglandin activity is reduced during spaceflight; 2) the inflight data support a major role for decreased prostaglandin production in the protein loss by muscle; and 3) the lack of consistent changes in GH, ACTH, and cortisol makes it unlikely that the HPA axis hormones are a major factor in the chronic muscle loss.

    ACKNOWLEDGEMENTS

We thank the numerous people in the Space and Life Sciences Directorate of the National Aeronautics and Space Administration (NASA)-Lyndon Baines Johnson Space Center at Houston and Lockheed-Martin Government Services Division for implementing this experiment. Special thanks are due to the crews of SLS1 and SLS2 for their cooperation. We also acknowledge and thank 1) Dr. Helen Lane and the urine monitoring system team at the Johnson Space Center for their efforts over the years to ensure accurate collection of the dietary data and usable urine samples; 2) Dr. Carolyn L. Huntoon, the Principal Investigator of experiment E192 for providing us with the dietary data, catecholamine values, and some of the cortisol data as part of the SLS1 and SLS2 investigators' data-sharing agreement; 3) Dr. C. M. Schroeder for assistance with the statistical analyses, and 4) Dr. C. E. Wade of NASA-Ames Research Center for helpful discussions.

    FOOTNOTES

This work was supported by NASA contract BE9-17276 and by National Institute of General Medical Sciences Grant GM-40586.

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. §1734 solely to indicate this fact.

Address for reprint requests: T. P. Stein, Dept. of Surgery, Univ. of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, 2 Medical Center Dr., Stratford, NJ 08084.

Received 16 June 1998; accepted in final form 8 September 1998.

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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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