Diagnostic ultrasound at MACH 20: retroperitoneal and pelvic imaging in space.

An operationally available diagnostic imaging capability augments spaceflight medical support by facilitating the diagnosis, monitoring and treatment of medical or surgical conditions, by improving medical outcomes and, thereby, by lowering medical mission impacts and the probability of crew evacuation due to medical causes. Microgravity-related physiological changes occurring during spaceflight can affect the genitourinary system and potentially cause conditions such as urinary retention or nephrolithiasis for which ultrasonography (U/S) would be a useful diagnostic tool. This study describes the first genitourinary ultrasound examination conducted in space, and evaluates image quality, frame rate, resolution requirements, real-time remote guidance of nonphysician crew medical officers and evaluation of on-orbit tools that can augment image acquisition. A nonphysician crew medical officer (CMO) astronaut, with minimal training in U/S, performed a self-examination of the genitourinary system onboard the International Space Station, using a Philips/ATL Model HDI-5000 ultrasound imaging unit located in the International Space Station Human Research Facility. The CMO was remotely guided by voice commands from experienced, earth-based sonographers stationed in Mission Control Center in Houston. The crewmember, with guidance, was able to acquire all of the target images. Real-time and still U/S images received at Mission Control Center in Houston were of sufficient quality for the images to be diagnostic for multiple potential genitourinary applications. Microgravity-based ultrasound imaging can provide diagnostic quality images of the retroperitoneum and pelvis, offering improved diagnosis and treatment for onboard medical contingencies. Successful completion of complex sonographic examinations can be obtained even with minimally trained nonphysician ultrasound operators, with the assistance of ground-based real-time guidance.

Invited review: gender issues related to spaceflight: a NASA perspective.

This minireview provides an overview of known and potential gender differences in physiological responses to spaceflight. The paper covers cardiovascular and exercise physiology, barophysiology and decompression sickness, renal stone risk, immunology, neurovestibular and sensorimotor function, nutrition, pharmacotherapeutics, and reproduction. Potential health and functional impacts associated with the various physiological changes during spaceflight are discussed, and areas needing additional research are highlighted. Historically, studies of physiological responses to microgravity have not been aimed at examining gender-specific differences in the astronaut population. Insufficient data exist in most of the discipline areas at this time to draw valid conclusions about gender-specific differences in astronauts, in part due to the small ratio of women to men. The only astronaut health issue for which a large enough data set exists to allow valid conclusions to be drawn about gender differences is orthostatic intolerance following shuttle missions, in which women have a significantly higher incidence of presyncope during stand tests than do men. The most common observation across disciplines is that individual differences in physiological responses within genders are usually as large as, or larger than, differences between genders. Individual characteristics usually outweigh gender differences per se.

The risk of renal stone formation during and after long duration space flight.

BACKGROUND: The formation of a renal stone during space flight may have serious negative effects on the health of the crewmember and the success of the mission. Urinary biochemical factors and the influence of dietary factors associated with renal stone development were assessed during long duration Mir Space Station missions. METHODS: Twenty-four-hour urine samples were collected prior to, during and following long duration space flight. The relative urinary supersaturation of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were determined. RESULTS: Changes in the urinary biochemistry of crewmembers during long duration spaceflight demonstrated increases in the supersaturation of the stone-forming salts. In-flight hypercalciuria was evident in a number of individual crewmembers and 24-hour dietary fluid intake and urine volume were significantly lower. During flight, there was a significant increase in brushite supersaturation. CONCLUSIONS: These data suggest acute effects of space flight and postflight changes in the urinary biochemistry favoring increased crystallization in the urine. The effects of dietary intake, especially fluid intake, may have a significant impact on the potential for renal stone formation. Efforts are now underway to assess the efficacy of a countermeasure to mitigate the increased risk.

Urine volume and its effects on renal stone risk in astronauts.

BACKGROUND: Urine composition in astronauts during and immediately after spaceflight changes in ways that increase the renal stone-forming potential for calcium oxalate, calcium phosphate, and uric acid saturation. We examined the effect of urine volume on the risk of renal stone formation in 356 astronauts. METHODS: Renal stone-forming risk was evaluated from 24-h urine samples collected from astronauts before and after 4- to 17-d Space Shuttle flights. Urinary chemistries were performed and the relative supersaturations of calcium oxalate, brushite, sodium urate, struvite, and uric acid saturation were calculated from the biochemical results. RESULTS: Urinary supersaturation levels of stone-forming salts were inversely related to urinary output both before and after spaceflight. Urine volume > 2 L x d(-1) reduced the risk of renal-stone development without affecting urinary citrate concentrations as compared with the increased risk observed in those astronauts who excreted urine volumes < L x d(-1). CONCLUSION: Results from this study indicate that increasing daily urinary output alone is an effective countermeasure to reduce the renal stone-forming risk immediately after spaceflight. However, increasing urinary output during flight may not be entirely effective in minimizing the potential risk of renal stone formation due to the changes in the urine chemistry in astronauts exposed to microgravity. KEYWORDS: urine volume, spaceflight, renal calculi.

Shear stress differentially regulates PGHS-1 and PGHS-2 protein levels in human endothelial cells.

The secretion of prostacyclin (PGI2) by endothelial cells is regulated by shear stress. Prostaglandin H synthase (PGHS) is considered to be a key limiting enzyme in the synthesis of PGI2 from arachidonic acid. Endothelial cells were cultured in the presence of 4, 15, or 25 dyn/cm2 shear stress using a parallel plate flow chamber to assess the effect of shear stress on both PGHS isoforms, PGHS-1 and PGHS-2. In cells exposed to 4, 15, or 25 dyn/cm2 shear stress PGHS-1 and PGHS-2 protein levels initially decreased. The decrease was followed by a sustained increase for PGHS-1 but only a transient increase for PGHS-2. The duration of the PGHS-2 increase depended on the magnitude of the shear stress. The effect of altering shear stress levels on PGHS protein levels in cells preconditioned to either 4, 15, or 25 dyn/cm2 shear stress for 48 h was also studied. Changing shear stress levels effected PGHS-2 but not PGHS-1. Increases in shear stress levels from 4 to 15 or 25 dyn/cm2 caused a decrease in PGHS-2. In contrast, decreases in shear stress levels from 15 or 25 to 4 dyn/cm2 caused PGHS-2 to increase. There was a continual decrease in PGHS-2 when the shear stress was changed from 15 to 25 or 25 to 15 dyn/cm2. In summary, the regulation of PGHS-2 by shear stress is dependent upon the magnitude of the shear stress, whereas the regulation of PGHS-1 protein levels seems to be independent of the shear stress magnitude. The regulation of PGHS-1 and PGHS-2 protein levels by shear stress indicates that these proteins play an important role in the maintenance of cardiovascular homeostasis as regulators of PGI2 production.

Effects of microgravity on urinary osteopontin.

Increased risk of renal stone formation during space flight has been linked primarily to increased calcium excretion from bone demineralization induced by space flight. Other factors contributing to increased risk include increased urinary calcium oxalate supersaturation, while urinary citrate, magnesium and volume are all decreased. The aim of this study was to increase the predictive value of stone risk profiles for crew members during space flight by evaluating the excretion of urinary protein inhibitors of calcium crystallization so that more comprehensive stone risk profiles could relate mineral saturation to the concentrations of inhibitor proteins. Levels of urinary osteopontin (uropontin) are reported in a series of 14 astronauts studied before, during, and after space flights. During space flight, a compensatory increase in uropontin excretion was not observed. However, the uropontin excretion of a majority of astronauts was increased during the period after space flight and was maximal at 2 wk after landing. The downward shift in the molecular size of uropontin observed in samples obtained during space flight was shown to result from storage at ambient temperature during flight, rather than an effect of microgravity on uropontin synthesis.

Mathematical model to estimate risk of calcium-containing renal stones.

BACKGROUND/AIMS: Astronauts exposed to microgravity during the course of spaceflight undergo physiologic changes that alter the urinary environment so as to increase the risk of renal stone formation. This study was undertaken to identify a simple method with which to evaluate the potential risk of renal stone development during spaceflight. METHOD: We used a large database of urinary risk factors obtained from 323 astronauts before and after spaceflight to generate a mathematical model with which to predict the urinary supersaturation of calcium stone forming salts. RESULT: This model, which involves the fewest possible analytical variables (urinary calcium, citrate, oxalate, phosphorus, and total volume), reliably and accurately predicted the urinary supersaturation of the calcium stone forming salts when compared to results obtained from a group of 6 astronauts who collected urine during flight. CONCLUSIONS: The use of this model will simplify both routine medical monitoring during spaceflight as well as the evaluation of countermeasures designed to minimize renal stone development. This model also can be used for Earth-based applications in which access to analytical resources is limited.

Space flight and the risk of renal stones.

Exposure to the microgravity environment results in many metabolic and physiological changes to humans. Body fluid volumes, electrolyte levels, and bone and muscle undergo changes as the human body adapts to the weightless environment. This investigation examined the role of these physiologic changes to the potentially serious consequences of renal stone formation. The influence of dietary factors on the urinary biochemistry were assessed. Data collected immediately after Space Shuttle flights indicated changes in the urine chemistry favoring an increased risk of calcium oxalate and uric acid stone formation (Whitson et al., 1993). During short term Shuttle space flights, in-flight changes observed included increased urinary calcium and decreased urine volume, pH and citrate resulting in a greater risk for calcium oxalate and calcium phosphate stone formation (Whitson et al, 1997). Results from long duration Shuttle-Mir missions followed a similar trend and demonstrated decreased fluid intake and urine volume resulting in a urinary environment saturated with the calcium stone-forming salts. The increased risk occurs rapidly upon exposure to microgravity, continues throughout the space flight and following landing.

Spaceflight modulates insulin-like growth factor binding proteins and glucocorticoid receptor in osteoblasts.

Rat osteoblasts were cultured for 4 or 5 days during a Space Shuttle mission. After 20-h treatment with 1alpha,25-dihydroxyvitamin D3, conditioned media were harvested and cellular DNA and/or RNA were fixed on board. The insulin-like growth factor binding protein (IGF BP)-3 levels in the media were three- and tenfold higher than in ground controls on the fourth and fifth flight days, as quantitated by Western ligand blotting and radioimmunoassay, respectively. The increased IGF BP-3 protein levels correlated with two- to threefold elevation of IGF BP-3 mRNA levels, obtained by reverse transcription-polymerase chain reaction. The IGF BP-5 mRNA levels in flight cultures were 33-69% lower than in ground controls. The IGF BP-4 mRNA levels in flight cultures were 75% lower than in ground controls on the fifth day but were not different on the fourth day. The glucocorticoid receptor mRNA levels in flight cultures were increased by three- to eightfold on the fourth and fifth days compared with levels in ground controls. These data suggest potential mechanisms underlying spaceflight-induced osteopenia.

Renal stone risk assessment during Space Shuttle flights.

PURPOSE: The metabolic and environmental factors influencing renal stone formation before, during, and after Space Shuttle flights were assessed. We established the contributing roles of dietary factors in relationship to the urinary risk factors associated with renal stone formation. MATERIALS AND METHODS: 24-hr. urine samples were collected prior to, during space flight, and following landing. Urinary and dietary factors associated with renal stone formation were analyzed and the relative urinary supersaturation of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were calculated. RESULTS: Urinary composition changed during flight to favor the crystallization of calcium-forming salts. Factors that contributed to increased potential for stone formation during space flight were significant reductions in urinary pH and increases in urinary calcium. Urinary output and citrate, a potent inhibitor of calcium-containing stones, were slightly reduced during space flight. Dietary intakes were significantly reduced for a number of variables, including fluid, energy, protein, potassium, phosphorus and magnesium. CONCLUSIONS: This is the first in-flight characterization of the renal stone forming potential in astronauts. With the examination of urinary components and nutritional factors, it was possible to determine the factors that contributed to increased risk or protected from risk. In spite of the protective components, the negative contributions to renal stone risk predominated and resulted in a urinary environment that favored the supersaturation of stone-forming salts. Dietary and pharmacologic therapies need to be assessed to minimize the potential for renal stone formation in astronauts during/after space flight.

Quantification of urinary uric acid in the presence of thymol and thimerosal by high-performance liquid chromatography.

A high-performance liquid chromatographic method was developed as an alternative to automated enzymatic analysis of uric acid in human urine preserved with thymol and/or thimerosal. Uric acid (tR = 10 min) and creatinine (tR = 5 min) were separated and quantified during isocratic elution (0.025 M acetate buffer, pH 4.5) from a mu Bondapak C18 column. The uric-acid peak was identified chemically by incubating urine samples with uricase. The thymol/thimerosal peak appeared at 31 min during the washing step and did not interfere with the analysis. We validated the high-performance liquid chromatographic method for linearity, precision and accuracy, and the results were found to be excellent.

Subnormal norepinephrine release relates to presyncope in astronauts after spaceflight.

Postflight orthostatic intolerance is experienced by virtually all astronauts but differs greatly in degree of severity. We studied cardiovascular responses to upright posture in 40 astronauts before and after spaceflights lasting up to 16 days. We separated individuals according to their ability to remain standing without assistance for 10 min on landing day. Astronauts who could not remain standing on landing day had significantly smaller increases in plasma norepinephrine levels with standing than did those who could remain standing (105 +/- 41 vs. 340 +/- 62 pg/ml; P = 0.05). In addition, they had significantly lower standing peripheral vascular resistance (23 +/- 3 vs. 34 +/- 3 mmHg.1l-1).min; P = 0.02) and greater decreases in systolic (-28 +/- 4 vs. -11 +/- 3 mmHg; P = 0.002) and diastolic (-14 +/- 7 vs. 3 +/- 2 mmHg; P = 0.0003) pressures. The presyncopal group also had significantly lower supine (16 +/- 1 vs. 21 +/- 2 mmHg.1l-1).min; P = 0.04) and standing (23 +/- 2 vs. 32 +/- 2 mmHg.1l-1).min; P = 0.038) vascular resistance, supine (66 +/- 2 vs. 73 +/- 2 mmHg; P = 0.008) and standing (69 +/- 4 vs. 77 +/- 2 mmHg; P = 0.007) diastolic pressure, and supine (109 +/- 3 vs. 114 +/- 2 mmHg; P = 0.05) and standing (99 +/- 4 vs. 108 +/- 3 mmHg; P = 0.006) systolic pressures before flight. This is the first study to clearly document these differences among presyncopal and nonpresyncopal astronauts after spaceflight and also offer the possibility of preflight prediction of postflight susceptibility. These results clearly point to hypoadrenergic responsiveness, possibly centrally mediated, as a contributing factor in postflight orthostatic intolerance. They may provide insights into autonomic dysfunction in Earthbound patients.

Microgravity induces prostaglandin E2 and interleukin-6 production in normal rat osteoblasts: role in bone demineralization.

It has been suggested that microgravity alters bone metabolism. Evidence for this phenomenon includes the negative calcium balance and decreased bone density in astronauts, as well as, inhibition of bone formation in rats flown for 2 to 3 weeks. However, the specific mechanisms that modulate these changes in microgravity are unknown. The purpose of this study was to clarify the mechanism of microgravity-induced bone demineralization using normal rat osteoblasts obtained from femur marrow cultures. The osteoblasts were cultured for 5 days during a Shuttle-Spacelab flight (STS-65). After collection of the culture medium, the cellular DNA and RNA were fixed on board. Enzyme-immunoassay of the culture medium for prostaglandin E2 (PGE2) indicated that microgravity induced a 4.5- to 136-fold increase in flight samples as compared to the ground control cultures. This increase of PGE2 production was consistent with a 3.3- to 9.5-fold elevation of inducible prostaglandin G/H synthase-2 (PGHS-2) mRNA, quantitated by reverse transcription-polymerase chain reaction (RT-PCR). The mRNA induction for the constitutive isozyme PGHS-1 was less than that for PGHS-2. The interleukin-6 (IL-6) mRNA was also increased (6.4- to 9.3-fold) in microgravity as compared to the ground controls. Since PGE2 and IL-6 are both known to play a role in osteoclast formation and bone resorption, these data provide molecular mechanisms that contribute to our understanding of microgravity-induced alterations in the bone resorption process.

Clinical and biochemical presentation of gouty diathesis: comparison of uric acid versus pure calcium stone formation.

PURPOSE: We compared gouty diathesis with uric acid versus calcium stones. MATERIALS AND METHODS: We retrospectively reviewed clinical and laboratory data from 95 gouty diathesis patients (28 with uric acid and 67 with calcium stones) and 99 normal subjects. RESULTS: Of the gouty diathesis patients gouty arthritis was present in 21% of those with uric acid and 12% of those with calcium stones. Hyperuricemia developed in 43% of those with uric acid and 27% of those with calcium stones, and 2% of controls. Urinary pH was independent of the net gastrointestinal absorption of alkali in the gouty diathesis groups. Urinary pH and citrate increased after potassium citrate treatment. CONCLUSIONS: The characteristic features of primary gout were present in both gouty diathesis groups and both are responsive to treatment.

Changes in sympathoadrenal response to standing in humans after spaceflight.

Plasma catecholamine levels and cardiovascular responses to standing were determined in astronauts before and after several Space Shuttle missions. Blood pressure, heart rate, and cardiac output were measured and blood samples for catecholamine analyses were drawn at the end of the supine and standing periods. Supine plasma norepinephrine and epinephrine concentrations increased 34 and 65%, respectively, on landing day compared with before flight. Standing on landing day resulted in a 65 and 91% increase in plasma norepinephrine and epinephrine, respectively. Supine and standing norepinephrine levels remained elevated 3 days after landing while epinephrine levels returned to preflight levels. On landing day, supine heart rate and systolic blood pressure increased 18 and 8.9%, respectively, and standing heart rate and diastolic blood pressure were elevated by 38 and 19%, respectively. On standing, stroke volume was decreased by 26% on landing day compared with before flight. Collectively, these data indicate that the decreased orthostatic function after spaceflight results largely from the decreased stroke volume. Possible mechanisms contributing to this condition are discussed.

Melatonin and cortisol assessment of circadian shifts in astronauts before flight.

Melatonin and cortisol were measured in saliva and urine samples to assess the effectiveness of a 7-day protocol combining bright-light exposure with sleep shifting in eliciting a 12-hr phase-shift delay in eight U.S. Space Shuttle astronauts before launch. Baseline acrophases for 15 control subjects with normal sleep-wake cycles were as follows: cortisol (saliva) at 0700 (0730 in urine); melatonin (saliva) at 0130 (6-hydroxymelatonin sulfate at 0230 in urine). Acrophases of the astronaut group fell within 2.5 hr of these values before the treatment protocols were begun. During the bright-light and sleep-shifting treatments, both absolute melatonin production and melatonin rhythmicity were diminished during the first 3 treatment days; total daily cortisol levels remained constant throughout the treatment. By the fourth to sixth day of the 7-day protocol, seven of the eight crew members showed phase delays in all four measures that fell within 2 hr of the expected 11- to 12-hr shift. Although cortisol and melatonin rhythms each corresponded with the phase shift, the rhythms in these two hormones did not correspond with each other during the transition.

Acute effects of head-down tilt and hypoxia on modulators of fluid homeostasis.

In an effort to understand the interaction between acute postural fluid shifts and hypoxia on hormonal regulation of fluid homeostasis, the authors measured the responses to head-down tilt with and without acute exposure to normobaric hypoxia. Plasma atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), plasma aldosterone (ALD), and plasma renin activity (PRA) were measured in six healthy male volunteers who were exposed to a head-down tilt protocol during normoxia and hypoxia. The tilt protocol consisted of a 17 degrees head-up phase (30 minutes), a 28 degrees head-down phase (1 hour), and a 17 degrees head-up recovery period (2 hours, with the last hour normoxic in both experiments). Altitude equivalent to 14,828 ft was simulated by having the subjects breathe an inspired gas mixture with 13.9% oxygen. The results indicate that the postural fluid redistribution associated with a 60-minute head-down tilt induces the release of ANP and cGMP during both hypoxia and normoxia. Hypoxia increased cGMP, cAMP, ALD, and PRA throughout the protocol and significantly potentiated the increase in cGMP during head-down tilt. Hypoxia had no overall effect on the release of ANP, but appeared to attenuate the increase with head-down tilt. This study describes the acute effects of hypoxia on the endocrine response during fluid redistribution and suggests that the magnitude, but not the direction, of these changes with posture is affected by hypoxia.

Hypergravity signal transduction and gene expression in cultured mammalian cells.

A number of studies have been conducted during space flight and with clinostats and centrifuges, suggesting that gravity effects the proliferation and differentiation of mammalian cells in vitro. However, little is known about the mechanisms by which mammalian cells respond to changes in gravitational stress. This paper summarizes studies designed to clarify the effects of hypergravity on the cultured human HeLa cells and to investigate the mechanism of hypergravity signal transduction in these cells.