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NASA’s vision for future exploration missions depends on the ability to protect astronauts’ health and safety for performance of Extravehicular Activity (EVA), and to allow astronauts to safely egress from vehicles in a variety of landing scenarios (e.g. water landing upon return to Earth and undefined planetary/lunar landings). Prolonged exposure to spaceflight results in diminished tolerance to prolonged physical activity, decreased cardiac and sensorimotor function, and loss of bone mineral density, muscle mass, and muscle strength. For over 50 years exercise has been the primary countermeasure against these physiologic decrements during spaceflight, and while the resulting protection is adequate for ISS missions (i.e., Soyuz landing, microgravity EVAs), there is little information regarding time-course changes in muscle and aerobic performance. As spaceflight progresses towards longer exploration missions and vehicles with less robust exercise capabilities compared to ISS, countermeasures will need to be combined and optimized to protect crew health and performance across all organ systems over the course of exploration missions up to 3 years in duration. This will require a more detailed understanding of the dynamic effects of spaceflight on human performance. Thus, the focus of this study is quantifying decrements in physical performance over different mission durations, and to provide detailed information on the physiological rational for “why” and “when” observed changes in performance occur. The research proposed will temporally profile changes in astronauts’ cardiorespiratory fitness, muscle mass, strength, and endurance over spaceflight missions of 2 months, 6 months, and up to 1 year in duration. Additionally, an extrapolation model will provide predictions for changes associated with exploration missions 2-3 years in duration. To accomplish these objectives astronauts will be asked to participate in pre, in, post-flight measurement of muscle performance, muscle size, cardiorespiratory fitness and submaximal performance capabilities, as well as non-invasive assessment of cerebral and muscle oxygenation and perfusion (Table 1). Additionally, ambulatory and in-flight exercise, nutrition, and sleep will be monitored using a variety of commercial technologies and in-flight assessment tools. Significance: Our detailed testing protocol will provide valuable information for describing how and when spaceflight-induced muscle and aerobic based adaptations occur over the course of spaceflight missions up to and beyond 1 year. This information will be vital in the assessment as to whether humans can be physically ready for deep space exploration such as Mars missions with current technology, or if additional mitigation strategies are necessary.

Spaceflight impacts human physiology, including well documented immune system dysregulation. Diet, immune function, and the microbiome are interlinked, but diet is the only one of these factors that we have the ability to easily, and significantly, alter on Earth or during flight. As we understand dietary impacts on physiology more thoroughly, we may then improve the spaceflight diet to improve crew health and potentially reduce spaceflight-associated physiological alterations. It is expected that increasing the consumption of fruits and vegetables and bioactive compounds (e.g., omega-3 fatty acids, lycopene, flavonoids) and therefore enhancing overall nutritional intake from the nominal shelf-stable, fully-processed space food system could serve as a countermeasure to improve human immunological profiles, the taxonomic profile of the gut microbiota, and nutritional status, especially where currently dysregulated during spaceflight. This interdisciplinary study will determine the effect of the current shelf-stable spaceflight diet compared to an "enhanced" shelf-stable spaceflight diet (25% more foods rich in omega-3 fatty acids, lycopene, flavonoids, and more fruits, and vegetables in general). The NASA Human Exploration Research Analog (HERA) 2017 missions, consisting of four 45-day missions with closed chamber confinement and realistic mission simulation in a high-fidelity mock space vehicle, will serve as a platform to replicate mission stressors and the effects on crew biochemistry, immunology, and the gut microbiome. Bio sampling of crewmembers is scheduled for selected intervals pre- and in-mission. Data collection also includes dietary intake recording. Outcome measures will include immune markers (e.g., peripheral leukocyte distribution, inflammatory cytokine profiles, T cell function), the taxonomic and metatranscriptomic profile of the gut microbiome, and nutritional status biomarkers and metabolites. Statistical evaluations will determine physiological and biochemical shifts in relation to nutrient intake and study phase. To date, sample collection has been completed for 2 crewmembers from the first mission, aka Campaign 4 Mission 1. Mission 2 was terminated after 22 days due to effects of Hurricane Harvey, and sample collection was not completed. Sample collection will continue for Campaign 4 Mission 3 and 4 prior to comprehensive sample analysis. Beneficial improvements will provide evidence of the impact of diet on crew health and adaptation to this spaceflight analog, and will aid in the design and development of more-efficient targeted dietary interventions for exploration missions.

Long duration missions will require astronauts to subsist on a closed food system for at least three years. Resupply will not be an option, and the food supply will be older at the time of consumption and more static in variety than previous missions. The space food variety requirements that will both supply nutrition and support continued interest in adequate consumption for a mission of this duration is unknown. Limited food variety of past space programs (Gemini, Apollo, International Space Station) as well as in military operations resulted in monotony, food aversion, and weight loss despite relatively short mission durations of a few days up to several months. In this study, food consumption data from 10 crew members on 3-6-month International Space Station missions was assessed to determine what percentage of the existing food variety was used by crew members, if the food choices correlated to the amount of time in orbit, and whether commonalities in food selections existed across crew members. Complete mission diet logs were recorded on ISS flights from 2008 - 2014, a period in which space food menu variety was consistent, but the food system underwent an extensive reformulation to reduce sodium content. Food consumption data was correlated to the Food on Orbit by Week logs, archived Data Usage Charts, and a food list categorization table using TRIFACTA software and queries in a SQL SERVER 2012 database.

Spaceflight impacts human physiology, including well documented immune system dysregulation. Diet, immune function, and the microbiome are interlinked, but diet is the only one of these factors that we have the ability to easily, and significantly, alter on Earth or during flight. As we understand dietary impacts on physiology more thoroughly, we may then improve the spaceflight diet to improve crew health and potentially reduce flight-associated physiological alterations. It is expected that increasing the consumption of fruits and vegetables and bioactive compounds (e.g.,omega-3 fatty acids, lycopene, flavonoids) and therefore enhancing overall nutritional intake from the nominal shelf-stable, fully-processed space food system could serve as a countermeasure to improve human immunological profiles, the taxonomic profile of the gut microbiota, and nutritional status, especially where currently dysregulated during spaceflight. This interdisciplinary study will determine the effect of the current shelf-stable spaceflight diet compared to an "enhanced" shelf-stable spaceflight diet (25% more foods rich in omega-3 fatty acids, lycopene, flavonoids, fruits, and vegetables). The NASA Human Exploration Research Analog (HERA) 2017 missions, consisting of closed chamber confinement, realistic mission simulation, in a high-fidelity mock space vehicle, will serve as a platform to replicate mission stressors and the dysregulated physiology observed in astronauts. Biosampling of crew members will occur at selected intervals, with complete dietary tracking. Outcome measures will include immune markers (e.g., peripheral leukocyte distribution, inflammatory cytokine profiles, T cell function), the taxonomic and metatranscriptomic profile of the gut microbiome, and nutritional status biomarkers and metabolites. Data collection will also include complete dietary tracking. Statistical evaluations will determine physiological and biochemical shifts in relation to nutrient in take and study phase. Beneficial improvements will provide evidence of the impact of diet on crew health and adaptation to this spaceflight analog, and will aid in the design and development of more-efficient targeted dietary interventions.

Introduction. NASA's Human Research Program is focused on addressing health risks associated with long-duration missions on the International Space Station (ISS) and future exploration-class missions beyond low Earth orbit. Visual acuity changes observed after short-duration missions were largely transient, but now more than 50 percent of ISS astronauts have experienced more profound, chronic changes with objective structural findings such as optic disc edema, globe flattening and choroidal folds. These structural and functional changes are referred to as the visual impairment and intracranial pressure (VIIP) syndrome. Development of VIIP symptoms may be related to elevated intracranial pressure (ICP) secondary to spaceflight-induced cephalad fluid shifts, but this hypothesis has not been tested. The purpose of this study is to characterize fluid distribution and compartmentalization associated with long-duration spaceflight and to determine if a relation exists with vision changes and other elements of the VIIP syndrome. We also seek to determine whether the magnitude of fluid shifts during spaceflight, as well as any VIIP-related effects of those shifts, are predicted by the crewmember's pre-flight status and responses to acute hemodynamic manipulations, specifically posture changes and lower body negative pressure. Methods. We will examine a variety of physiologic variables in 10 long-duration ISS crewmembers using the test conditions and timeline presented in the figure below. Measures include: (1) fluid compartmentalization (total body water by D2O, extracellular fluid by NaBr, intracellular fluid by calculation, plasma volume by CO rebreathe, interstitial fluid by calculation); (2) forehead/eyelids, tibia, and calcaneus tissue thickness (by ultrasound); (3) vascular dimensions by ultrasound (jugular veins, cerebral and carotid arteries, vertebral arteries and veins, portal vein); (4) vascular dynamics by MRI (head/neck blood flow, cerebrospinal fluid pulsatility); (5) ocular measures (optical coherence tomography; intraocular pressure; 2-dimensional ultrasound including optic nerve sheath diameter, globe flattening, and retina-choroid thickness; Doppler ultrasound of ophthalmic and retinal arteries and veins); (6) cardiac variables by ultrasound (inferior vena cava, tricuspid flow and tissue Doppler, pulmonic valve, stroke volume, right heart dimensions and function, four-chamber views); and (7) ICP measures (tympanic membrane displacement, otoacoustic emissions). Pre- and post-flight, acute head-down tilt will induce cephalad fluid shifts, whereas lower body negative pressure will oppose these shifts. Controlled Mueller maneuvers will manipulate cardiovascular variables. Through interventions applied before, during, and after flight, we intend to fully evaluate the relationship between fluid shifts and the VIIP syndrome. Discussion. Ten subjects have consented to participate in this experiment, including the recent One-Year Mission crewmembers, who have recently completed R plus180 testing; all other subjects have completed pre-flight testing. Preliminary results from the One-Year Mission crewmembers will be presented, including measures of ocular structure and function, vascular dimensions, fluid distribution, and non-invasive estimates of intracranial pressure.

The paradox of fragility fracture in the presence of non-osteoporotic bone mineral density in older patients with type 2 diabetes mellitus (DM2) makes it difficult to clinically predict fracture in this vulnerable group. Serum osteocalcin (OC), a marker of bone turnover, increases with normal skeletal aging indicating risk of fracture. However, OC has been reported to be lower in patients with DM2. An inverse association between higher glycated hemoglobin levels (HbA1c) and lower serum OC in older DM2 patients triggered discussions encouraging further investigation. A key question to be answered is whether changes in glucose metabolism is responsible for bone metabolic changes, ultimately leading to increased risk of fragility fractures in DM2 patients. While these studies were conducted among Caucasian and Asian populations, this has not been studied in Hispanic populations who suffer from a higher prevalence of DM2. The Cameron County Hispanic Cohort (CCHC) in Texas is a homogeneous Hispanic cohort known to have high prevalence of DM2 (30%). Our preliminary data from this cohort reported OC levels lower than the suggested threshold for fragility fracture in post-menopausal women. We further investigated whether bone turnover in older CCHC adults with DM2 show a normal pattern of skeletal aging. Samples and data were obtained from a nested cohort of 68 (21 men and 47 women) Hispanic older adults (≥50 years) who had a diagnosis of DM2. Given high prevalence of uncontrolled DM2 in this cohort, we divided population into two groups: i) poor DM2 control with HbA1c level ≥8 (48% men and 38% women) and ii) good DM2 control with HbA1c level <8). A crosssectional analysis documented associations between serum OC and age adjusted HbA1c levels. There was no direct association between age and OC concentrations in our study. Higher HbA1c was associated with lower serum OC in men (odds ratio -6.5, 95% confidence interval -12.7 to - 0.3, p < 0.04). No significant associations were identified in women. Bone turnover in older Hispanic men with DM2 in our study does not reflect normal pattern of skeletal aging. It is unclear why similar results were not identified in women. We will continue to follow this cohort to investigate longitudinal trend of changes of bone turnover and its relationship with HbA1c in both men and women of this cohort.

The cephalad fluid shift induced by microgravity has been hypothesized to elevate intracranial pressure (ICP) and contribute to the development of the visual impairment/intracranial pressure (VIIP) syndrome experienced by many astronauts during and after long-duration space flight. In addition, elevated ambient partial pressure of carbon dioxide (PCO2) on the International Space Station (ISS) has also been hypothesized to contribute to the development of VIIP. We seek to determine if an acute, mild CO2 exposure, similar to that occurring on the ISS, combined with the cephalad fluid shift induced by head-down tilt will induce ophthalmic and ICP changes consistent with the VIIP syndrome.

Stress and anxiety-related problems are among the most common and costly behavioral health problems in society, and for those working in operational environments (i.e. astronauts, flight controllers, military) this can seriously impact crew performance, safety, and wellbeing. Technology-based interventions are effective for treating behavioral health problems, and can significantly improve the delivery of evidence-based health care. This study is evaluating the effectiveness, usefulness, and usability of a self-guided multimedia stress management and resilience training program in a randomized controlled trial (RCT) with a sample of flight controllers at Johnson Space Center. The intervention, SMART-OP (Stress Management and Resilience Training for Optimal Performance), is a six-session, cognitive behavioral-based computer program that uses self-guided, interactive activities to teach skills that can help individuals build resilience and manage stress. In a prior RCT with a sample of stressed but otherwise healthy individuals, SMART-OP reduced perceived stress and increased perceived control over stress in comparison to an Attention Control (AC) group. SMART-OP was rated as "highly useful" and "excellent" in usability and acceptability. Based on α-amylase data, individuals in SMART-OP recovered quicker and more completely from a social stress test as compared to the AC group [1]. In the current study, flight controllers are randomized either to receive SMART-OP training, or to a 6-week waitlist control period (WLC) before beginning SMART-OP. Eligible participants include JSC flight controllers and instructors without any medical or psychiatric disorder, but who are stressed based on self-report. Flight controllers provide a valid analog sample to astronauts in that they work in an operational setting, use similar terminology to astronauts, are mission-focused, and work under the same broader work culture. The study began in December 2014, and to date 79 flight controllers and instructors have expressed interest in the study, 49 of those were cleared for participation, we have screened 44 for eligibility, and 23 have met inclusion criteria. Recruitment is ongoing and the study will continue until December 2016. Outcome measures include perceived stress, perceived control over stress, resilience, mood, personality, emotion regulation, sleep, health behaviors, and psychophysiological data such as 24-hour heart rate, alpha amylase, and urinary and salivary cortisol. We are also collecting user feedback such as usability, working alliance, usefulness, and treatment credibility.

Data from the Nutritional Status Assessment protocol provided biochemical evidence that the one-carbon metabolic pathway may be altered in individuals experiencing vision-related issues during and after space flight (1, 2). Briefly, serum concentrations of homocysteine, cystathionine, 2-methylcitric acid, and methylmalonic acid were significantly (P<0.001) higher (25-45%) in astronauts with ophthalmic changes than in those without such changes (1). These differences existed before, during, and after flight. Serum folate was lower (P<0.01) during flight in individuals with ophthalmic changes. Preflight serum concentrations of cystathionine and 2-methylcitric acid, and mean in-flight serum folate, were significantly (P<0.05) correlated with postflight changes in refraction (1). A follow-up study was conducted to evaluate a small number of known polymorphisms of enzymes in the one-carbon pathway, and to evaluate how these relate to vision and other medical aspects of the eye. Specifically, we investigated 5 polymorphisms in MTRR, MTHFR, SHMT, and CBS genes and their association with ophthalmic changes after flight in 49 astronauts. The number of G alleles of MTRR 66 and C alleles of SHMT1 1420 both contributed to the odds of visual disturbances (3). Block regression showed that B-vitamin status at landing and genetics were significant predictors for many of the ophthalmic outcomes studied (3). In conclusion, we document an association between MTRR 66 and SHMT1 1420 polymorphisms and space flightinduced vision changes. These data document that individuals with an altered 1-carbon metabolic pathway may be predisposed to anatomic and/or physiologic changes that render them susceptible to ophthalmic damage during space flight.

Many nutritional factors influence bone, from the basics of calcium and vitamin D, to factors which influence bone through acid/base balance, including protein, sodium, and more. Fibroblast growth factor 23 (FGF23) is a recently identified factor, secreted from osteocytes, which is involved in classic (albeit complex) feedback loops controlling phosphorus homeostasis through both vitamin D and parathyroid hormone (PTH) (1, 2). As osteocytes are gravity sensing cells, it is important to determine if there are changes in FGF23 during spaceflight. In extreme cases, such as chronic kidney disease, FGF23 levels are highly elevated. FGF23 imbalances, secondary to dietary influences, may contribute to skeletal demineralization and kidney stone risk during spaceflight.

Elevated bone resorption is a hallmark of human spaceflight and bed rest indicating that elevated remodeling is a major factor in the etiology of space flight bone loss. In a collaborative effort between the NASA and JAXA space agencies, we are testing whether an antiresorptive drug would provide additional benefit to in-flight exercise to ameliorate bone loss and hypercalciuria during long-duration spaceflight. Measurements of bone loss include DXA, QCT, pQCT, urinary and blood biomarkers. We have completed analysis of R+1year data from 7 crewmembers treated with alendronate during flight, as well as immediate post flight (R+<2wks) data from 6 of 10 concurrent controls without treatment. The treated astronauts used the Advanced Resistive Exercise Device (ARED) during their missions. The purpose of this report is twofold: 1) to report the results of inflight, post flight and one year post flight bone measures compared with available controls with and without the use of ARED; and 2) to discuss preliminary data on concurrent controls. The figure below compares the BMD changes in ISS crewmembers exercising with and without the current ARED protocol and the alendronate treated crewmembers also using the ARED. This shows that the use of ARED prevents about half the bone loss seen in early ISS crewmembers and that the addition of an antiresorptive provides additional benefit. Resorption markers and urinary Ca excretion are not impacted by exercise alone but are significantly reduced with antiresorptive treatment. Bone measures for treated subjects, 1 year after return from space remain at or near baseline. DXA data for the 6 concurrent controls using the ARED device are similar to DXA data shown in the figure below. QCT data for these six indicate that the integral data are consistent with the DXA data, i.e., comparing the two control groups suggests significant but incomplete improvement in maintaining BMD using the ARED protocol. Biochemical data of the concurrent control group await sample return and analysis. The preliminary conclusion is that an antiresorptive may be an effective adjunct to exercise during long-duration spaceflight.

Many nutritional factors influence bone, from the basics of calcium and vitamin D, to factors which influence bone through acid/base balance, including protein, sodium, and more. Fibroblast growth factor 23 (FGF23) is a recently identified factor, secreted from osteocytes, which is involved in classic (albeit complex) feedback loops controlling phosphorus homeostasis through both vitamin D and parathyroid hormone (PTH) (1, 2). As osteocytes are gravity sensing cells, it is important to determine if there are changes in FGF23 during spaceflight. In extreme cases, such as chronic kidney disease, FGF23 levels are highly elevated. FGF23 imbalances, secondary to dietary influences, may contribute to skeletal demineralization and kidney stone risk during spaceflight. Presented with an imbalanced dietary phosphorus to calcium ratio, increased secretion of FGF23 will inhibit renal phosphorus reabsorption, resulting in increased excretion and reduced circulating phosphorus. Increased intake and excretion of phosphorus is associated with increased kidney stone risk in both the terrestrial and microgravity environments. Highly processed foods and carbonated beverages are associated with higher phosphorus content. Ideally, the dietary calcium to phosphorus ratio should be at minimum 1:1. Nutritional requirements for spaceflight suggest that this ratio not be less than 0.67 (3), while the International Space Station (ISS) menu provides 1020 mg Ca and 1856 mg P, for a ratio of 0.55 (3). Subjects in NASA's bed rest studies, by design, have consumed intake ratios much closer to 1.0 (4). FGF23 also has an inhibitory influence on PTH secretion and 1(alpha)-hydroxylase, both of which are required for activating vitamin D with the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Decreased 1,25-dihydroxyvitamin D will result in decreased intestinal phosphorus absorption, and increased urinary phosphorus excretion (via decreased renal reabsorption). Should a decrease in 1,25- dihydroxyvitamin D be necessary to reduce intestinal phosphorus absorption, calcium absorption will also proportionally be reduced, potentially leading to skeletal demineralization. Demineralization of bone can increase kidney stone risk, a medical issue that could prove detrimental to mission success. Given the interrelationships described above, we sought to determine circulating FGF23 concentrations in spaceflight and ground analog studies to better understand the potential effects of dietary phosphorus on bone and calcium metabolism. We analyzed serum from ISS astronauts participating in studies of bone biochemistry, including the Nutrition SMO and Pro K experiments, and we also evaluated FGF23 during extended-duration bed rest. Serum intact FGF23 levels were determined using an ELISA kit from Kainos laboratories in Japan. While initial evaluation of the data showed no changes over time during flight or bed rest, evaluation continues of FGF23 data in light of dietary factors, PTH, vitamin D status, and other biochemical and endocrine factors.

Iron stores are increased secondary to neocytolysis of red blood cells and a high dietary intake of iron during space flight. This raises concerns about the risk of excess iron causing oxidative damage in many tissues, including bone. Biomarkers of iron status, oxidative damage, and bone resorption during space flight were analyzed for 23 (16 M/7 F) International Space Station crewmembers as part of the Nutrition SMO project. Up to 5 in-flight blood samples and 24-h urine pools were collected over the course of the 4-6 month missions. Serum iron increased slightly during space flight and was decreased at landing (P < 0.0004). An increase in serum ferritin early in flight (217% in women and 68% in men, P < 0.0004), returning to preflight concentrations at landing, and a decrease in transferrin and transferrin receptors during flight indicated that a transient increase in iron stores occurred. No inflammatory response was observed during flight. The oxidative damage markers 8-hydroxy-2'-deoxyguanosine and prostaglandin F(sub 2(alpha)) were positively correlated (both P < 0.001) with serum ferritin. A greater area under the curve for ferritin during flight was correlated with greater changes in bone mineral density of several bone regions after flight (1). In a separate study (2), a ground-based investigation was conducted that examined the combined effects of radiation exposure and iron overload on sensitivity to radiation injury in several physiological systems in 12-wk male Sprague-Dawley rats. The rats were acclimated to an adequate iron diet (45 mg iron (ferric citrate)/kg diet) for 3 wk and then assigned to one of four groups: adequate iron (Fe) diet/no radiation, adequate Fe diet/ radiation, moderately high Fe diet (650 mg Fe (ferric citrate)/kg diet)/no radiation, and moderately high Fe diet/radiation. Animals remained on the assigned diet for 4 wk. Starting on day 14 of experimental diet treatment, animals were exposed to a fractionated dose (0.375 Gy) of Cs-137 every other day (3 Gy total dose). On day 29 (24 h after last radiation exposure), animals were euthanized. Oxidative stress markers in the liver, bone, eyes, and serum were assessed. There was evidence that the iron diet contributed to DNA damage as well as radiation exposure in the liver, eyes, and bone. Together, the results suggest that increased iron stores do constitute a risk factor for oxidative damage and bone resorption, during space flight and on Earth. Funded by the Human Health and Countermeasures Element of the NASA Human Research Program.

Spaceflight-induced bone loss is associated with increased bone resorption (1, 2), and either unchanged or decreased rates of bone formation. Resistive exercise had been proposed as a countermeasure, and data from bed rest supported this concept (3). An interim resistive exercise device (iRED) was flown for early ISS crews. Unfortunately, the iRED provided no greater bone protection than on missions where only aerobic and muscular endurance exercises were available (4, 5). In 2008, the Advanced Resistive Exercise Device (ARED), a more robust device with much greater resistance capability, (6, 7) was launched to the ISS. Astronauts who had access to ARED, coupled with adequate energy intake and vitamin D status, returned from ISS missions with bone mineral densities virtually unchanged from preflight (7). Bone biochemical markers showed that while the resistive exercise and adequate energy consumption did not mitigate the increased bone resorption, bone formation was increased (7, 8). The typical drop in circulating parathyroid hormone did not occur in ARED crewmembers. In 2014, an updated look at the densitometry data was published. This study confirmed the initial findings with a much larger set of data. In 42 astronauts (33 male, 9 female), the bone mineral density response to flight was the same for men and women (9), and those with access to the ARED did not have the typical decrease in bone mineral density that was observed in early ISS crewmembers with access to the iRED (Figure 1) (7). Biochemical markers of bone formation and resorption responded similarly in men and women. These data are encouraging, and represent the first in-flight evidence in the history of human space flight that diet and exercise can maintain bone mineral density on long-duration missions. However, the maintenance of bone mineral density through bone remodeling, that is, increases in both resorption and formation, may yield a bone with strength characteristics different from those that existed before space flight. Studies to assess bone strength after flight are underway at NASA, to better understand the results of bone remodeling. Studies are also underway to evaluate optimized exercise protocols and nutritional countermeasures. Regardless, there is clear evidence of progress being made to protect bone during spaceflight.

The Nutritional Status Assessment Supplemental Medical Objective was initiated to expand nominal clinical nutrition testing of ISS astronauts, and to gain a better understanding of the time course of changes in nutritional status during flight. The primary activity of this effort was collecting blood and urine samples during flight for analysis after return to Earth. Samples were subjected to a battery of tests. The resulting data provide a comprehensive survey of how nutritional status and related systems are affected by 4-6 months of space flight. Analysis of these data has yielded many findings to date, including: Vision. Documented evidence that biochemical markers involved in one-carbon metabolism were altered in crewmembers who experienced vision-related issues during and after flight (1). Iron, Oxidative Stress, and Bone. In-flight data document a clear association of increased iron stores, markers of oxidative damage to DNA, and bone loss (2). Exercise. Documented that well-nourished crewmembers performing heavy resistance exercise returned from ISS with bone mineral densities unchanged from preflight (3). Furthermore, the response of bone to space flight and exercise countermeasures was the same in men and women (4). Body Mass. Crewmembers lose 2-5% of their body mass in the first month of flight, and maintain the lower body mass during flight (5). Additionally, the two devices to measure body mass on orbit, the SLAMMD and BMMD, provide similar results (5). Cytokines. Findings indicated that a pattern of persistent physiological adaptations occurs during space flight that includes shifts in immune and hormonal regulation (6). Fish/Bone. Documented a relationship between fish intake and bone loss in astronauts (that is, those who ate more fish lost less bone) (7). Vitamin K. Documented that in generally well-fed and otherwise healthy individuals, vitamin K status and bone vitamin K-dependent proteins are unaffected by space flight (and bed rest) (8). Testosterone. Documented that blood concentrations of testosterone were unchanged during flight, but a transient decline occurred after landing (9). Calcium. Nutrition SMO data contributed to the ISS Program by helping understand how and why the Urine Processor Assembly clogged with calcium sulfate precipitate (10). Sample Processing. Ground-based analytical testing results have also been published (11).

On-orbit firings of both liquid and solid rocket motors provide localized disturbances to the plasma in the upper atmosphere. Large amounts of energy are deposited to ionosphere in the form of expanding exhaust vapors which change the composition and flow velocity. Charge exchange between the neutral exhaust molecules and the background ions (mainly O+) yields energetic ion beams. The rapidly moving pickup ions excite plasma instabilities and yield optical emissions after dissociative recombination with ambient electrons. Line-of-sight techniques for remote measurements rocket burn effects include direct observation of plume optical emissions with ground and satellite cameras, and plume scatter with UHF and higher frequency radars. Long range detection with HF radars is possible if the burns occur in the dense part of the ionosphere. The exhaust vapors initiate plasma turbulence in the ionosphere that can scatter HF radar waves launched from ground transmitters. Solid rocket motors provide particulates that become charged in the ionosphere and may excite dusty plasma instabilities. Hypersonic exhaust flow impacting the ionospheric plasma launches a low-frequency, electromagnetic pulse that is detectable using satellites with electric field booms. If the exhaust cloud itself passes over a satellite, in situ detectors measure increased ion-acoustic wave turbulence, enhanced neutral and plasma densities, elevated ion temperatures, and magnetic field perturbations. All of these techniques can be used for long range observations of plumes in the ionosphere. To demonstrate such long range measurements, several experiments were conducted by the Naval Research Laboratory including the Charged Aerosol Release Experiment, the Shuttle Ionospheric Modification with Pulsed Localized Exhaust experiments, and the Shuttle Exhaust Ionospheric Turbulence Experiments.

Astronauts on long duration space flight missions to the moon or mars are exposed to radiation and have increase iron (Fe) stores, both of which can independently induce oxidative stress and may exacerbate bone mass loss and strength. We hypothesize a high Fe diet and a fractionated gamma radiation exposure would increase oxidative stress and lower bone mass. Three mo-old, SD rats (n=32) were randomized to receive an adequate Fe diet (45 mg Fe/kg diet) or a high Fe diet (650 mg Fe/kg diet) for 4 wks and either a cumulative 3 Gy dose (fractionated 8 x 0.375 Gy) of gamma radiation (Cs-137) or sham exposure starting on day 14. Elisa kit assessed serum catalase, clinical analyzer assessed serum Fe status and ex vivo pQCT scans measured bone parameters in the proximal/midshaft tibia and femoral neck. Mechanical strength was assessed by 3-pt bending and femoral neck test. There is a significant decrease in trabecular bone mineral density (BMD) from radiation (p less than 0.05) and a trend in diet (p=0.05) at the proximal tibia. There is a significant interaction in cortical BMD from the combined treatments at the midshaft tibia (p less than 0.05). There is a trending decrease in total BMD from diet (p=0.07) at the femoral neck. In addition, high serum Fe was correlated to low trabecular BMD (p less than 0.05) and high serum catalase was correlated to low BMD at all 3 bone sites (p less than 0.05). There was no difference in the max load of the tibia or femoral neck. Radiation and a high iron diet increases iron status and catalase in the serum and decreases BMD.

Space flight has many negative effects on human physiology, including bone and muscle loss. Bone and muscle are two systems that are positively affected by dietary intake of fish and n-3 fatty acids. The mechanism is likely to be related to inhibition by n-3 fatty acids of inflammatory cytokines (such as TNF) and thus inhibition of downstream NF-kB activation. We have documented this effect in a 3-dimensional cell culture model, where NF-kB activation in osteoclasts was inhibited by eicosapentaenoic acid, an n-3 fatty acid. We have also indentified that NF-kB activation in peripheral blood mononuclear cells of Space Shuttle crews. We found that after Shuttle flights of ~2 wk, expression of the protein p65 (evidence of NF-kB activation) was increased at landing (P less than 0.001). When evaluating the effects of n-3 fatty acid intake on bone breakdown after 60 d of bed rest (a weightlessness analog). We found that after 60 d of bed rest, greater intake of n-3 fatty acids was associated with less N-telopeptide excretion (Pearson r = -0.62, P less than 0.05). We also evaluated the relationship of fish intake and bone loss in astronauts after 4 to 6 mo missions on the International Space Station. Higher consumption of fish during flight was associated with higher bone mineral density (Pearson r = 0.46, P less than 0.05). Together, these findings provide evidence of the cellular mechanism by which n-3 fatty acids can inhibit bone loss, and preliminary human evidence of the potential for n-3 fatty acids to counteract bone loss associated with space flight. This study was supported by the NASA Human Research Program.

Animal models and human studies suggest that osteocytes regulate the skeleton s response to mechanical unloading at the cellular level in part by an increase in sclerostin, an inhibitor of the anabolic Wnt pathway. However, few studies have reported changes in serum sclerostin in humans exposed to reduced mechanical loading. Thus, we determined changes in serum sclerostin and bone turnover markers in healthy adult men who participated in a controlled bed rest study. Seven healthy adult men (31 +/- 3 yrs old) underwent 90-day six-degree head down tilt bed rest at the University of Texas Medical Branch in Galveston's Institute for Translational Sciences - Clinical Research Center (ITS-CRC). Serum sclerostin, PTH, serum markers of bone turnover (bone specific alkaline phosphatase, RANKL/OPG, and osteocalcin), urinary calcium and phosphorus excretion, and 24 hour pooled urinary markers of bone resorption (NTX, DPD, PYD) were evaluated pre-bed rest (BL), bed rest day 28 (BR-28), bed rest day 60 (BR-60), and bed rest day 90 (BR-90). In addition, bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry (DXA) at BL, BR-60, and post bed rest day 5 (BR+5). Data are reported as mean +/- standard deviation. We used repeated measures ANOVA to compare baseline values to BR-28, BR-60, and BR-90. RESULTS Consistent with prior reports, BMD declined significantly (1-2% per month) at weight-bearing skeletal sites (spine, hip, femur neck, and calcaneus). Serum sclerostin levels were elevated above BL at BR-28 (+29% +/- 20%, p = 0.003), BR-60 (+42% +/- 31%, p < 0.001), and BR-90 (22% +/- 21%, p = 0.07). Serum PTH levels were reduced at BR-28 (-17% +/- 16%, p = 0.02), BR-60 (-24% +/- 14%, p = 0.03), and returned to baseline at BR-90 (-21% +/- 21%, p = 0.14). Serum bone turnover markers did not change, however urinary bone resorption markers and calcium were significantly elevated following bed rest (p < 0.01). CONCLUSION We observed an increase of serum sclerostin associated with decreased serum PTH and elevated bone resorption markers in otherwise healthy men subjected to long-term immobilization.

Science On a Sphere (SOS) is a large visualization system, developed by the National Oceanic and Atmospheric Administration (NOAH), that uses computers running Redhat Linux and four video projectors to display animated data onto the outside of a sphere. Said another way, SOS is a stationary globe that can show dynamic, animated images in spherical form. Visualization of cylindrical data maps show planets, their atmosphere, oceans, and land, in very realistic form. The SOS system uses 4 video projectors to display images onto the sphere. Each projector is driven by a separate computer, and a fifth computer is used to control the operation of the display computers. Each computer is a relatively powerful PC with a high-end graphics card. The video projectors have native XGA resolution. The projectors are placed at the corners of a 30' x 30' square with a 68" carbon fiber sphere suspended in the center of the square. The equator of the sphere is typically located 86" off the floor. SOS uses common image formats such as JPEG, or TIFF in a very specific, but simple form; the images are plotted on an equatorial cylindrical equidistant projection, or as it is commonly known, a latitude/longitude grid, where the image is twice as wide as it is high (rectangular). 2048x] 024 is the minimum usable spatial resolution without some noticeable pixelation. Labels and text can be applied within the image, or using a timestamp-like feature within the SOS system software. There are two basic modes of operation for SOS: displaying a single image or an animated sequence of frames. The frame or frames can be setup to rotate or tilt, as in a planetary rotation. Sequences of images that animate through time produce a movie visualization, with or without an overlain soundtrack. After the images are processed, SOS will display the images in sequence and play them like a movie across the entire sphere surface. Movies can be of any arbitrary length, limited mainly by disk space and can be animated at frame rates up to 30 frames per second. Transitions, special effects, and other computer graphics techniques can be added to a sequence through the use of off-the-shelf software, like Final Cut Pro. However, one drawback is that the Sphere cannot be used in the same manner as a flat movie screen; images cannot be pushed to a "side", a highlighted area must be viewable to all sides of the room simultaneously, and some transitions do not work as well as others. We discuss these issues and workarounds in our poster.

We demonstrate that variations in the Ca isotope ratios in urine rapidly and quantitatively reflect changes in bone mineral balance. This variation occurs because bone formation depletes soft tissue of light Ca isotopes, while bone resorption releases that isotopically light Ca back into soft tissue. In a study of 12 individuals confined to bed rest, a condition known to induce bone resorption, we show that Ca isotope ratios shift in a direction consistent with net bone loss after just 7 days, long before detectible changes in bone density occur. Consistent with this interpretation, the Ca isotope variations track changes observed in N-teleopeptide, a bone resorption biomarker, while bone-specific alkaline phosphatase, a bone formation biomarker, is unchanged. Ca isotopes can in principle be used to quantify net changes in bone mass. Ca isotopes indicate an average loss of 0.62 +/- 0.16 % in bone mass over the course of this 30-day study. The Ca isotope technique should accelerate the pace of discovery of new treatments for bone disease and provide novel insights into the dynamics of bone metabolism.

Until 2006, it was not been possible to assess nutritional status of crewmembers on the ISS during flight because blood and urine could not be collected during ISS missions. Postflight observations of alterations in status of several nutrients are troubling, and we require the ability to monitor the status of these nutrients during flight to determine if there is a specific impetus or timeframe for these changes. In addition to the monitoring of crew nutritional status during flight, in-flight sample collection would allow better assessment of countermeasure effectiveness. Collecting samples during flight is one of the objectives of SMO 016E, and it is also designed to expand the current medical requirement for nutritional assessment (MR016L) to include additional normative markers for assessing crew health and countermeasure effectiveness. Additional markers of bone metabolism will be measured to better monitor bone health and the effectiveness of countermeasures to prevent bone resorption. New markers of oxidative damage will be measured to better assess the type of oxidative insults that occur during space flight. The array of nutritional assessment variables will be expanded to include ones that will allow us to better understand changes in folate, vitamin K, and vitamin B6 status, as well as risk factors for cardiovascular and oxidative damage during and after flight. Stress hormones and hormones that affect bone and muscle metabolism will also be measured. Measuring these additional variables will allow us to better monitor the health of crewmembers and make more accurate recommendations for their rehabilitation. Several nutritional assessment variables are altered at landing, but it is not known how long these changes persist. We extended the original protocol to include an additional postflight blood and urine sample collection 30 days after landing. Data are being collected before, during, and after flight. These data will provide a complete survey of how nutritional status and related systems are affected by space flight. Analyzing the data will help us to define nutritional requirements for long-duration missions. This expanded set of measurements will also aid in the identification of nutritional countermeasures to counteract, for example, the deleterious effects of microgravity on bone and muscle and the effects of space radiation.

Maintaining an intact nutrient supply in the food system flown on spacecraft is a critical issue for mission success and crew health and safety. Early polar expeditions and exploration expeditions by sailing vessels have taught us that a deficiency, or excess, of even a single vitamin in the food supply can be catastrophic. Evidence from ground-based research indicates that some vitamins are destroyed and fatty acids are oxidized (and therefore rendered dangerous or useless) by different types of radiation and by conditions of long-term storage. We hypothesize that radiation and long-term storage in the space-flight environment will affect the stability of vitamins, amino acids, and fatty acids in the space food system. The research objectives of our ongoing stability studies are to determine the stability of water- and fat-soluble vitamins, fatty acids, and amino acids in the space food supply before and after space flight on the International Space Station (ISS). Foods were analyzed after 2 weeks (a flight control), 11, 19, and 28 months of flight. Along with the space-flown foods, ground-based controls matched for time, light, and temperature are analyzed. The flight studies complement planned ground-based studies of the effects of radiation on vitamins, amino acids, and fatty acids. Flight studies are needed because a model based on ground-based data cannot predict all of the effects of the space-flight environment. Flight studies provide a more accurate test system to determine the effects on these nutrients of the temperature, and radiation conditions in the space-flight environment. Ground studies are required to evaluate longer missions and higher radiation levels expected outside low-Earth orbit. In addition to providing information about nutrient stability in space, the results of these studies will help NASA determine if a need exists to develop special packaging that can ensure stability of foods and nutrients in space, or if further studies of nutrient metabolism or nutrient requirements are needed.

The purpose of this research is to determine whether anti-resorptive pharmaceuticals such as bisphosphonates, in conjunction with the routine in-flight exercise program, will protect ISS crewmembers from the regional decreases in bone mineral density and bone strength and the increased renal stone risk documented on previous long-duration space flights [1-3]. Losses averaged ~ 1 to 2 percent per month in such regions as the lumbar spine and hip. Although losses showed significant heterogeneity among individuals and between bones within a given subject, space flight-induced bone loss was a consistent finding. More than 90 percent of astronauts and cosmonauts on long-duration flights (average 171 days) aboard Mir and the ISS, had a minimum 5 percent loss in at least one skeletal site, 40 percent of them had a 10 percent or greater loss in at least one skeletal site, and 22 percent of the Mir cosmonauts experienced a 15 to 20 percent loss in at least one site. These losses occurred even though the crewmembers performed time-consuming in-flight exercise regimens. Moreover, a recent study of 16 ISS astronauts using quantitative computed tomography (QCT) demonstrated trabecular bone losses from the hip averaging 2.3 percent per month [4]. These losses were accompanied by significant losses in hip bone strength that may not be recovered quickly [5]. This rapid loss of bone mass results from a combination of increased and uncoupled remodeling, as demonstrated by increased resorption with little or no change in bone formation markers [6-7]. This elevated remodeling rate likely affects the cortical and trabecular architecture and may lead to irreversible changes. In addition to bone loss, the resulting hypercalciuria increases renal stone risk. Therefore, it is logical to attempt to attenuate this increased remodeling with anti-resorption drugs such as bisphosphonates. Success with alendronate was demonstrated in a bed rest study [8]. This work has been extended to space flight and two dosing regimens: 1) an oral dose of 70 mg of alendronate taken weekly during flight or 2) a single intravenous (IV) dose of 4 mg of zoledronic acid given several weeks before flight. Currently the study is focusing on the oral option because of NASA s safety concerns with the IV-administered drug. The protocol requests 10 male or female crewmembers on ISS flights of 90 days or longer. Controls are 16 previous ISS crewmembers with QCT scans of the hip performed by these same investigators. The primary outcome measure for this study is hip trabecular bone mineral density measured by QCT, but other measures of bone mass are performed including peripheral QCT (pQCT) and dual-energy x-ray absorptiometry. Serum and urinary bone markers and renal stone risk measured before, during, and after flight are included. Postflight data are currently being collected from 2 ISS crewmembers. Two additional crewmembers will return this spring after ~6-month missions. To date no untoward effects have been encountered.

Although elder self-neglect is the most common form of elder mistreatment, its pathophysiology is not well understood. Alpha-tocopherol is a lipid soluble antioxidant required for the preservation of cell membranes. Since the association between tocopherol and cognitive impairment in older adults has been described, we explored the possibility of its role in elder self-neglect. OBJECTIVE: (1) To determine whether serum tocopherol levels are associated with elder self-neglect, and (2) to assess the association of serum tocopherol levels and cognitive function in elder self-neglect. METHODS: Serum tocopherol levels were measured in a cohort of 67 self-neglecting elders and 67 matched controls, recruited for the Consortium for Research in Elder Self-neglect of Texas. Pearson s correlation tests were performed to assess bivariate associations between serum tocopherol levels and cognitive function. RESULTS: Mean serum alpha-tocopherol levels were 10.8 +/- 4.7 ug/mL in self-neglect group and 13.0 +/- 4.9 ug/mL in control group (p = 0.006, unpaired student s t-test). None of the participants from either group had alpha-tocopherol level lower than the reference range. Mean serum gamma-tocopherol levels were 2.0 +/- 1.0 ug/mL in self-neglect group and 2.0 +/- 1.1 in control group (p=0.83). Proportion of the elders with gamma-tocopherol level lower than the reference range were 4.5% (3/66) in self-neglect group and 10.4% (7/67) in control group (p=0.32, Fisher s Exact Test). Among the self-neglecting elders, no association was found between serum alpha-tocopherol levels and the Mini-Mental State Examination (MMSE) or the Wolf-Klein Clock Drawing Test (CDT) scores (r =-0.42, p=0.75 for MMSE; r=0.08, p=0.54 for CDT). No association was found between serum gamma-tocopherol levels and the MMSE or the CDT (r=-0.12, p=0.35 for MMSE; r=0.05, p=0.68 for CDT). CONCLUSION: In our sample, neither alpha-tocopherol nor gamma-tocopherol appears to have a role in pathophysiology of elder self-neglect. Nevertheless, significantly lower serum alpha-tocopherol levels in the self neglect group merits further research.

Obtaining vitamin D is critical for space travelers because they lack ultraviolet light exposure and have an insufficient dietary supply of vitamin D. Despite the provision of 400 IU vitamin D supplements to International Space Station (ISS) early crewmembers, vitamin D status was consistently lower after flight than before flight, and in several crewmembers has decreased to levels considered clinically significant. Vitamin D has long been known to play a role in calcium metabolism, and more recently its non-calcitropic functions have been recognized. According to the results of several recent studies, functionally relevant measures indicate that the lower limit of serum 25-hydroxyvitamin D (a marker of vitamin D status) should be raised from the current 23 nmol/L to 80 nmol/L. The mean preflight serum 25-hydroxyvitamin D (25-OH vit D) for U.S. ISS crewmembers to date is 63 +/- 16 nmol/L, and after a 4- to 6-mo space flight it typically decreases 25-30% despite supplementation (400 IU/d). The sub-optimal pre- and postflight vitamin D status is an issue that needs to be addressed, to allow NASA to better define the appropriate amount of supplemental vitamin D to serve as a countermeasure against vitamin D deficiency in astronaut crews. A series of ground-based and flight studies in multiple models have been conducted, including Antarctica in winter months when UV-B radiation levels are essentially zero, bed rest where subjects are not exposed to UV-B radiation for 60-90 days, in free-living individuals in Houston, and in International Space Station crewmembers. In these studies, we looked at dose regimen and efficacy, compliance issues, as well as toxicity. Preliminary results from these studies will be presented. Together, the data from these studies will enable us to provide space crews with evidence-based recommendations for vitamin D supplementation. The findings also have implications for other persons with limited UV light exposure, including polar workers and the elderly.

The impact of microgravity on the human body is a significant concern for space travelers. Since mechanical loading is a main reason for bone loss, artificial gravity might be an effective countermeasure to the effects of microgravity. In a 21-day 6 head-down tilt bed rest (HDBR) pilot study carried out by NASA, USA, the utility of artificial gravity (AG) as a countermeasure to immobilization-induced bone loss was tested. Blood and urine were collected before, during, and after bed rest for bone marker determinations. Bone mineral density was determined by DXA and pQCT before and after bed rest. Urinary excretion of bone resorption markers (n-telopeptide and helical peptide) were increased from pre-bed rest, but there was no difference between the control and the AG group. The same was true for serum c-telopeptide measurements. Bone formation markers were affected by bed rest and artificial gravity. While bone-specific alkaline phosphatase tended to be lower in the AG group during bed rest (p = 0.08), PINP, another bone formation marker, was significantly lower in AG subjects than CN before and during bed rest. PINP was lower during bed rest in both groups. For comparison, artificial gravity combined with ergometric exercise was tested in a 14-day HDBR study carried out in Japan (Iwase et al. J Grav Physiol 2004). In that study, an exercise regime combined with AG was able to significantly mitigate the bed rest-induced increase in the bone resorption marker deoxypyridinoline. While further study is required to more clearly differentiate bone and muscle effects, these initial data demonstrate the potential effectiveness of short-radius, intermittent AG as a countermeasure to the bone deconditioning that occurs during bed rest and spaceflight. Future studies will need to optimize not only the AG prescription (intensity and duration), but will likely need to include the use of exercise or other combined treatments.

It has not been possible to assess nutritional status of crew members on the ISS during flight because blood and urine could not be collected during ISS missions. Postflight observations of alterations in nutritional status for several nutrients are troubling, and we require the ability to monitor the status of these nutrients during flight to determine if there is a specific impetus or timeframe for these changes. In addition to the monitoring of crew nutritional status during flight, in-flight sample collection would allow better assessment of countermeasure effectiveness. SMO 016E is also designed to expand the current medical requirement for nutritional assessment (MR016L) to include additional normative markers for assessing crew health and countermeasure effectiveness. Additional markers of bone metabolism will be measured to better monitor bone health and the effectiveness of countermeasures to prevent bone resorption. New markers of oxidative damage will be measured to better assess the type of oxidative insults that occur during space flight. The array of nutritional assessment parameters will be expanded to include parameters that will allow us to better understand changes in folate and vitamin B6 status, and related cardiovascular risk factors during and after flight. Additionally, stress hormones and hormones that affect bone and muscle metabolism will also be measured. This additional assessment will allow us to better monitor the health of crew members and make more accurate recommendations for their rehabilitation. Several nutritional assessment parameters are altered at landing, but it is not known how long these changes persist. We extended the current protocol to include an additional postflight blood and urine sample collection 30 days after landing. Data are being collected before, during, and after flight. These data will provide a complete survey of how nutritional status and related systems are affected by space flight. Analyzing the data will help us to define nutritional requirements for long-duration missions. This expanded set of measurements will also aid in the identification of nutritional countermeasures to counteract, for example, the deleterious effects of microgravity on bone and muscle and the effects of space radiation.

The impact of microgravity on the human body is a significant concern for space travelers. We report here initial results from a pilot study designed to explore the utility of artificial gravity (AG) as a countermeasure to the effects of microgravity, specifically to bone loss. After an initial phase of adaptation and testing, 15 male subjects underwent 21 days of 6 head-down bed rest to simulate the deconditioning associated with space flight. Eight of the subjects underwent 1 h of centrifugation (AG, 1 gz at the heart, 2.5 gz at the feet) each day for 21 days, while 7 of the subjects served as untreated controls (CN). Blood and urine were collected before, during, and after bed rest for bone marker determinations. At this point, preliminary data are available on the first 8 subjects (6 AG, and 2 CN). Comparing the last week of bed rest to before bed rest, urinary excretion of the bone resorption marker n-telopeptide increased 95 plus or minus 59% (mean plus or minus SD) in CN but only 32 plus or minus 26% in the AG group. Similar results were found for another resorption marker, helical peptide (increased 57 plus or minus 0% and 35 plus or minus 13% in CN and AG respectively). Bone-specific alkaline phosphatase, a bone formation marker, did not change during bed rest. At this point, sample analyses are continuing, including calcium tracer kinetic studies. These initial data demonstrate the potential effectiveness of short-radius, intermittent AG as a countermeasure to the bone deconditioning that occurs during bed rest.

Elder self-neglect is the most common, and most compelling form of elder mistreatment. Individuals who cannot provide the basic needs for themselves may develop social, functional, and physical deficits. The CREST project has the goal of systematically characterizing these individuals, and the objective of the study reported here is to characterize aspects of their nutritional status. Self-neglect (SN) subjects referred from Adult Protective Services were recruited and consented. Control (CN) subjects were matched for age, gender, race, and socio-economic status when possible. Reported here are data on 47 SN subjects (age 77 +/- 7, mean +/- SD; body weight 76 kg +/- 26) and 40 CN subjects (77 +/- 7, 79 kg +/- 20). Blood samples were analyzed for indices of nutritional status. SN subjects had higher serum concentrations of homocysteine (p < 0.01) and methylmalonic acid (p < 0.05). Red blood cell folate levels were lower (p < 0.01) in the SN subjects and serum folate levels tended (p < 0.07) to be lower, also. C-reactive protein concentrations were higher than 10 mg/dL in 36% of SN subjects and 18% of CN subjects. Total cholesterol and triglyceride concentrations were similar in the two groups. These data demonstrate that the self-neglecting elderly population is at risk with respect to several markers of nutritional status.

Elder self-neglect is a form of elder mistreatment. The systematic characterization of self-neglecting individuals is the goal of the CREST project. Reported here is the evaluation of fat-soluble vitamin status. Self-neglect (SN) subjects were recruited and consented following referral from Adult Protective Services. Control (CN) subjects were matched for age, gender, race, and socioeconomic status, as possible. We report here on 47 SN subjects (age 77 plus or minus 7, mean plus or minus SD; body weight 76 kg plus or minus 26) and 40 CN subjects (77 y plus or minus 7, 79 kg plus or minus 20). Blood samples were analyzed for indices of fat-soluble vitamin status. Plasma retinol (p less than 0.01) was lower in SN subjects. Plasma tocopherol tended (p less than 0.06) to be lower in SN subjects, while gamma-tocopherol was unchanged. SN subjects tended to have lower serum 25-OH vitamin D (p less than 0.11), and to be vitamin D deficient (26% below 23 mmol/L). Hypercalcemia occurred more often in SN subjects (23% had values above 2.56 mmol/L), as did elevated parathyroid hormone concentrations (p less than 0.05). These data demonstrate that many nutrients are affected in the self-neglecting elderly, and that long-term deficits are evident by the nature of changes in fat soluble vitamins.

Long-term exposure to microgravity can cause a severe musculoskeletal loss and cardiovascular deconditioning in astronauts. In this report, the effectiveness of combined supine treadmill exercise in a lower body negative pressure chamber (LBNPex) and flywheel resistive exercise (Rex) countermeasures was determined to prevent bone loss, reduced aerobic upright exercise capacity and reduced muscle strength. We hypothesized that exercise subjects (EX) would show less decrease in bone mineral density (BMD), peak oxygen consumption (VO2pk) and knee extensor strength (KES) than control subjects (CON). Sixteen healthy female subjects (34 plus or minus 4yrs, 164 plus or minus 6.5cm, 58 plus or minus 5kg; mean plus or minus SD) participated in a 60-d 6 degree head-down tilt bed rest (BR) study after providing written informed consent. Subjects were assigned to one of two groups: a non- exercising CON group or an EX group performing LBNPex 2-4 d/wk and Rex every 3rd-d. VO2pk was measured with a maximal, graded, upright treadmill test performed pre-BR and on 3-d after BR. BMD was assessed pre-BR and 3-d after BR by dual energy x-ray absorptiometry total body DEXA scan (DEXA; HOLOGIC QDR 4500 Elite ). A Cybex dynamometer was employed to measure the isokinetic KES before and 5-d after BR. Two-way repeated measures ANOVA were performed with time as the repeated factor. Statistical significance was set at p less than 0.05. CON experienced a significant decrease in BMD in the trochanter (PRE: 0.670 0.045; POST: 0.646 0.352 g(raised dot) per square centimeter) and in the whole hip (PRE: 0.894 0.059; POST: 0.858 0.057 g(raised dot) per square centimeter). BMD also decreased significantly in EX in the trochanter (PRE: 0.753 plus or minus 0.0617; POST: 0.741 plus or minus 0.061 g(raised dot) per square centimeter) and whole hip (PRE: 0.954 plus or minus 0.067; POST: 0.935 plus or minus 0.069 g(raised dot) per square centimeter). BMD losses were significantly less in EX than in CON subjects. VO2pk was significantly decreased in the CON after BR (PRE: 38.0 plus or minus 4.8; POST: 29.9 plus or minus 4.2 ml(raised dot) per kilogram per minute), but not in the EX (PRE: 39.0 plus or minus 2.0; POST: 37.8 plus or minus 1.9 ml(raised dot) per kilogram per minute). KES was significantly reduced by 30% in CON (PRE: 113 plus or minus 12; POST: 78 plus or minus 8 N-m), but was not different in EX (PRE: 126 plus or minus 25; POST: 115 plus or minus 25 N-m). The combination LBNPex and Rex during 60-d BR protects against cardiovascular and musculoskeletal deconditioning and may be an efficacious countermeasure for prolonged space flight.

Dietary control and nutrient intake are critical aspects of any metabolic study, but this is especially true in the case of bed rest studies. We sought to define nutrient requirements, develop menus, and implement them in a series of three long-duration bed rest studies. With regard to energy intake, the goal was to maintain subject body weight to within 3% of their body weight on day 3 of bed rest (after fluid shift had occurred). For other nutrients, intakes were based on the NASA space flight nutritional requirements (with some adaptations based on the ground-based model used here). A secondary goal was to develop menus with foods similar to those expected to be approved for space flight (however, this was relaxed to attain desired nutrient intakes). This paper also describes the role of the research dietitian as part of the multi-disciplinary team and the importance of the metabolic kitchen staff. It also provides insight into some of the dietary challenges that arise during extended-duration bed rest studies. Regardless of the overall objective of the study, nutrition must be carefully planned, implemented, and monitored for results to be uncompromised.

Ground-based analogs of spaceflight are an important means of studying physiological and nutritional changes associated with space travel, particularly since exploration missions are anticipated, and flight research opportunities are limited. A clinical nutritional assessment of the NASA Extreme Environment Mission Operation V (NEEMO) crew (4 M, 2 F) was conducted before, during, and after the 14-d saturation dive. Blood and urine samples were collected before (D-12 and D-1), during (MD 7 and MD 12), and after (R + 0 and R + 7) the dive. The foods were typical of the spaceflight food system. A number of physiological changes were reported both during the dive and post dive that are also commonly observed during spaceflight. Serum hemoglobin and hematocrit were decreased (P less than 0.05) post dive. Serum ferritin and ceruloplasmin significantly increased during the dive, while transferring receptors tended to go down during the dive and were significantly decreased by the last day (R + 0). Along with significant hematological changes, there was also evidence for increased oxidative damage and stress during the dive. 8-hydroxydeoxyguanosine was elevated (P less than 0.05) during the dive, while glutathione peroxidase and superoxide disrnutase activities were decreased (P less than 0.05) during the dive. Serum C-reactive protein (CRP) concentration also tended to increase during the dive, suggesting the presence of a stress-induced inflammatory response, Decreased leptin during the dive (P less than 0.05) may also be related to the increased stress. Similar to what is observed during spaceflight, subjects had decreased energy intake and weight loss during the dive. Together, these similarities to spaceflight provide a model to further define the physiological effects of spaceflight and investigate potential countermeasures.

In several studies we tested the concepts that diet can alter acid-base balance and that reducing the dietary acid load has a positive effect on maintenance of bone. In study 1, (n = 11, 60-90 d bed rest), the renal acid load of the diet was estimated from its chemical composition, and was positively correlated with urinary markers of bone resorption (P less than 0.05); that is, the greater the acid load, the greater the excretion of bone resorption markers. In study 2, in males (n = 8, 30 d bed rest), an estimate of the ratio of nonvolatile acid precursors to base precursors in the diet was positively correlated (P less than 0.05) with markers of bone resorption. In study 3, for 28 d subjects received either a placebo (n = 6) or an essential amino acid supplement (n = 7) that included methionine, a known acid precursor. During bed rest (28 d), urinary calcium was greater than baseline levels in the supplemented group but not the control group (P less than 0.05), and in the supplemented group, urinary pH decreased (P less than 0.05). In study 4, less bone resorption occurred in space crew members who received potassium citrate (n = 6) during spaceflight of 4-6 months than in crew members who received placebo or were not in the study (n = 8) (P less than 0.05). Reducing acid load has the potential to mitigate increased bone resorption during spaceflight, and may serve as a bone loss countermeasure.

Long-term exposure to weightlessness leads to cardiovascular and musculoskeletal deconditioning. In this report, the effectiveness of combined supine treadmill exercise in a lower body negative pressure chamber (LBNPex) and flywheel resistive exercise (Rex) countermeasures was determined to prevent bone loss, reduced aerobic upright exercise capacity and reduced muscle strength. We hypothesized that exercise subjects would show less decrease in bone mineral density (BMD), peak oxygen consumption (VO2pk) and knee extensor strength (KES) than control subjects. Sixteen healthy female subjects participated in a 60-d 6(sup 0) head-down tilt bed rest (BR) study after providing written informed consent. Subjects were assigned to one of two groups: a non-exercising control group CON or an exercise group EX performing LBNPex 2-4 d/wk and Rex every 3rd-d. VO2pk was measured with a maximal, graded, upright treadmill test performed pre-BR and on 3-d after BR. BMD was assessed before and 3-d after BR. Isokinetic KES was measured before and 5-d after BR. Two-way repeated measures ANOVA were performed. Statistical significance was set at p less than 0.05. CON experienced a significant decrease in BMD in the trochanter (PRE: 0.670 plus or minus 0.045; POST: 0.646 plus or minus 0.352 g (raised dot) per square centimeter) and in the whole hip (PRE=0.894 plus or minus 0.059; POST: 0.858 plus or minus 0.057 g (raised dot) per square centimeter). BMD also decreased significantly in EX in the trochanter (PRE: 0.753 plus or minus 0.0617; POST: 0.741 plus or minus 0.061 g (raised dot) per square centimeter) and whole hip (PRE: 0.954 plus or minus 0.067; POST: 0.935 plus or minus 0.069 g (raised dot) per square centimeter). BMD losses were significantly less in EX than in CON subjects. VO2pk was significantly decreased in the CON after BR (PRE: 38.0 plus or minus 4.8; POST: 29.9 plus or minus 4.2 ml (raised dot) per kilogram per minute), but not in the EX (PRE: 39.0 plus or minus 2.0; POST: 37.8 plus or minus 1.9 ml (raised dot) per kilogram per minute). KES was significantly reduced by 30% in Con (PRE: 113 plus or minus 12; POST: 78 plus or minus 8 N-m), but was not different in EX (PRE: 126 plus or minus 25; POST: 115 plus or minus 25 N-m). The combination LBNPex and Rex during 60-d BR protects against cardiovascular and musculoskeletal deconditioning and may be efficacious countermeasure for prolonged space flight.

High-protein and acidogenic diets induce hypercalciuria. Foods or supplements with excess sulfur-containing amino acids increase endogenous sulfuric acid production and therefore have the potential to increase calcium excretion and alter bone metabolism. In this study, effects of an amino acid/carbohydrate supplement on bone resorption were examined during bed rest. Thirteen subjects were divided at random into two groups: a control group (Con, n = 6) and an amino acid-supplemented group (AA, n = 7) who consumed an extra 49.5 g essential amino acids and 90 g carbohydrate per day for 28 days. Urine was collected for n-telopeptide (NTX), deoxypyridinoline (DPD), calcium, and pH determinations. Bone mineral content was determined and potential renal acid load was calculated. Bone-specific alkaline phosphatase was measured in serum samples collected on day 1 (immediately before bed rest) and on day 28. Potential renal acid load was higher in the AA group than in the Con group during bed rest (P < 0.05). For all subjects, during bed rest urinary NTX and DPD concentrations were greater than pre-bed rest levels (P < 0.05). Urinary NTX and DPD tended to be higher in the AA group (P = 0.073 and P = 0.056, respectively). During bed rest, urinary calcium was greater than baseline levels (P < 0.05) in the AA group but not the Con group. Total bone mineral content was lower after bed rest than before bed rest in the AA group but not the Con group (P < 0.05). During bed rest, urinary pH decreased (P < 0.05), and it was lower in the AA group than the Con group. These data suggest that bone resorption increased, without changes in bone formation, in the AA group.

Defining optimal nutrient requirements is imperative to ensure crew health on long-duration space exploration missions. To date, nutrient requirement data have been extremely limited because of small sample sizes and difficulties associated with collecting biological samples. In this study, we examined changes in body composition, bone metabolism, hematology, general blood chemistry, and blood levels of selected vitamins and minerals after long-duration (128-195 d) space flight aboard the International Space Station. Crew members consumed an average of 80% of the recommended energy intakes, and on landing day their body weight had decreased (P=0.051). After flight, hematocrit was less, and serum femtin was greater than before flight (P<0.01). Serum iron, ferritin saturation, and transferrin had decreased after flight. The finding that other acute-phase proteins, including ceruloplasmin, retinol binding protein, transthyretin, and albumin were not changed after flight suggests that the changes in iron metabolism may not be strictly due to an inflammatory response. Urinary 8- hydroxy-2'-deoxyguanosine concentration was greater and superoxide dismutase was less after flight, indicating that oxidative damage had increased (P<0.05). Despite the reported use of vitamin D supplements during flight, serum 25-hydroxyvitamin D was significantly decreased after flight (P<0.01). Bone resorption was increased after flight, as indicated by several urinary markers of bone resorption. Bone formation, assessed by serum concentration of bone-specific alkaline phosphatase, was elevated only in crew members who landed in Russia, probably because of the longer time lapse between landing and sample collection. These data provide evidence that bone loss, compromised vitamin D status, and oxidative damage remain critical concerns for long-duration space flight.

During spaceflight, skeletal unloading results in loss of bone mineral density (BMD). This occurs primarily in the spine and lower body regions. This loss of skeletal mass could prove hazardous to astronauts on flights of long duration. In this study, intense resistance exercise was used to test whether a training regimen would prevent the loss of BMD that accompanies disuse. Nine subjects (5 men, 4 women) participated in a supine maximal resistance exercise training program during 17 wk of horizontal bed rest. These subjects were compared with 18 control subjects (13 men, 5 women) who followed the same bed rest protocol without exercise. Determination of treatment effect was based on measures of BMD, bone metabolism markers, and calcium balance obtained before, during, and after bed rest. Exercisers and controls had significantly (P < 0.05) different means, represented by the respective following percent changes: lumbar spine BMD, +3% vs. -1%; total hip BMD, +1% vs. -3%; calcaneus BMD, +1% vs. -9%; pelvis BMD, -0.5% vs. -3%; total body BMD, 0% vs. -1%; bone-specific alkaline phosphatase, +64% vs. 0%; alkaline phosphatase, +31% vs. +5%; osteocalcin, +43% vs. +10%; 1,25 dihydroxyvitamin D, +12% vs. -15%; parathyroid hormone intact molecule, +18% vs. -25%; and serum and ionized calcium, -1% vs. +1%. The difference in net calcium balance was also significant (+21 mg/day vs. -199 mg/day, exercise vs. control). The gastrocnemius and soleus muscle volumes decreased significantly in the exercise group, but the loss was significantly less than observed in the control group. The results indicate that resistance exercise had a positive treatment effect and thus might be useful as a countermeasure to prevent the deleterious skeletal changes associated with long-duration spaceflight.

Because of the variability of collagen crosslinks, their use as markers for bone resorption is often criticized. We hypothesized that the variability could be reduced by collecting urine for 24 hours (or longer) instead of using single voids, and by not normalizing to creatinine. Urine samples were collected from 22 healthy subjects during two or more 24-hour periods. Each 24-hour pool and each 2nd void of the day were analyzed for N-telopeptide (NTX), pyridinium (PYD), and deoxypyridinoline (DPD) crosslinks. Data were analyzed by using linear regression. For NTX, R2 for the two, 2nd-void samples (n = 38) was 0.55, whereas R2 for the two 24-hour pools was 0.51 or 0.52, expressed per day or per creatinine. For PYD and DPD, R2 for the 2nd-void samples was 0.26 and 0.18, R2 for the 24-hour pools expressed per day was 0.58 and 0.74, and R2 for the 24-hour pools expressed per creatinine was 0.65 and 0.76, respectively. Regression of the 2nd void and the corresponding 24-hour pool, expressed per day, yielded R2 = 0.19, 0.19, and 0.08, for NTX, PYD, and DPD, respectively (n = 76 each). For the 2nd-void sample and its corresponding 24-hour pool, expressed per creatinine, R2 = 0.24, 0.33, and 0.08, respectively. In a separate study, the coefficient of variation for NTX was reduced (P < 0.05) when data from more than one 24-hour collection were combined. Thus, the variability inherent in crosslink determinations can be reduced by collecting urine for longer periods. In research studies, the high variability of single-void collections, compounded by creatinine normalization, may alter or obscure findings.

Previous exercise in space has lacked sufficient loads to maintain preflight cardiovascular and musculoskeletal mass and function. Lower body negative pressure (LBNP) produces a static force equivalent to one Earth body weight by each 52 mm Hg of LBNP during supine posture. LBNP also provides transmural blood pressures simulating upright exercise. Thus, this artificial-gravity concept may help maintain cardiovascular and musculoskeletal systems of crewmembers during prolonged exposure to microgravity. Currently available, bungee cord assisted, treadmill exercise is limited by harness discomfort, lower than normal loads, abnormal post-flight gait, and the absence of gravitational blood pressures within the vascular system. PURPOSE: This project evaluates a method to create artificial gravity using supine LBNP treadmill exercise to prevent loss of physiologic function in microgravity simulated by 30 days of bed rest. Identical twins were used as volunteers so that statistical power could be maximized. This countermeasure is being transitioned to space flight. CURRENT STATUS OF RESEARCH Methods: Six sets of identical twins (6 females and 14 males, 21-36 years) remained in 6 head-down tilt (HDT) bed rest for 30 days to simulate prolonged microgravity. Six subjects were randomly selected to exercise supine in an LBNP chamber for 40 minutes six days per week (EX group), while their twin brothers served as non-exercise controls (CON). Pressure within the exercise LBNP chamber was adjusted to increase load, hence increasing exercise intensity. During supine treadmill exercise, LBNP (52-63 mmHg) was applied to produce foot ward forces equivalent to those for upright running on Earth at 1.0-1.2 times body weight (BW) and subjects performed an interval exercise protocol (40-80% peak exercise capacity [VO2pk]). Five minutes of resting LBNP immediately followed each exercise session. Results: Orthostatic tolerance time decreased significantly after 30 days bed rest in the CON group, but was relatively maintained in the EX group. VO2pk was maintained in EX males, but not in CON males. Isokinetic knee strength (extension, peak torque) decreased significantly in CON males, but was preserved in EX males. The EX group had significantly higher spine muscle strength after bed rest than the CON group. The cross-sectional area of spinal muscle at L4/5 level decreased significantly in the CON group but not in the EX group. Urinary n-telopeptide excretion, an index of bone resorption, was increased during bed rest in CON, but not in EX subjects. This suggests protection by LBNP exercise against the increase in bone resorption typically seen in simulated and actual microgravity. Significant changes in bone mineral density (BMD) in the spine and ribs were observed in CON subjects, but not in EX subjects. Conclusions: Our treadmill exercise protocol within LBNP plus a short period of post-exercise LBNP maintains orthostatic responses, upright exercise capacity and other important physiologic parameters during bed rest. These results document the efficacy of our apparatus and exercise protocol for maintaining physiologic structure and function during long-duration microgravity as simulated by 30 days of HDT bed rest. FUTURE PLANS: More sets of female identical twins are needed to reach significance. The LBNP exercise chamber will be redesigned for flight.

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.

Adequate nutrition is critical during long-term spaceflight, as is the ability to easily monitor dietary intake. A comprehensive nutritional status assessment profile was designed for use before, during and after flight. It included assessment of both dietary intake and biochemical markers of nutritional status. A spaceflight food-frequency questionnaire (FFQ) was developed to evaluate intake of key nutrients during spaceflight. The nutritional status assessment protocol was evaluated during two ground-based closed-chamber studies (60 and 91 d; n = 4/study), and was implemented for two astronauts during 4-mo stays on the Mir space station. Ground-based studies indicated that the FFQ, administered daily or weekly, adequately estimated intake of key nutrients. Chamber subjects maintained prechamber energy intake and body weight. Astronauts tended to eat 40--50% of WHO-predicted energy requirements, and lost >10% of preflight body mass. Serum ferritin levels were lower after the chamber stays, despite adequate iron intake. Red blood cell folate concentrations were increased after the chamber studies. Vitamin D stores were decreased by > 40% on chamber egress and after spaceflight. Mir crew members had decreased levels of most nutritional indices, but these are difficult to interpret given the insufficient energy intake and loss of body mass. Spaceflight food systems can provide adequate intake of macronutrients, although, as expected, micronutrient intake is a concern for any closed or semiclosed food system. These data demonstrate the utility and importance of nutritional status assessment during spaceflight and of the FFQ during extended-duration spaceflight.

Microgravity is associated with alterations in protein metabolism of both muscle and bone. That pancreas-derived insulin is essential to the normal maintenance of body protein balance is well known. The importance of altered endocrine pancreas function in microgravity is not yet established. We proposed to examine the influence of a microgravity model system, the High Aspect Ratio Vessel (HARV) upon islets of Langerhans from Wistar Furth rats. Islets were cultured in the HARV for 48 hr in Medium-199 and contrasted to static control islets (PLATE). Nitrogenous compounds elaborated into the media (micromoles/ml) were analyzed at 0 and 48 hr of culture and compared to PLATE with a 2-way ANOVA (HARV vs Hour).

The loss of bone during spaceflight is considered a physiological obstacle for the exploration of other planets. This report of calcium metabolism before, during, and after long-duration spaceflight extends results from Skylab missions in the 1970s. Biochemical and endocrine indexes of calcium and bone metabolism were measured together with calcium absorption, excretion, and bone turnover using stable isotopes. Studies were conducted before, during, and after flight in three male subjects. Subjects varied in physical activity, yet all lost weight during flight. During flight, calcium intake and absorption decreased up to 50%, urinary calcium excretion increased up to 50%, and bone resorption (determined by kinetics or bone markers) increased by over 50%. Osteocalcin and bone-specific alkaline phosphatase, markers of bone formation, increased after flight. Subjects lost approximately 250 mg bone calcium per day during flight and regained bone calcium at a slower rate of approximately 100 mg/day for up to 3 mo after landing. Further studies are required to determine the time course of changes in calcium homeostasis during flight to develop and assess countermeasures against flight-induced bone loss.

The final decade of the millennium has seen an enormous amount of on-orbit life sciences research, including both short- and long-duration flight research. Life sciences dedicated Space Shuttle flights have made intensive research opportunities available to study on the acute adaptation to weightlessness. The NASA/Mir Science Program combined resources of the USA and Russia to provide the first long-duration flight opportunities for the United States since the Skylab program of the early 1970s. Many of the results of these studies are still being evaluated, and in some cases data are still being collected to assess long-term readaptation to gravity after several months in weightlessness. The surge in life sciences research during this decade serves as a preamble to the opportunities to be provided by the latest addition to the Earth-orbiting structures--the International Space Station.

Space flight induces endocrine changes that perturb metabolism. This altered metabolism affects both the astronauts' body composition and the nutritional requirements necessary to maintain their health. During the last 25 years, a combination of studies conducted on Skylab (the first U.S. space laboratory), U.S. Shuttle flights, and Soviet and Russian flights provides a range of data from which general conclusions about energy and protein requirements can be drawn. We have reviewed the endocrine data from those studies and related it to changes in body composition. From these data it appears that protein and energy intake of astronauts are similar to those on Earth. However, a combination of measures, including exercise, appropriate diet, and, potentially, drugs, is required to provide the muscle health needed for long duration space flight.

Extended exposure to weightlessness results in bone loss. However, little information exists as to the precise nature or time course of this bone loss. Bone resorption results in the release of collagen breakdown products, including N-telopeptide and the pyridinium (PYD) cross-links, pyridinoline and deoxypyridinoline. Urinary pyridinoline and deoxypyridinoline are known to increase during bed rest. We assessed excretion of PYD cross-links and N-telopeptide before, during, and after long (28-day, 59-day, and 84-day) Skylab missions, as well as during short (14-day) and long (119-day) bed-rest studies. During space flight, the urinary cross-link excretion level was twice those observed before flight. Urinary excretion levels of the collagen breakdown products were also 40-50% higher, during short and long bed rest, than before. These results clearly show that the changes in bone metabolism associated with space flight involve increased resorption. The rate of response (i.e. within days to weeks) suggests that alterations in bone metabolism are an early effect of weightlessness. These studies are important for a better understanding of bone metabolism in space crews and in those who are bedridden.