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NASA NTRS2008

National Aeronautics and Space Administration Biological Specimen Repository

The National Aeronautics and Space Administration Biological Specimen Repository (Repository) is a storage bank that is used to maintain biological specimens over extended periods of time and under well-controlled conditions. Samples from the International Space Station (ISS), including blood and urine, will be collected, processed and archived during the preflight, inflight and postflight phases of ISS missions. This investigation has been developed to archive biosamples for use as a resource for future space flight related research. The International Space Station (ISS) provides a platform to investigate the effects of microgravity on human physiology prior to lunar and exploration class missions. The storage of crewmember samples from many different ISS flights in a single repository will be a valuable resource with which researchers can study space flight related changes and investigate physiological markers. The development of the National Aeronautics and Space Administration Biological Specimen Repository will allow for the collection, processing, storage, maintenance, and ethical distribution of biosamples to meet goals of scientific and programmatic relevance to the space program. Archiving of the biosamples will provide future research opportunities including investigating patterns of physiological changes, analysis of components unknown at this time or analyses performed by new methodologies.

McMonigal, Kathleen A.↗

NASA NTRS2009

NASA Biological Specimen Repository

The NASA Biological Specimen Repository (NBSR) has been established to collect, process, annotate, store, and distribute specimens under the authority of the NASA/JSC Committee for the Protection of Human Subjects. The International Space Station (ISS) provides a platform to investigate the effects of microgravity on human physiology prior to lunar and exploration class missions. The NBSR is a secure controlled storage facility that is used to maintain biological specimens over extended periods of time, under well-controlled conditions, for future use in approved human spaceflight-related research protocols. The repository supports the Human Research Program, which is charged with identifying and investigating physiological changes that occur during human spaceflight, and developing and implementing effective countermeasures when necessary. The storage of crewmember samples from many different ISS flights in a single repository will be a valuable resource with which researchers can validate clinical hypotheses, study space-flight related changes, and investigate physiological markers All samples collected require written informed consent from each long duration crewmember. The NBSR collects blood and urine samples from all participating long duration ISS crewmembers. These biological samples are collected pre-flight at approximately 45 days prior to launch, during flight on flight days 15, 30, 60 120 and within 2 weeks of landing. Postflight sessions are conducted 3 and 30 days following landing. The number of inflight sessions is dependent on the duration of the mission. Operations began in 2007 and as of October 2009, 23 USOS crewmembers have completed or agreed to participate in this project. As currently planned, these human biological samples will be collected from crewmembers covering multiple ISS missions until the end of U.S. presence on the ISS or 2017. The NBSR will establish guidelines for sample distribution that are consistent with ethical principles, protection of crewmember confidentiality, prevailing laws and regulations, intellectual property policies, and consent form language. A NBSR Advisory Board composed of representatives of all participating agencies will be established to evaluate each request by an investigator for use of the samples to ensure the request reflects the mission of the NBSR.

Pietrzyk, Robert↗

NASA NTRS2009

International Space Station Air Quality Assessed According to Toxicologically-Grouped Compounds

Scores of compounds are found in the International Space Station (ISS) atmospheric samples that are returned to the Johnson Space Center Toxicology Laboratory for analysis. Spacecraft Maximum Allowable Concentrations (SMACs) are set with the view that each compound is present as if there were no other compounds present. In order to apply SMACs to the interpretation of the analytical data, the toxicologist must employ some method of combining the potential effects of the aggregate of compounds found in the atmospheric samples. The simplest approach is to assume that each quantifiable compound has the potential for some effect in proportion to the applicable SMAC, and then add all the proportions. This simple paradigm disregards the fact that most compounds have potential to adversely affect only a few physiological systems, and their effects would be independent rather than additive. An improved approach to dealing with exposure to mixtures is to add the proportions only for compounds that adversely affect the same physiological system. For example, toxicants that cause respiratory irritation are separated from those that cause neurotoxicity or cardio-toxicity. Herein we analyze ISS air quality data according to toxicological groups with a view that this could be used for understanding any crew symptoms occurring at the time of the sample. In addition, this approach could be useful in post-flight longitudinal surveys where the flight surgeon may need to identify post-flight, follow-up medical studies because of on-orbit exposures that target specific physiological systems.

James, John T.↗

NASA NTRS2010

International Space Station Air Quality Assessed According to Toxicologically-Grouped Compounds

Scores of compounds are found in the International Space Station (ISS) atmospheric samples that are returned to the Johnson Space Center Toxicology Laboratory for analysis. Spacecraft Maximum Allowable Concentrations (SMACs) are set with the view that each compound is present as if there were no other compounds present. In order to apply SMACs to the interpretation of the analytical data, the toxicologist must employ some method of combining the potential effects of the aggregate of compounds found in the atmospheric samples. The simplest approach is to assume that each quantifiable compound has the potential for some effect in proportion to the applicable SMAC, and then add all the proportions. This simple paradigm disregards the fact that most compounds have potential to adversely affect only a few physiological systems, and their effects would be independent rather than additive. An improved approach to dealing with exposure to mixtures is to add the proportions only for compounds that adversely affect the same physiological system. For example, toxicants that cause respiratory irritation are separated from those that cause neurotoxicity or cardio-toxicity. Herein we analyze ISS air quality data according to toxicological groups with a view that this could be used for understanding any crew symptoms occurring at the time of the sample acquisition. In addition, this approach could be useful in post-flight longitudinal surveys where the flight surgeon may need to identify post-flight, follow-up medical studies because of on-orbit exposures that target specific physiological systems.

James, John T.↗

NASA NTRS2010

The Value of Biomedical Simulation Environments to Future Human Space Flight Missions

With the ambitious goals to send manned missions to asteroids and onto Mars, substantial work will be required to ensure the well being of the men and women who will undertake these difficult missions. Unlike current International Space Station or Shuttle missions, astronauts will be required to endure long-term exposure to higher levels of radiation, isolation and reduced gravity. These new operation conditions will pose health risks that are currently not well understood and perhaps unanticipated. Therefore, it is essential to develop and apply advanced tools to predict, assess and mitigate potential hazards to astronaut health. NASA s Digital Astronaut Project (DAP) is working to develop and apply computational models of physiologic response to space flight operation conditions over various time periods and environmental circumstances. The collective application and integration of well vetted models assessing the physiology, biomechanics and anatomy is referred to as the Digital Astronaut. The Digital Astronaut simulation environment will serve as a practical working tool for use by NASA in operational activities such as the prediction of biomedical risks and functional capabilities of astronauts. In additional to space flight operation conditions, DAP s work has direct applicability to terrestrial biomedical research by providing virtual environments for hypothesis testing, experiment design, and to reduce animal/human testing. A practical application of the DA to assess pre and post flight responses to exercise is illustrated and the difficulty in matching true physiological responses is discussed.

Mulugeta, Lealem↗

NASA NTRS2003

Excercise Within LBNP as an Artificial Gravity Countermeasure

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.

Hargens, A. R.↗

NASA NTRS2000

Cellular Responses to Mechanical Stress Selected Contribution: A Three-Dimensional Model for Assessment of in Vitro Toxicity in Balaena Mysticetus Renal Tissue

This study established two- and three-dimensional renal proximal tubular cell cultures of the endangered species bowhead whale (Balaena mysticetus), developed SV40-transfected cultures, and cloned the 61-amino acid open reading frame for the metallothionein protein, the primary binding site for heavy metal contamination in mammals. Microgravity research, modulations in mechanical culture conditions (modeled microgravity), and shear stress have spawned innovative approaches to understanding the dynamics of cellular interactions, gene expression, and differentiation in several cellular systems. These investigations have led to the creation of ex vivo tissue models capable of serving as physiological research analogs for three-dimensional cellular interactions. These models are enabling studies in immune function, tissue modeling for basic research, and neoplasia. Three-dimensional cellular models emulate aspects of in vivo cellular architecture and physiology and may facilitate environmental toxicological studies aimed at elucidating biological functions and responses at the cellular level. Marine mammals occupy a significant ecological niche (72% of the Earth's surface is water) in terms of the potential for information on bioaccumulation and transport of terrestrial and marine environmental toxins in high-order vertebrates. Few ex vivo models of marine mammal physiology exist in vitro to accomplish the aforementioned studies. Techniques developed in this investigation, based on previous tissue modeling successes, may serve to facilitate similar research in other marine mammals.

Goodwin, T. J.↗

NASA NTRS2010

NASA Biological Specimen Repository

The NASA Biological Specimen Repository (NBSR) was established in 2006 to collect, process, preserve and distribute spaceflight-related biological specimens from long duration ISS astronauts. This repository provides unique opportunities to study longitudinal changes in human physiology spanning may missions. The NBSR collects blood and urine samples from all participating ISS crewmembers who have provided informed consent. These biological samples are collected once before flight, during flight scheduled on flight days 15, 30, 60, 120 and within 2 weeks of landing. Postflight sessions are conducted 3 and 30 days after landing. The number of in-flight sessions is dependent on the duration of the mission. Specimens are maintained under optimal storage conditions in a manner that will maximize their integrity and viability for future research The repository operates under the authority of the NASA/JSC Committee for the Protection of Human Subjects to support scientific discovery that contributes to our fundamental knowledge in the area of human physiological changes and adaptation to a microgravity environment. The NBSR will institute guidelines for the solicitation, review and sample distribution process through establishment of the NBSR Advisory Board. The Advisory Board will be composed of representatives of all participating space agencies to evaluate each request from investigators for use of the samples. This process will be consistent with ethical principles, protection of crewmember confidentiality, prevailing laws and regulations, intellectual property policies, and consent form language. Operations supporting the NBSR are scheduled to continue until the end of U.S. presence on the ISS. Sample distribution is proposed to begin with selections on investigations beginning in 2017. The availability of the NBSR will contribute to the body of knowledge about the diverse factors of spaceflight on human physiology.

McMonigal, K. A.↗

NASA NTRS2011

Legacy of Biomedical Research During the Space Shuttle Program

The Space Shuttle Program provided many opportunities to study the role of spaceflight on human life for over 30 years and represented the longest and largest US human spaceflight program. Outcomes of the research were understanding the effect of spaceflight on human physiology and performance, countermeasures, operational protocols, and hardware. The Shuttle flights were relatively short, < 16 days and routinely had 4 to 6 crewmembers for a total of 135 flights. Biomedical research was conducted on the Space Shuttle using various vehicle resources. Specially constructed pressurized laboratories called Spacelab and SPACEHAB housed many laboratory instruments to accomplish experiments in the Shuttle s large payload bay. In addition to these laboratory flights, nearly every mission had dedicated human life science research experiments conducted in the Shuttle middeck. Most Shuttle astronauts participated in some life sciences research experiments either as test subjects or test operators. While middeck experiments resulted in a low sample per mission compared to many Earth-based studies, this participation allowed investigators to have repetition of tests over the years on successive Shuttle flights. In addition, as a prelude to the International Space Station (ISS), NASA used the Space Shuttle as a platform for assessing future ISS hardware systems and procedures. The purpose of this panel is to provide an understanding of science integration activities required to implement Shuttle research, review biomedical research, characterize countermeasures developed for Shuttle and ISS as well as discuss lessons learned that may support commercial crew endeavors. Panel topics include research integration, cardiovascular physiology, neurosciences, skeletal muscle, and exercise physiology. Learning Objective: The panel provides an overview from the Space Shuttle Program regarding research integration, scientific results, lessons learned from biomedical research and countermeasure development.

Hayes, Judith C.↗

NASA NTRS2011

Optimizing Muscle Parameters in Musculoskeletal Modeling Using Monte Carlo Simulations

Astronauts assigned to long-duration missions experience bone and muscle atrophy in the lower limbs. The use of musculoskeletal simulation software has become a useful tool for modeling joint and muscle forces during human activity in reduced gravity as access to direct experimentation is limited. Knowledge of muscle and joint loads can better inform the design of exercise protocols and exercise countermeasure equipment. In this study, the LifeModeler(TM) (San Clemente, CA) biomechanics simulation software was used to model a squat exercise. The initial model using default parameters yielded physiologically reasonable hip-joint forces. However, no activation was predicted in some large muscles such as rectus femoris, which have been shown to be active in 1-g performance of the activity. Parametric testing was conducted using Monte Carlo methods and combinatorial reduction to find a muscle parameter set that more closely matched physiologically observed activation patterns during the squat exercise. Peak hip joint force using the default parameters was 2.96 times body weight (BW) and increased to 3.21 BW in an optimized, feature-selected test case. The rectus femoris was predicted to peak at 60.1% activation following muscle recruitment optimization, compared to 19.2% activation with default parameters. These results indicate the critical role that muscle parameters play in joint force estimation and the need for exploration of the solution space to achieve physiologically realistic muscle activation.

Hanson, Andrea↗

NASA NTRS2011

Psychophysiological Studies in Extreme Environments

This paper reviews the results from two studies that employed the methodology of multiple converging indicators (physiological measures, subjective self-reports and performance metrics) to examine individual differences in the ability of humans to adapt and function in high stress environments. The first study was a joint collaboration between researchers at the US Army Research Laboratory (ARL) and NASA Ames Research Center. Twenty-four men and women active duty soldiers volunteered as participants. Field tests were conducted in the Command and Control Vehicle (C2V), an enclosed armored vehicle, designed to support both stationary and on-the-move operations. This vehicle contains four computer workstations where crew members are expected to perform command decisions in the field under combat conditions. The study objectives were: 1) to determine the incidence of motion sickness in the C2V relative to interior seat orientation/position, and parked, moving and short-haul test conditions; and 2) to determine the impact of the above conditions on cognitive performance, mood, and physiology. Data collected during field tests included heart rate, respiration rate, skin temperature, and skin conductance, self-reports of mood and symptoms, and cognitive performance metrics that included seven subtests in the DELTA performance test battery. Results showed that during 4-hour operational tests over varied terrain motion sickness symptoms increased; performance degraded by at least 5 percent; and physiological response profiles of individuals were categorized based on good and poor cognitive performance. No differences were observed relative to seating orientation or position.

Toscano, William B.↗

NASA NTRS2012

Paramyxovirus Infection Mimics In Vivo Cellular Dynamics in Three-Demensional Human Bronchio-Epithelial Tissue-Like Assemblies

Respiratory syncytial virus and parainfluenza virus cause severe respiratory disease, especially in infants, children and the elderly. An in vitro model that accurately mimics infection of the human respiratory epithelium (HRE) would facilitate vaccine development greatly. Monolayer cultures traditionally used to study these viruses do not accurately and precisely differentiate the replication efficiencies of wild type and attenuated viruses. Therefore, we engineered novel three-dimensional (3D) tissue-like assemblies (TLAs) of human broncho-epithelial (HBE) cells to produce a more physiologically relevant in vitro model of the HRE. TLAs resemble HRE structurally and by expression of differentiated epithelial cell markers. Most significantly, wild type viruses exhibited a clear growth advantage over attenuated strains in TLAs unlike monolayer cultures. In addition, the TLAs responded to virus infection by secreting pro-inflammatory mediators similar to the respiratory epithelia of infected children. These characteristics make the TLA model a valuable platform technology to develop and evaluate live, attenuated respiratory virus vaccine candidates for human use. Respiratory virus diseases, the most frequent and least preventable of all infectious diseases, range in severity from the common cold to severe bronchiolitis and pneumonia . Two paramyxoviruses, respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3), are responsible for a majority of the most severe respiratory diseases of infants and young children. RSV causes 70% of all bronchiolitis cases and is a major cause of morbidity and mortality worldwide, especially in infants. PIV3 causes 10-15% of bronchiolitis and pneumonia during infancy, second only to RSV, and 40% of croup in infants To date, licensed vaccines are not available to prevent these respiratory diseases. At present, traditional monkey kidney (Vero and LLC-MK2) and human (HEp-2) tissue culture cells and small animal models (mouse, cotton rat, guinea pig, ferret, and hamster) fail to accurately imitate viral replication and human disease states (8). Lacking an authentic model has impeded the development and evaluation of live, attenuated vaccine candidates. Development of a physiologically relevant in vitro tissue culture model that reproduces characteristics of the HRE, the primary target of RSV and PIV3, would aid in predicting clinical attenuation and safety of vaccine candidates. Successful tissue engineering of a 3D human intestinal model using novel NASA technology inspired the development of a tri-culture 3D model for the HRE. Sequential layering of primary mesenchymal cells (comprised of normal human fibroblasts and endothelial cells) followed by BEAS-2B epithelial cells derived from human bronchi and tracheae were recapitulated on Cultisphere and/or cytodex3 microcarriers in cylindrical vessels that rotate horizontally creating an organized epithelial structure. Horizontal rotation randomizes the gravity vector modeling aspects of microgravity. Mesenchymal and epithelial cells grown under these conditions reproduce the structural organization, multi-cellular complexity, and differentiation state of the HRE. The opportunity to study respiratory viruses in a nasal epithelium model is invaluable because the most promising respiratory virus vaccine candidates are live attenuated viruses for intranasal administration. Here we characterize the interactions of respiratory viruses and epithelial cells grown under modeled microgravity in comparison to gravity-ladened monolayers. 3D HBE TLAs and traditional monolayers (2D) are infected at 35 C, the upper temperature of the upper HRE, to simulate in vivo infection conditions. Growth kinetics of wild type (wt) RSV and PIV3 viruses were compared in 2D and 3D cells to that of strains attenuated in humans or rhesus macaques. This novel 3D HBE model also offers an opportunity to study whether the epithelial cell function, especially in host defenses recapitulated by mimicking the structural organization of the HRE. In vivo, airway epithelial cells play a significant and dynamic role in host defense by blocking paracellular permeability and modulating airway function through cellular interactions or tight junctions. As regulators of the innate immune response, epithelial cells constitutively express cytokines, chemokines, and colony stimulating factors including RANTES, IL-8, IL-6, GM-CSF, and G-CSF for proactive host defense. In response to viral infection, epithelial cells induce potent immuno-modulatory and pro-inflammatory cytokines that recruit phagocytic and inflammatory cells to clear the virus and enhance protection. Although disease pathogenesis is classically attributed to the cytopathic effects of the pathogen, severe disease states associated with RSV and PIV3 are attributed to the inflammatory response, especially in infants. RSV is a potent inducer of cytokines and pro-inflammatory mediators in epithelial cells in vivo. A differentiated human epithelial model independent of the complete functional immune system will help elucidate the role of epithelial cells in respiratory disease. We reported here, virus and host cell interactions in 3D HBE TLAs are similar to that in vivo. Because the epithelial cell organization of the TLAs impacts not only the expression of airway epithelial characteristics, but also cellular communication, the TLAs represent a more physiologically relevant model of the HRE than BEAS-2B or other non-tumour monolayer models of respiratory disease. As a result, wild type respiratory viruses have a clear growth advantage over attenuated viruses in TLAs unlike traditional monolayers. In addition, the TLAs respond to wild type virus infection by secreting pro-inflammatory mediators characteristic of infected HRE. TLAs expressing microbial defense mechanisms provide an excellent model to study the interactions of respiratory pathogens with their host and to identify the innate immunity mediators. Therefore, 3D HBE TLAs offer advantages for the study of respiratory viruses and the development of viral vaccine candidates.

Deatly, Anne M.↗

NASA NTRS2010

Modelling the Future Hydroclimatology of the Lower Fraser River and its Impacts on the Spawning Migration Survival of Sockeye Salmon

Short episodic high temperature events can be lethal for migrating adult Pacific salmon (Oncorhynchus spp.). We downscaled temperatures for the Fraser River, British Columbia to evaluate the impact of climate warming on the frequency of exceeding thermal thresholds associated with salmon migratory success. Alarmingly, a modest 1.0 C increase in average summer water temperature over 100 years (1981-2000 to 2081-2100) tripled the number of days per year exceeding critical salmonid thermal thresholds (i.e. 19.0 C). Refined thresholds for two populations (Gates Creek and Weaver Creek) of sockeye salmon (Oncorhynchus nerka) were defined using physiological constraint models based on aerobic scope. While extreme temperatures leading to complete aerobic collapse remained unlikely under our warming scenario, both populations were increasingly forced to migrate upriver at reduced levels of aerobic performance (e.g. in 80% of future simulations, => 90% of salmon encountered temperatures exceeding population specific thermal optima for maximum aerobic scope; T(sub opt)) = 16.3 C for Gates Creek and T(sub sopt)=14.5 C for Weaver Creek). Assuming recent changes to river entry timing persist, we also predicted dramatic increases in the probability of freshwater mortality for Weaver Creek salmon due to reductions in aerobic, and general physiological, performance (e.g. in 42% of future simulations =>50% of Weaver Creek fish exceeded temperature thresholds associated with 0 - 60% of maximum aerobic scope). Potential for adaptation via directional selection on run-timing was more evident for the Weaver Creek population. Early entry Weaver Creek fish experienced 25% (range: 15 - 31%) more suboptimal temperatures than late entrants, compared with an 8% difference (range: 0 - 17%) between early and late Gates Creek fish. Our results emphasize the need to consider daily temperature variability in association with population-specific differences in behaviour and physiological constraints when forecasting impacts of climate change on migratory survival of aquatic species.

Hague, M. J.↗

NASA NTRS2013

Effects of the 8 psia / 32% O2 Atmosphere on the Human in the Spaceflight Environment

Extravehicular activity (EVA) is at the core of a manned space exploration program. There are elements of exploration that may be safely and effectively performed by robots, but there are critical elements of exploration that will require the trained, assertive, and reasoning mind of a human crewmember. To effectively use these skills, NASA needs a safe, effective, and efficient EVA component integrated into the human exploration program. The EVA preparation time should be minimized and the suit pressure should be low to accommodate EVA tasks without undue fatigue, physical discomfort, or suit-related trauma. Commissioned in 2005, the Exploration Atmospheres Working Group (EAWG) had the primary goal of recommending to NASA an internal environment that allowed efficient and repetitive EVAs for missions that were to be enabled by the former Constellation Program. At the conclusion of the EAWG meeting, the 8.0 psia and 32% oxygen (O2) environment were recommended for EVA intensive phases of missions. As a result of selecting this internal environment, NASA gains the capability for efficient EVA with low risk of decompression sickness (DCS), but not without incurring additional negative stimulus of hypobaric hypoxia to the already physiologically challenging spaceflight environment. This paper provides a literature review of the human health and performance risks associated with the 8 psia/32% O2 environment. Of most concern are the potential effects on the central nervous system including increased intracranial pressure, visual impairment, sensorimotor dysfunction, and oxidative damage. Other areas of focus include validation of the DCS mitigation strategy, incidence and treatment of acute mountain sickness (AMS), development of new exercise countermeasures protocols, effective food preparation at 8 psia, assurance of quality sleep, and prevention of suit-induced injury. As a first effort, the trade space originally considered in the EAWG was re-evaluated looking for ways to decrease the hypoxic dose by further enriching the O2% or increasing the pressure. After discussion with the NASA engineering and materials community, it was determined that the O2 could be enriched from 32% to 34% and the pressure increased from 8.0 to 8.2 psia without significant penalty. These two small changes increase alveolar O2 pressure by 11 mmHg, which is expected to significantly benefit crewmembers. The 8.2/34 environment (inspired O2 pressure = 128 mmHg) is also physiologically equivalent to the staged decompression atmosphere of 10.2 psia / 26.5% O2 (inspired O2 pressure = 127 mmHg) used on 34 different shuttle missions for approximately a week each flight. Once decided, the proposed internal environment, if different than current experience, should be evaluated through appropriately simulated research studies. In many cases, the human physiologic concerns can be investigated effectively through integrated multi-discipline ground-based studies. Although missions proposing to use an 8.2/34 environment are still years away, it is recommended that these studies begin early enough to ensure that the correct decisions pertaining to vehicle design, mission operational concepts, and human health countermeasures are appropriately informed.

Environmental control↗

NASA NTRS2014

Effects of Radiation and Dietary Iron on Expression of Genes and Proteins Involved in Drug Metabolism

Liver function, especially the rate of metabolic enzyme activities, determines the concentration of circulating drugs and the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Dietary factors and exposure to radiation are aspects of spaceflight that are potential oxidative stressors and both can be modeled in ground experiments. In this experiment, we examined the effects of high dietary iron and low dose gamma radiation (individually and combined) on the gene expression of enzymes involved in drug metabolism, redox homeostasis, and DNA repair. METHODS All procedures were approved by the JSC Animal Care and Use Committee. Male Sprague-Dawley rats were divided into 4 groups (n=8); control, high Fe diet (650 mg iron/kg), radiation (fractionated 3 Gy exposure from a Cs- 137 source) and combined high Fe diet + radiation exposure. Animals were euthanized 24h after the last treatment of radiation; livers were removed immediately and flash -frozen in liquid nitrogen. Expression of genes thought to be involved in redox homeostasis, drug metabolism and DNA damage repair was measured by RT-qPCR. Where possible, protein expression of the same genes was measured by western blotting. All data are expressed as % change in expression normalized to reference gene expression; comparisons were then made of each treatment group to the sham exposed/ normal diet control group. Data was considered significant at p< 0.5. RESULTS Among the redox homeostasis genes examined, metallothionein showed a significant down regulation in the radiation treated group (-3.85 fold) and a trend toward down regulation in the high Fe + rad group. Metallothionein is involved in the regulation of physiological metals and also has antioxidant activities. Among the drug metabolism genes examined, ATP binding cassette subfamily B (Abcb1b) gene expression increased more than 10-fold in both groups that received radiation treatments. This increased expression was also seen at the protein level. This ABC transporter carries many different compounds across cell membranes, including administered medications. The cytochrome P450 2E1 enzyme, a mixed-function oxidase that deactivates some medications and activates others, showed about a 2-fold increase in gene expression in both radiation-treated groups, with a trend toward increased expression at the protein level. Expression of epoxide hydrolase, which detoxifies polycyclic aromatic hydrocarbons, showed similar 2-fold increases. Among the DNA repair genes examined, expression of RAD51 was significantly down regulated (1.5 fold) in the radiation treated group. RAD51 is involved in repair of double-stranded DNA breaks. CONCLUSION This experiment used 2 different sources of physiological oxidative stress, administered separately and together, and examined their impacts on liver gene and protein expression. It is clear that significant changes occurred in expression of several genes and proteins in the radiation-treated animals. If the results from this ground analog of portions of the spaceflight environment hold true for the spaceflight environment itself, the physiological roles of the affected enzymes (drug transport and metabolism, redox homeostasis) could mean consequences in redox homeostasis or the pharmacokinetics of administered medications

Faust, K. M.↗

NASA NTRS2014

Body Unloading Associated with Space Flight and Bed-rest Impacts Functional Performance

The goal of the Functional Task Test study is to determine the effects of space flight on functional tests that are representative of high priority exploration mission tasks and to identify the key underlying physiological factors that contribute to decrements in performance. Ultimately this information will be used to assess performance risks and inform the design of countermeasures for exploration class missions. We are currently conducting studies on both ISS crewmembers and on subjects experiencing 70 days of 6 degrees head-down bed-rest as an analog for space flight. Bed-rest provides the opportunity for us to investigate the role of prolonged axial body unloading in isolation from the other physiological effects produced by exposure to the microgravity environment of space flight. This allows us to parse out the contribution of the body unloading component on functional performance. In this on-going study both ISS crewmembers and bed-rest subjects were tested using an interdisciplinary protocol that evaluated functional performance and related physiological changes before and after 6 months in space and 70 days of 6 head-down bed-rest, respectively. Functional tests included ladder climbing, hatch opening, jump down, manual manipulation of objects and tool use, seat egress and obstacle avoidance, recovery from a fall, and object translation tasks. Crewmembers were tested three times before flight, and on 1, 6 and 30 days after landing. Bed-rest subjects were tested three times before bed-rest and immediately after getting up from bed-rest as well as 1, 6 and 12 days after reambulation. A comparison of bed-rest and space flight data showed a significant concordance in performance changes across all functional tests. Tasks requiring a greater demand for dynamic control of postural equilibrium (i.e. fall recovery, seat egress/obstacle avoidance during walking, object translation, jump down) showed the greatest decrement in performance. Functional tests with reduced requirements for postural stability (i.e. hatch opening, ladder climb, manual manipulation of objects and tool use) showed little reduction in performance. Bed-rest results indicate that body support unloading experienced during space flight plays a central role in postflight alteration of functional task performance. These data point to the importance of providing axial body loading as a central component of an inflight training system that will integrate cardiovascular, resistance and sensorimotor adaptability training modalities into a single interdisciplinary countermeasure system.

Bloomberg, J. J.↗

NASA NTRS2014

Translational Research and Medicine at NASA: From Earth to Space and Back Again

The Space Environment provides many challenges to the human physiology and therefore to extended habitation and exploration. Translational research and medical strategies are meeting these challenges by combining Earth based medical solutions with innovative and developmental engineering approaches. Translational methodologies are current applied to spaceflight related dysregulations in the areas of: (1) cardiovascular fluid shifts, intracranial hypertension and neuro-ocular impairment 2) immune insufficiency and suppression/viral re-expression, 3) bone loss and fragility (osteopenia/osteoporosis) and muscle wasting, and finally 4) radiation sensitivity and advanced ageing. Over 40 years of research into these areas have met with limited success due to lack of tools and basic understanding of central issues that cause physiologic maladaptaion and distrupt homeostatis. I will discuss the effects of living in space (reduced gravity, increased radiation and varying atmospheric conditions [EVA]) during long-duration, exploration-class missions and how translational research has benefited not only space exploration but also Earth based medicine. Modern tools such as telemedicine advances in genomics, proteomics, and metabolomics (Omicssciences) has helped address syndromes, at the systemic level by enlisting a global approach to assessing spaceflight physiology and to develop countermeasures thereby permitting our experience in space to be translated to the Earth's medical community.

Goodwin, Thomas J.↗

NASA NTRS2014

NASA's Approach to Critical Risks for Extended Human Space Flight

Planetary Robotic and Human Spaceflight Exploration Humans are exposed to a great variety of hazards in the space environment. These include the effects of weightlessness, radiation, isolation and confinement, altered day-night cycles, and others. These inherent hazards have both physiological and behavioral consequences. The adaptive capabilities of humans in these situations is remarkable, and often exceed our expectations. However, the demanding environment and challenging operational pace can push some of these adaptive processes to their limits. The NASA Human Research Program (HRP) is tasked with mitigating the most serious of these effects on human health, safety, and performance, in long-duration space flight. This can involve the development and deployment of physiological countermeasures, better understanding of the physiological alterations and avoidance of exacerbating situations, inputs to the design of future spacecraft to minimize risks, and in some cases the awareness that some level of risk might have to be accepted based on the resulting consequences and their likelihood. HRP has identified a few areas that are of special concern due to their severity, lack of understanding of underlying causes, or potential for negative impact on health or performance. Some of these areas are visual impairment possibly due to increased intracranial pressure, behavioral and performance problems due to sleep deficits and isolation, and acute and chronic effects of radiation. These problems can, if not addressed, be expected to increase on longer and more distant missions. The evidence from spaceflight, laboratory, and analog studies that supports the selection of the most critical risks will be discussed. Current and planned research programs that address these risks, and their anticipated outcomes, will also be described.

Shelhamer, Mark↗