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Overview of NASA's space radiation research program.

NASA is developing the knowledge required to accurately predict and to efficiently manage radiation risk in space. The strategy employed has three research components: (1) ground-based simulation of space radiation components to develop a science-based understanding of radiation risk; (2) space-based measurements of the radiation environment on planetary surfaces and interplanetary space, as well as use of space platforms to validate predictions; and, (3) implementation of countermeasures to mitigate risk. NASA intends to significantly expand its support of ground-based radiation research in line with completion of the Booster Applications Facility at Brookhaven National Laboratory, expected in summer of 2003. A joint research solicitation with the Department of Energy is under way and other interagency collaborations are being considered. In addition, a Space Radiation Initiative has been submitted by the Administration to Congress that would provide answers to most questions related to the International Space Station within the next 10 years.

Cosmic Radiation↗

Man in space: the use of animal models.

Animals have traditionally preceded man into space. During animal and human travels in space over the past almost 30 years, numerous anatomical, physiological, and biochemical changes have been observed. In order to safely qualify humans for extended duration space missions, scientific research needs to be performed. It may be possible to achieve many of these research goals with flight crews serving as experimental subjects; however, to do this with human subjects alone is impractical. Therefore, the use of animal surrogates as experimental subjects is essential to provide the missing information on the effects of spaceflights, to validate countermeasures, and to test medical treatment techniques which will be necessary for long duration missions. This research to assure human health, safety, and productivity in future extended duration space flights will include flights on NASA's Space Shuttle, unmanned biosatellites, and the Space Station Freedom.

Aerospace Medicine↗

High-resolution magnetic resonance imaging of the intraorbital optic nerve and subarachnoid space in patients with papilledema and optic atrophy.

OBJECTIVE: To evaluate the orbital portion of the optic nerve and the subarachnoid space using fast spin-echo magnetic resonance imaging in normal subjects and in patients with papilledema or optic atrophy. DESIGN: Measurements of the optic nerve complex on coronal images were made using high-resolution magnetic resonance imaging with fast spin-echo sequences. PATIENTS: Twenty-one patients, including 5 patients with papilledema due to congenital hydrocephalus, intracranial tumors, or meningitis, as well as 16 patients with optic atrophy, were studied. Sixteen healthy volunteers served as controls. MAIN OUTCOME MEASURES: The longitudinal diameter of the optic nerve, the longitudinal outer diameter of the subarachnoid space, the diameter ratio, and the area of the subarachnoid space were determined. RESULTS: In normal subjects, the ring-shaped area of high signal intensity that represented the subarachnoid space was widest behind the globe, then narrowed toward the orbital apex. In patients with papilledema, the area of the subarachnoid space was markedly dilated, the optic nerve was compressed, and the nerve sheath was widened, resulting in a small diameter ratio compared with that of controls. Patients with pallor of the temporal aspect of the optic disc appeared to exhibit dilation of the subarachnoid space; the size of the optic nerve was decreased more than that of the nerve sheath, resulting in a small diameter ratio compared with controls. Patients with complete pallor of the disc, however, exhibited hyperintense optic nerve complexes without a ring-shaped appearance toward the orbital apex. CONCLUSION: Fast spin-echo magnetic resonance imaging appears useful for objectively evaluating the optic nerve and surrounding subarachnoid space in patients with papilledema and optic atrophy.

Adolescent↗

Phosphonates as 31P-NMR markers of extra- and intracellular space and pH in perfused rat liver.

We evaluated phosphonates (Po) as markers of the extra- and intracellular space in perfused rat liver. (i) In- and outwash behaviour of phenylphosphonate (PhePo), 3-amino-propylphosphonate (NProPo) and methyl phosphonate (MePo) was compared with that of creatine phosphate (CrP), a marker of the extracellular space, and of dimethyl methylphosphonate (MePoMe2), a marker of the total water-accessible space. In- and outwash of CrP was accurately predicted by the time constant (approximately 12 s) for the in- and outwash of inulin, a standard marker of the extracellular space. MePoMe2 rapidly distributed over the total liver volume (about three times the CrP accessible space). PhePo, NProPo and MePo washed rapidly into the extracellular space with CrP, and then steadily spilled over into the MePoMe2-accessible space. Upon outwash, Po signals rapidly declined in phase with that of CrP. Residual Po (PhePo >> NProPo approximately equal to MePo) reflected the amount internalized during prolonged (60 min) inwash. Proportional amounts of residual Po were found in extracts of livers harvested after outwash of perfusate and extracellular markers. Consistent with exclusion from the cells, CrP went undetected in these extracts. (ii) The resonance frequency of residual PhePo after outwash of the extracellular fraction corresponded with the pH reported by cytosolic P1 and responded to transient changes of the intracellular pH, induced by perfusion with and withdrawal of 20 mM NH4Cl. (iii) MePoMe2 homogeneously distributed over perfusate, parenchyma and bile, consistent with unrestricted permeability. Other Po were transported transcellularly and excreted in bile. CrP was virtually excluded from the bile, attesting to a minimal role for 'bulk-phase pinocytotic' transcellular transport, or for 'paracellular' leakage. In summary, charged Po can be used as extracellular markers in liver, provided experimental conditions are adjusted to minimize their internalization. Some Po (e.g. PhePo) can reach intracellular concentrations which suffice for the compound to act as a reporter molecule of the cytosolic pH.

Animals↗

Organization and development of the perivascular space system in the neurohypophysis of the laboratory mouse.

The organization of the system of perivascular space around the capillaries in the neurohypophysis was studied in the adult and developing laboratory mouse by the use of histological silver impregnation and electron microscopical techniques. In the median eminence short and long extensions, arising mainly from the shallow space around capillary loops of the primary plexus of the portal system, formed radiations into the adjacent neural tissue of the external zone. The tissue of the neural lobe was separable into non-vascular regions dominated by undilated portions of neurosecretory nerve fibres and pituicytes, and neurovascular regions with perivascular space extensions forming an extensive system of connections between neighbouring capillaries. In the median eminence, the system of extensions of the perivascular space was estimated to increase the neurovascular contact surface area by at least 50%, implying an increased efficiency of the organ without a notable increase of its volume. The possibility that the ramifications of the perivascular space imply an enhanced uptake rate into the bloodstream and a subsequent increased concentration of the neurohormones in the portal blood, was discussed. During development of the median eminence, differentiation of perivascular space extensions of the adult type started in the juvenile of about three weeks of age, when shallow capillary loops had been formed. In the neural lobe, perivascular space ramifications were already present when the internal capillaries were formed and were fairly frequent in ten-day young. At the age of three to four weeks the organization of the system was similar to that of the adult animal.

Animals↗

Calbindins decreased after space flight.

Exposure of the body to microgravity during space flight causes a series of well-documented changes in Ca2+ metabolism, yet the cellular and molecular mechanisms leading to these changes are poorly understood. Calbindins, vitamin D-dependent Ca2+ binding proteins, are believed to have a significant role in maintaining cellular Ca2+ homeostasis. In this study, we used biochemical and immunocytochemical approaches to analyze the expression of calbindin-D28k and calbindin-D9k in kidneys, small intestine, and pancreas of rats flown for 9 d aboard the space shuttle. The effects of microgravity on calbindins in rats from space were compared with synchronous Animal Enclosure Module controls, modeled weightlessness animals (tail suspension), and their controls. Exposure to microgravity resulted in a significant and sustained decrease in calbindin-D28k content in the kidney and calbindin-D9k in the small intestine of flight animals, as measured by enzyme-linked immunosorbent assay (ELISA). Modeled weightlessness animals exhibited a similar decrease in calbindins by ELISA. Immunocytochemistry (ICC) in combination with quantitative computer image analysis was used to measure in situ the expression of calbindins in the kidney and the small intestine, and the expression of insulin in pancreas. There was a large decrease of immunoreactivity in renal distal tubular cell-associated calbindin-D28k and in intestinal absorptive cell-associated calbindin-D9k of space flight and modeled weightlessness animals compared with matched controls. No consistent difference in pancreatic insulin immunoreactivity between space flight, modeled weightlessness, and controls was observed. Regression analysis of results obtained by quantitative ICC and ELISA for space flight, modeled weightlessness animals, and their controls demonstrated a significant correlation. These findings after a short-term exposure to microgravity or modeled weightlessness suggest that a decreased expression of calbindins may contribute to the disorders of Ca2+ metabolism induced by space flight.

Animals↗

Effects of space flight on GLUT-4 content in rat plantaris muscle.

The effects of 14 days of space flight on the glucose transporter protein (GLUT-4) were studied in the plantaris muscle of growing 9-week-old, male Sprague Dawley rats. The rats were randomly separated into five groups: pre-flight vivarium ground controls (PF-VC) sacrificed approximately 2 h after launch; flight groups sacrificed either approximately 5 h (F-R0) or 9 days (F-R9) after the return from space; and synchronous ground controls (SC-R0 and SC-R9) sacrificed at the same time as the respective flight groups. The flight groups F-R0 and F-R9 were exposed to micro-gravity for 14 days in the Spacelab module located in the cargo bay of the shuttle transport system--58 of the manned Space Shuttle for the NASA mission named "Spacelab Life Sciences 2". Body weight and plantaris weight of SC-R0 and F-R0 were significantly higher than those of PF-VC. Neither body weight nor plantaris muscle weight in either group had changed 9 days after the return from space. As a result, body weight and plantaris muscle weight did not differ between the flight and synchronous control groups at any of the time points investigated. The GLUT-4-content (cpm/microgram membrane protein) in the plantaris muscle did not show any significant change in response to 14 days of space flight or 9 days after return. Similarly, citrate synthase activity did not change during the course of the space flight or the recovery period. These results suggest that 14 days of space flight does not affect muscle mass or GLUT-4 content of the fast-twitch plantaris muscle in the rat.

Animals↗

Space-time clustering analyses of testicular cancer amongst 15-24-year-olds in Northern England.

There has been speculation that environmental exposures may be involved in the aetiology of testicular cancer in adolescent boys and young men. Indirect evidence for this hypothesis would be provided by the finding of space-time clustering. To examine this we have looked for evidence of space-time clustering using data from a population-based cancer registry from Northern England. All cases of testicular cancer diagnosed in males aged 15-24 years during the period 1968-2002 were included in the study. Tests for space-time interactions between cases were applied with fixed thresholds of close in space and close in time. Addresses at birth and diagnosis were used in the analyses. To adjust for the effect of varying population density tests were repeated replacing fixed geographical distances with nearest neighbour thresholds. A total of 257 cases of testicular cancer were identified for analysis. Overall there was no evidence for space-time clustering. However, there was statistically significant space-time clustering for 15-19-year-old based on time of birth and place of diagnosis (p<0.001). The very limited finding of space-time clustering may provide tentative evidence for an environmental, or infectious component to aetiology. However, it may well be a chance finding. A larger study based on national data is required.

Adolescent↗

Transport, distribution space and intracellular concentration of the anti-inflammatory drug niflumic acid in the perfused rat liver.

Transport and distribution space of niflumic acid in the perfused rat liver were investigated employing the multiple-indicator dilution technique with constant infusion of the drug (step input). Niflumic acid permeated the cell membrane in both directions at very high rates and its distribution in the cellular space was flow-limited; at least at 37 degrees, the rates of influx and efflux could not be measured. Dissociation of the niflumic acid-albumin complex also occurred at very high rates. The apparent space of distribution of niflumic acid in the liver depended on the concentration of the drug and varied between 4.37 (1 mM) and 43.5 (10 microM) times the water space; even with 90% extracellular binding to albumin, the apparent space of distribution of niflumic acid was 5.1 times greater than the water space. The high apparent spaces of distribution reflected the high intracellular concentrations. The ratio of intracellular bound plus free concentration to the extracellular bound plus free concentration (Ci/Ce) varied between 6.62 (1 mM portal niflumic acid) and 71.0 (10 microM portal niflumic acid). Metabolic transformation depended on the concentration of the free form. Intracellular binding is probably the major reason for the high concentration of the drug in the hepatic tissue.

Animals↗

Blood-brain barrier permeability and the brain extracellular space in acute cerebral inflammation.

The diffusion properties of the brain cortical extracellular space have never been examined in models of inflammation, even though inflammation can cause increased blood-brain barrier permeability. Uptake of intravascular 125I-labelled albumin and the diffusion of the tetramethylammonium ion within the brain extracellular space was measured in an experimental brain abscess to determine the effect of acute inflammation upon blood-brain barrier permeability and diffusion properties of the cortical extracellular space. The blood-brain transfer constant for albumin was increased in the abscess region, indicating that an increase in blood-brain barrier permeability occurred in animals inoculated with a weakly pathogenic strain of Staphylococcus aureus. The volume fraction of the extracellular space, as measured by the diffusion of tetramethylammonium ion, ranged from 0.19 to 0.23 in bacteria inoculated subjects and from 0.21 to 0.22 in controls. The tortuosity of the extracellular space ranged from 1.40 to 1.42 in bacteria inoculated subjects and was 1.39 in controls. These results showed that the volume fraction and tortuosity of the cortical extracellular space were not affected by inflammation even though vascular permeability was increased. This result was supported by the finding that brain water content, measured in the same animals, was increased to a non-significant extent in the bacteria inoculated subjects. These findings lead to the conclusion that acute inflammation induced by a weak pathogen can cause increased blood-brain barrier permeability without a significant change in the diffusion properties of the brain cortical space.

Animals↗

An historical perspective on crew rescue and the role of the Association of Space Explorers.

The Association of Space Explorers (ASE) has actively encouraged the development of an international space rescue capability. Safe operations in space preclude loss of life and the associated suspension of flight operations. Spaceflight has well definable risks that history demonstrates are real. While none of those killed thus far in spaceflight-related accidents could have been saved by an international rescue capability, several non-fatal incidents indicate that a need exists. Space treaties include the principles of rescue on Earth and in space. For nearly 30 years, technical papers have addressed rescue principles, hardware concepts, operations and planning, and international cooperation. However, only the Apollo-Soyuz flight of 1975 represents any movement toward establishing an international rescue capability. Recently, prompted by the U.S. Congress, renewed interest in international rescue studies, as well as Space Station Freedom options, is apparent. International meetings on space safety and rescue have been conducted or are planned for the immediate future. The difficulties of launch readiness, limitations imposed by orbital mechanics, and practical implications of international cooperation have been, and are being addressed. Responsiveness, compatibility, and mutual support are key ingredients to any international rescue plan. The ASE, representing astronauts and cosmonauts from 17 nations, strongly urges the continuation of studies and discussions among the spacefaring nations.

Astronauts↗

Effect of space flights on plasma hormone levels in man and in experimental animal.

An important increase of plasma hormone levels like insulin, TSH and aldosterone was observed in human subjects after space flights, however in the changes of plasma content of ACTH, cortisol, adrenaline and noradrenaline the individual variations were observed in relation to number and duration of space flight. For evaluation of the effects of these changes in plasma hormone levels on metabolic processes also the experiments with small animals subjected to space flights on a board of biosatellite of Cosmos series were running. An elevation of plasma levels of corticosterone, adrenaline, noradrenaline and insulin was found in rats after the space flights of duration from 7 to 20 days. It was demonstrated, that the increase of corticosterone in plasma is followed by the activation of enzymes involved in the amino acid metabolism in rat liver (tyrosine aminotransferase, tryptophanpyrolase, alanine aminotransferase and aspartate aminotransferase). After a short recovery period (2 to 6 days) the plasma corticosterone concentration and also the activity of liver enzymes returned to control levels. The exposition of animals to stress stimuli during this revcovery period showed higher response of corticosterone levels in flight rats as compared to intact controls. The increase of plasma catecholamine levels was not followed by elevation of lipolysis in adipose tissue. This is due to lower response of adipose tissue to catecholamine because a decrease of the stimulation of lipolysis by noradrenaline was observed in animals after space flight. The increase of insulin was not followed by adequate decrease of glucose concentration suggesting a disturbances in glucose utilization similarly as in cosmonauts after a long-term space flight. These results showed that changes in plasma hormone levels, observed after space flight, affected the regulation of metabolic processes in tissues.

Animals↗

The effect of space flight on the board of the satellite Cosmos 2044 on plasma hormone levels and liver enzyme activities of rats.

The aim of present experiment was to study the changes of corticosterone, insulin and glucose levels in plasma, of the activity of enzymes involved in aminoacid metabolism in liver and the binding of insulin to specific receptors of cell membrane from liver and also of adipose tissue of rats exposed to space flight for 14 days on biosatellite Cosmos 2044. Adult male Wistar rats (body mass 300-370 g) were divided into five groups: intact control rats (AC), rats exposed to space flight (F), animals in synchronous model experiment (S), rats in antiorthostatic hypokinesia (A) and so called operated control group (C). Half of all groups (5 animals) except the intact control were operated 3 days before the experiment (fibulas on both hind legs were broken). The flight animals were sacrificed 5-6 hours after landing. It was observed that plasma insulin levels are increased in rat exposed to 14-day space flight and in synchron experiments. A significant increase of plasma glucose levels was found in flight rats in spite of high insulin concentrations suggesting that in rats exposed to 14-day space a deterioration of tissue sensitivity to insulin could by present. No significant differences of specific insulin binding to liver plasma membrane fraction in flight and intact control animals were observed. A decrease of insulin binding capacity in liver was found in rats in antiorthostatic hypokinesia (A). However in the membrane of adipocytes an important increase of insulin receptors was noted in rats subjected to space flight. These results suggest, that the liver and adipocyte insulin receptors of flight rats did not respond to the increased plasma insulin levels by "down regulation". The determination of plasma corticosterone levels showed that in flight rats and animals exposed to antiorthostatic hypokinesia the plasma hormone levels are significantly elevated. A significant increase of tyrosine aminotransferase and tryptophan pyrrolase activities in liver of flight rats and those exposed to hypokinesia was observed. Also the elevation of alanine amino-transferase in liver was observed in flight rats, while, the activity of aspartate aminotransferase in liver was similar in control and flight animals. These results showed that the changes in liver enzyme activities in rats after 14-day space flight are in agreement with the results observed in previous experiments after a shorter space flight (7 days).

Adipose Tissue↗

The action of glucagon infused via the hepatic artery in anterograde and retrograde perfusion of the rat liver is not a function of the accessible cellular spaces.

The metabolic action of glucagon in the different spaces that can be reached via the hepatic artery in the bivascularly perfused rat liver of fed rats was investigated. When perfusion was performed in the anterograde mode, glucagon (10 mM) was infused either into the portal vein (type 1 experiment) or into the hepatic artery (type 2); in the retrograde mode, the hormone was infused either into the hepatic vein (type 3) or into the hepatic artery (type 4). The aqueous cell spaces were measured by means of the multiple-indicator dilution technique. Glucose release, oxygen uptake and glycolysis (lactate plus pyruvate production) were measured as metabolic parameters. The following results were obtained. (1) The aqueous cell space accessible via the hepatic artery in the type 2 experiment was 0.63 ml/g; in the type 4 experiment this space was 0.18 ml/g (only periportal cells); glucagon up to 10 nM did not affect these cellular spaces nor did it affect the vascular spaces. (2) The effects of glucagon on glucose release, oxygen uptake and glycolysis were practically the same in all types of experiment (1 to 4), i.e., the action of glucagon was not a function of the accessible cell spaces. (3) When the respiratory chain of the liver cells accessible via the hepatic artery in the type 4 experiment was inhibited by cyanide, glucagon still increased oxygen uptake; oxygen uptake stimulation by glucagon was completely blocked only when cyanide was given to all liver cells. (4) Calcium depletion did not affect the action of glucagon on glucose release and oxygen uptake in the type 4 experiment. It was concluded that, in addition to the receptor-elicited response, the action of glucagon can also be propagated by cell-to-cell communication.

Animals↗

Viability of Bacillus subtilis spores exposed to space environment in the M-191 experiment system aboard Apollo 16.

During the Apollo 16 space flight, in the experiment system M-191, (microbial response to space environment) spores of Bacillus subtilis 168 were exposed to space vacuum or solar UV irradiation with a peak wavelength of 254 nm or both. The effects of these space factors on the colony-forming ability of the spores were studied. It was found (i) that space vacuum alone did not affect the survival of pre-dried spores; (ii) that space vacuum in combination with solar UV irradiation with a peak wavelength of 254 nm had a synergistic effect, which may by attributed to a UV supersensitivity of the spores during vacuum exposure. These results agreed with findings of simulation experiments on earth. It was concluded that air dried spores may survive exposure to space vacuum if shielded against solar UV irradiation.

Bacillus subtilis↗

Why 8-year-olds cannot tell the difference between Steve Martin and Paul Newman: factors contributing to the slow development of sensitivity to the spacing of facial features.

Children are nearly as sensitive as adults to some cues to facial identity (e.g., differences in the shape of internal features and the external contour), but children are much less sensitive to small differences in the spacing of facial features. To identify factors that contribute to this pattern, we compared 8-year-olds' sensitivity to spacing cues with that of adults under a variety of conditions. In the first two experiments, participants made same/different judgments about faces differing only in the spacing of facial features, with the variations being kept within natural limits. To measure the effect of attention, we reduced the salience of featural information by blurring faces and occluding features (Experiment 1). To measure the role of encoding speed and memory limitations, we presented pairs of faces simultaneously and for an unlimited time (Experiment 2). To determine whether participants' sensitivity would increase when spacing distortions were so extreme as to make the faces grotesque, we manipulated the spacing of features beyond normal limits and asked participants to rate each face on a "bizarreness" scale (Experiment 3). The results from the three experiments indicate that low salience, poor encoding efficiency, and limited memory can partially account for 8-year-olds' poor performance on face processing tasks that require sensitivity to the spacing of features, a kind of configural processing that underlies adults' expertise. However, even when the task is modified to compensate for these problems, children remain less sensitive than adults to the spacing of features.

Adult↗

Extending or projecting peripersonal space with tools? Multisensory interactions highlight only the distal and proximal ends of tools.

The effects of tool-use on the brain's representation of the body and of the space surrounding the body ('peripersonal space') has recently been studied within a number of disciplines in cognitive neuroscience, and is also of great interest to philosophers and behavioural ecologists. To date, most experimental findings suggest that tool-use extends the boundary of peripersonal space-visual stimuli presented at the tips of tools interact more with simultaneous tactile stimuli presented at the hands than visual stimuli presented at the same distance, but not associated with the tools. We studied the proposed extension of peripersonal space by tool-use by measuring the effects of three different tool-use tasks on the integration of visual and tactile stimuli at three distances from participants' hands along two hand-held tools. When the tool-use task required using the shafts or the tips of the tools, visuotactile interactions were stronger at the tips of the tools than in the middle of the shaft. When the handles of the tools were used, however, visuotactile interactions were strongest near the hands and decreased with distance along the tools. These results suggest that tools do not simply 'extend' peripersonal space, but that just the tips of tools actively manipulated in extrapersonal space are incorporated into the brain's visuotactile representations of the body and of peripersonal space.

Adolescent↗

The SOS-LUX-TOXICITY-Test on the International Space Station.

For the safety of astronauts and to ensure the stability and integrity of the genome of microorganisms and plants used in bioregenerative life support systems, it is important to improve our knowledge of the combined action of (space) radiation and microgravity. The SOS-LUX-TOXICITY test, as part of the TRIPLE-LUX project (accepted for flight at Biolab in Columbus on the International Space Station, (ISS)), will provide an estimation of the health risk resulting from exposure of astronauts to the radiation environment of space in microgravity. The project will: (i) increase our knowledge of biological/health threatening action of space radiation and enzymatic DNA repair; (ii) uncover cellular mechanisms of synergistic interaction of microgravity and space radiation; (iii) provide specified biosensors for spacecraft milieu examination; and (iv) provide experimental data on stability and integrity of bacterial DNA in spacecrafts. In the bacterial biosensor "SOS-LUX-Test" developed at DLR (patent), bacteria are transformed with the pBR322-derived plasmid pPLS-1 or the similar, advanced plasmid SWITCH, both carrying the promoterless lux operon of Photobacterium leiognathi as the reporter element controlled by a DNA damage-dependent SOS promoter as sensor element. A short description of the space experiment is given, and the current status of adaptation of the SOS-LUX-Test to the ISS, i.e. first results of sterilization, biocompatibility and functional tests performed with the already available hardware and bread board model of the automated space hardware under development, is described here.

Bacteriological Techniques↗