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Animal studies and human data concerning blood concentration and serotonin contents and effects on high altitude performance
Animal studies on changes in bioelectric activity of brain during brief periods of weightlessness and acceleration stress
Animal study of body volume increase and pressure changes causing lungs and thorax expansion during decompression to near vacuum
Animal study showing aversiveness of simulated gravity and importance of separating rotation effects from effects of G forces
The Soviet biosatellite Cosmos 2044 carried adult rats on a spaceflight that lasted 13.8 days and was intended to repeat animal studies carrier out on Cosmos 1887. Skeletal tissue and tendon from animals flown on Cosmos 2044 were studied by light and electron microscopy, histochemistry, and morphometric techniques. Studies were confined to the bone cells and vasculature from the weight-bearing tibias. Results indicated that vascular changes at the periosteal and subperiosteal region of the tibia were not apparent by light microscopy or histochemistry. However, electron microscopy indicated that vascular influsions were present in bone samples from the flight animals. A unique combination of microscopy and histochemical techniques indicated that the endosteal osteoblasts from this same middiaphyseal region demonstrated a slight (but not statisticallly significant) reduction in bone cell activity. Electron-microscopic studies of the tendons from metatarsal bones showed a collagen fibril disorganization as a result of spaceflight. Thus changes described for Cosmos 1887 were present in Cosmos 2044, but the changes ascribed to spaceflight were not as evident.
The effects of hypokinesia on animals were studied by observing: (1) hormonal and mediator balance of the body; (2) gas exchange and tissue respiration; (3) protein content in skeletal muscles; (4) structure of skeletal muscles; and (5) function of skeletal muscles. Sharp limitation of motor activity causes interconnected processes of a dystropic and pathological character expressed as a reduction in the force of various muscle group with disturbance of velocity properties and motor coordination due to disturbances in the control link of the neuromuscular system.
Regulatory agencies are considering alternative approaches to assessing inhalation toxicity that utilizes in vitro studies with human cells and in silico modeling in lieu of additional animal studies. In support of this goal, computational fluid-particle dynamics models were developed to estimate site-specific deposition of inhaled aerosols containing the fungicide, chlorothalonil, in the rat and human for comparisons to prior rat inhalation studies and new human in vitro studies. Under bioassay conditions, the deposition was predicted to be greatest at the front of the rat nose followed by the anterior transitional epithelium and larynx corresponding to regions most sensitive to local contact irritation and cytotoxicity. For humans, simulations of aerosol deposition covering potential occupational or residential exposures (1–50 µm diameter) were conducted using nasal and oral breathing. Aerosols in the 1–5 µm range readily penetrated the deep region of the human lung following both oral and nasal breathing. Under actual use conditions (aerosol formulations >10 µm), the majority of deposited doses were in the upper conducting airways. Beyond the nose or mouth, the greatest deposition in the pharynx, larynx, trachea, and bronchi was predicted for aerosols in the 10–20 µm size range. Only small amounts of aerosols >20 µm penetrated past the pharyngeal region. Using the ICRP clearance model, local retained tissue dose metrics including maximal concentrations and areas under the curve were calculated for each airway region following repeated occupational exposures. These results are directly comparable with benchmark doses from in vitro toxicity studies in human cells leading to estimated human equivalent concentrations that reduce the reliance on animals for risk assessments.
Several examples are presented of radio transmitters swallowed, surgically implanted, or carried externally to study animal and human objects with minimum disturbance to normal activity patterns. Particular attention is given to the method of using satellite-borne receivers for determining the position of animals or other objects carrying fixed-frequency transmitters. The design and operation of the instrumentation necessary for this purpose are described.
Saturn S-4B workshop for manned, orbital animal research facilities - feasibility study
Of the many possible health challenges posed during extended exploratory missions to space, the effects of space radiation on cardiovascular disease and cancer are of particular concern. There are unique challenges to estimating those radiation risks; care and appropriate and rigorous methodology should be applied when considering small cohorts such as the NASA astronaut population. The objective of this work was to determine if there was sufficient evidence for excess risk of cardiovascular disease and cancer in early NASA astronaut cohorts. NASA astronauts in selection groups 1-7 were chosen; this relatively homogeneous cohort consists of 73 white males, who unlike today's astronauts, maintained similar smoking and drinking habits to the general US population, and have published radiation doses. The participants flew in space on missions Mercury through Shuttle and received space radiation doses between 0-74.1 milligrays. Cause of death information was obtained from the Lifetime Surveillance of Astronaut Health (LSAH) program at NASA Johnson Space Center. Mortality was compared with the US male population. Trends of mortality with dose were assessed using a logistic model, fitted by maximum likelihood. Only 32 (43.84 percent) of the 73 early astronauts have died. Standard mortality ratios (SMRs) for cancer (n=7, SMR=43.4, 95 percent CI 17.8, 84.9), all circulatory disease (n=7, SMR=33.2, 95 percent CI 13.7, 65.0), and ischemic heart disease (IHD) (n=5, SMR=40.1, 95 percent CI 13.2, 89.4) were significantly lower than for the US white male population. For cerebrovascular disease, the upper confidence interval for SMR included 100, indicating it was not significantly different from the US population (n=2, SMR = 77.0, 95 percent CI 9.4, 268.2). The power of the study is low and remains below 10 percent even when risks 10 times those reported in the literature are assumed. Due to small sample size, there is currently insufficient statistical power to evaluate space radiation exposure effects on mortality in NASA astronauts. In addition to a comprehensive longitudinal study of NASA astronauts, a research strategy of low dose epidemiology data integration with cell and animal studies should be utilized for space radiation risk assessment in the astronauts.
The purpose of this study was to determine the effects of the semicircular canals and otolith organs on respiration in humans. On the basis of animal studies, we hypothesized that vestibular activation would elicit a vestibulorespiratory reflex. To test this hypothesis, respiratory measures, arterial blood pressure, and heart rate were measured during engagement of semicircular canals and/or otolith organs. Dynamic upright pitch and roll (15 cycles/min), which activate the otolith organs and semicircular canals, increased respiratory rate (Delta2 +/- 1 and Delta3 +/- 1 breaths/min, respectively; P < 0.05). Dynamic yaw and lateral pitch (15 cycles/min), which activate the semicircular canals, increased respiration similarly (Delta3 +/- 1 and Delta2 +/- 1, respectively; P < 0.05). Dynamic chair rotation (15 cycles/min), which mimics dynamic yaw but eliminates neck muscle afferent, increased respiration (Delta3 +/- 1; P < 0.05) comparable to dynamic yaw (15 cycles/min). Increases in respiratory rate were graded as greater responses occurred during upright (Delta5 +/- 2 breaths/min) and lateral pitch (Delta4 +/- 1) and roll (Delta5 +/- 1) performed at 30 cycles/min. Increases in breathing frequency resulted in increases in minute ventilation during most interventions. Static head-down rotation, which activates otolith organs, did not alter respiratory rate (Delta1 +/- 1 breaths/min). Collectively, these data indicate that semicircular canals, but not otolith organs or neck muscle afferents, mediate increased ventilation in humans and support the concept that vestibular activation alters respiration in humans.
PNNL has engaged in discussions with several organizations regarding potential future collaborations. PNNL has developed the Lab-on-a-Fish prototypes and produced video instructions for an organization conducting research on shark eggs. Several organizations have expressed interest in using the Lab-on-a-Fish for their studies. We’ve also updated two versions of the Lab-on-a-Fish to expand its applications to a wider range of animal studies and accelerate its commercialization. The new design of the Lab-on-a-Fish, which incorporates PCB-based electrodes, has demonstrated the ability to capture clear ECG signals without the need for additional needle-shaped electrodes. This innovation eliminates the need for implanting electrodes beneath the fish's skin at specific locations, which is required with the current version of Lab-on-a-Fish. This change significantly simplifies the manufacturing and implantation process. For the Lab-on-a-Fish design that uses an optical pulse oximeter, the measurement results were primarily influenced by respiratory activity rather than heart rate. This occurred because the oximeter was placed beneath the operculum. Further research and development are needed to explore more suitable locations and methods for accurate pulse oximeter measurements.
The exact stimulus eliciting vomiting in animal studies of motion sickness is difficult to specify because the vestibular stimulation produced by many motion conditions is confounded by voluntary movements with animals. This is an important problem because experiments with animal models of motion sickness can provide useful information about antimotion sickness drugs or the role of neural mechanisms, only when animals are exposed to the same motion stimuli in each experimental session. A series of tests were conducted to determine the susceptibility of 15 adult squirrel monkeys to motion sickness in freely moving and restrained test conditions. Canal stimulation was varied by exposing the monkey in freely moving conditions to varying degrees of angular velocity (60, 90, 120, 150 deg/sec), and in restrained conditions to one angular velocity (150 deg/sec) and to cross-coupling effects of whole-body roll movements during rotation. Otolith stimulation was investigated by using sinusoidal vertical linear acceleration during free movement conditions, and off-vertical rotation and earth-horizontal (BBQ) rotation while restrained. The percentage of freely moving animal vomiting during vertical axis rotation was 27, 93, 86, and 92 for the angular velocities of 60, 90, 120, and 150 deg/sec respectively. None of the monkeys vomited during vertical axis rotation or cross-coupled rotation when restrained. Otolith stimulation appears to be a less provocative stimulus for the squirrel monkey as the percentage of animals vomiting were 13, 0, and 7 for the conditions of free movement during oscillation, restraint during off-vertical, and BBQ rotation respectively. Motion sickness to the point of vomiting occurred regularly only in conditions where self-motion was possible. Such effects could occur because voluntary movement during motion augments vestibular effects by producing self-inflicted cross-coupling, but the failure to elicit vomiting with experimenter-coupling cross-coupling argues against this interpretation. Alternatively, these results might imply that feedback from movement control mechanisms may play an important role in sensory conflict as suggested by Oman's sensory-motor conflict theory.
The observation mechanisms dealing with pressure, flow, morphology, temperature, etc. are discussed. The approach taken in the performance of this study was to (1) review ground and space-flight data on cardiovascular function, including earlier related ground-based and space-flight animal studies, Mercury, Gemini, Apollo, Skylab, and recent bed-rest studies, (2) review cardiovascular measurement parameters required to assess individual performance and physiological alternations during space flight, (3) perform an instrumentation survey including a literature search as well as personal contact with the applicable investigators, (4) assess instrumentation applicability with respect to the established criteria, and (5) recommend future research and development activity. It is concluded that, for the most part, the required instrumentation technology is available but that mission-peculiar criteria will require modifications to adapt the applicable instrumentation to a space-flight configuration.
INTRODUCTION: The ability to create intravenous fluids (IVF) in-situ from the potable water supply of a spaceflight vehicle or habitat is a desired capability for an exploration medical system. In order to define an acceptable volume of air in IVF bags, an understanding of the volume of venous gas embolism as it relates to negative outcomes is needed. The purpose of this study is to review the literature to determine if there is a known volume of gas that contributes to mortality and/or morbidity that could be used to define requirements for rapid IVF infusion in microgravity. METHODS: A literature review was conducted of the PubMed database using the syntax: (Venous) AND (Gas OR Air) AND (Embolism) AND (Morbidity) AND (Mortality) AND (Volume) as well as manual review of references from relevant articles. 151 articles were screened excluding partial text and pediatric articles. Studies were reviewed for identification of volume of venous gas embolism associated with morbidity and/or mortality, which identified 27 articles. RESULTS: Reviewed literature included animal studies, case reports, and review articles. A high variation of proposed volumes contributing to mortality was reported. The limited human data values ranged from 20 ml to 200 ml of infused air with mortality estimated to be 48 – 80%. No studies evaluated human morbidity in any capacity. DISCUSSION: The lack of consensus on the safe volume of infused air has potential ramifications for IVF use in spaceflight as current technologies to create IVF from potable water may introduce air in IVF bags. While current microgravity infusion protocols call for the use of inline air removal filters, commercially available options have flow rate limitations that preclude rapid infusion in a resuscitation scenario. Such filters may be used in parallel to increase flow rate, but the time required to set up such a system may exclude its use during a medical emergency. Additionally, these consumable filters drive up the overall mass and volume of the medical system. Identification of a safe volume of air in IVF would allow for guidelines for the in-situ production of IVF in future spaceflight vehicles/habitats.
Some epidemiological studies suggest that women are at greater risk for radiation-induced lung cancer than men, but this observation is not consistent across all studies. A scientific committee formed by the National Council on Radiation Protection and Measurement evaluated evidence for a sex difference in lung cancer risk from radiation exposuresby reviewing animal studies and assessing the biological plausibility that such a difference might exist. The committee identified four mechanisms that could potentially result in greater radiogenic lung cancer risks for women. The first of these is that radiation exposure increases the relative risk for a molecular subtype of spontaneous lung cancer that occurs predominantly in women. The second is that is that sex chromosome or gene expression differences between men and women places women at greater risk. The third is that hormonal differences between men and women, particularly for estrogen levels, puts women at greater risk. The fourth mechanism is that sex differences in immune system function underlie a sex difference in radiation associated lung cancer risk.None of these mechanisms hasyet been proven to play a role in radiogenic lung cancer risk.
Future space explorations beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure plays a major role in progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Our long-term goals are to define the mechanisms and risk of bone loss in the spaceflight environment and to facilitate the development of effective countermeasures. We had previously reported that exposure to low or high-LET radiation correlates with an acute increase in the expression of pro-osteoclastic and oxidative stress genes in bone during the early response to radiation followed by pathological changes in skeletal structure. We then conducted systematic screening for potential countermeasures against bone loss where we tested the ability of various antioxidants to mitigate the radiation-induced increase in expression of these markers. For the screen, 16-week old C57Bl6J mice were treated with a dietary antioxidant cocktail, injectable DHLA or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs radiation and one day later, marrow cells were collected and the relevant genes analyzed for expression levels. Among the candidate countermeasures tested, DP was most effective in reducing the expression of genes associated with bone loss. Furthermore, analysis of skeletal structure by microcomputed tomography (microCT) revealed that DP also prevents the radiation-induced deterioration in skeletal microarchitecture as indicated by parameters such as percent bone volume (BVTV), trabecular spacing and trabecular number. We also found that DP has similar protective effects on skeletal structure in a follow-up study using 1 Gy of sequential proton and iron, radiation species relevant to spaceflight. When cultured ex vivo under osteogenic conditions, bone marrow-derived cells from DP-fed animals exhibited increased colony numbers compared to control diet-fed animals. These findings suggest that DP exerts pro-osteogenic effects apart from its previously demonstrated anti-resorptive action, which may be one of the mechanisms underlying its radioprotective effect on bone. In conclusion, a diet enriched in certain types of antioxidants may be useful as an intervention for radiation-induced bone loss.
There is substantial evidence that anatomical connections exist between vestibular and autonomic nuclei. Animal studies have shown functional interactions between the vestibular and autonomic systems. The nature of these interactions, however, is complex and has not been fully defined. Vestibular stimulation has been consistently found to reduce blood pressure in animals. Given the potential interaction between vestibular and autonomic pathways this finding could be explained by a reduction in sympathetic activity. However, rather than sympathetic inhibition, vestibular stimulation has consistently been shown to increase sympathetic outflow in cardiac and splanchnic vascular beds in most experimental models. Several clinical observations suggest that a link between vestibular and autonomic systems may also exist in humans. However, direct evidence for vestibular/autonomic interactions in humans is sparse. Motion sickness has been found to induce forearm vasodilation and reduce baroreflex gain, and head down neck flexion induces transient forearm and calf vasoconstriction. On the other hand, studies using optokinetic stimulation have found either very small, variable, or inconsistent changes in heart rate and blood pressure, despite substantial symptoms of motion sickness. Furthermore, caloric stimulation severe enough to produce nystagmus, dizziness, and nausea had no effect on sympathetic nerve activity measured directly with microneurography. No effect was observed on heart rate, blood pressure, or plasma norepinephrine. Several factors may explain the apparent discordance of these results, but more research is needed before we can define the potential importance of vestibular input to cardiovascular regulation and orthostatic tolerance in humans.