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A command, control, and communications (C3) environment is described which will be applied to the evaluation of performance of aircrews, particularly in situations in which they are subjected to chemical defense protection drugs and antihistamines.
Bed rest has been a normal procedure used by physicians for centuries in the treatment of injury and disease. Exposure of patients to prolonged bed rest in the horizontal position induces adaptive deconditioning responses. While deconditioning responses are appropriate for patients or test subjects in the horizontal position, they usually result in adverse physiological responses (fainting, muscular weakness) when the patient assume the upright posture. These deconditioning responses result from reduction in hydrostatic pressure within the cardiovascular system, virtual elimination of longitudinal pressure on the long bones, some decrease in total body metabolism, changes in diet, and perhaps psychological impact from the different environment. Almost every system in the body is affected. An early stimulus is the cephalic shift of fluid from the legs which increases atrial pressure and induces compensatory responses for fluid and electrolyte redistribution. Without countermeasures, deterioration in strength and muscle function occurs within 1 wk while increased calcium loss may continue for months. Research should also focus on drug and carbohydrate metabolism.
Topics discussed in this volume include space motion sickness, cardiovascular adaptation, fluid shifts, extravehicular activity, general physiology, perception, vestibular response modifications, vestibular physiology, and pharmacology. Papers are presented on the clinical characterization and etiology of space motion sickness, ultrasound techniques in space medicine, fluid shifts in weightlessness, Space Shuttle inflight and postflight fluid shifts measured by leg volume changes, and the probability of oxygen toxicity in an 8-psi space suit. Consideration is also given to the metabolic and hormonal status of crewmembers in short-term space flights, adaptive changes in perception of body orientation and mental image rotation in microgravity, the effects of a visual-vestibular stimulus on the vestibulo-ocular reflex, rotation tests in the weightless phase of parabolic flight, and the mechanisms of antimotion sickness drugs.
The ability of buspirone to prevent motion sickness and the mechanism of the buspirone action were tested in cats pretreated (s.c. injection) by buspirone 30 min before being subjected to motion stimulus (in a device described by Crampton and Lucot, 1985) or to an injection of an emetic drug xylazine (using only cats susceptible to motion sickness or to xylazine, respectively). Buspirone treatment was found to block motion sickness with an effective dose-50 of 0.46 mg/kg. Buspirone pretreatment (with 4.0 mg/kg) has also significantly blocked vomiting in cats later injected with 0.66 mg/kg xylazine. The results indicate that buspirone is acting at the vomiting center, the point of convergence for the separate mechanisms subserving chemically-induced emesis and motion sickness.
Radioligand binding studies were used to analyze muscarinic cholinergic receptor subtypes in human cortex and pons. Muscarinic cholinergic receptors were labeled by H-3-quinuclidinyl benzilate (H-3-QNB). Scopolamine was equipotent in both brain regions and did not discriminate subtypes of H-3-QNB binding. By contrast, the M1 selective antagonist pirenzepine was approximately 33-fold more potent in human cortex than pons. Carbachol, a putative M2 selective agonist, was more than 100-fold more potent in human pons than cortex. These results demonstrate that the human pons contains a relatively large proportion of carbachol-sensitive muscarinic cholinergic receptors. Drugs targeted to this subpopulation of muscarinic cholinergic receptors may prove to be effective anti-motion sickness agents with less side effects than scopolamine.
NASA is one of the few research centers concerned with motion sickness. Since the physiology of man has been developed in the one-gravity field Earth, the changes experienced by man in space are unique, and often result in symptoms that resemble motion sickness on Earth. NASA is concerned with motion sickness because it is very uncomfortable for the astronauts. Another concern of NASA is the possibility of a motion sickness astronaut regurgitating while he or she is sealed in an airtight space suit. This could be fatal. Motivated by these reasons, NASA spent thousands of dollars in research and development for a drug or technique for combating motion sickness. Several different treatments were developed for this disorder. Three of the most effective ways of combatting motion sickness are discussed.
Human serum albumin (HSA) crystals are provided in the form of tetragonal plates having the space groups P42(sub 1)2, the crystals being grown to sizes in excess of 0.5 mm in two dimensions and a thickness of 0.1 mm. Growth of the crystals is carried out by a hanging drop method wherein a precipitant solution containing polyethylene glycol (PEG) and a phosphate buffer is mixed with an HSA solution, and a droplet of mixed solution is suspended over a well of precipitant solution. Crystals grow to the desired size in 3 to 7 days. Concentration of reagents, pH and other parameters are controlled within prescribed limits. The resulting crystals exhibit a size and quality such as to allow performance of x ray diffraction studies and enable the conduct of drug binding studies as well as genetic engineering studies.
During the 1988 NASA Summer Faculty Fellowship Program, it was proposed that the loss of skeletal calcium upon prolonged exposure to microgravity could be explained, in part, by a renal maladjustment characterized by an increased urinary excretion of calcium. It was theorized that because the conservation of body fluids and electrolytes depends upon the energy of adenosine triphosphate and enzymes that control the use of its energy for renal ion transport, an induction of renal sodium and potassium-dependent adenosine triphosphatase (Na + K ATPase) by oral loading with potassium would increase the reabsorption of sodium directly and that of calcium indirectly, leading to improved hydration and to reduced calcium loss. Preliminary studies showed the following. Rats drinking water containing 0.2 M potassium chloride for six to 13 days excreted in urine 22 muEq of calcium and 135 muEq of sodium per 100 grams of body weight per day. The corresponding values for control rats drinking tap water were 43 muEq and 269 muEq respectively. Renal Na + K ATPase activity in potassium loaded rats was higher than in controls. Thus, oral potassium loading resulted in increased Na + K ATPase activity and diminished urinary excretion of calcium and of sodium as predicted by the hypothesis. An extension of these studies to humans has the potential of resulting in development of harmless, non-invasive, drug-free, convenient measures to reduce bone loss and other electrolyte and fluid problems in space travelers exposed to prolonged periods of microgravity.
To determine the possible biochemical consequences of prolonged weightlessness on liver function, tissue samples from rats that had flown aboard Cosmos 1887 were analyzed for hepatic protein, glycogen and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the hepatic glycogen content and HMG-CoA reductase activities of the rats flown on Cosmos 1887, and a decrease in the amount of microsomal cytochrome P sub 450 and the activity of aniline hydroxylase, a cytochrome P sub 450-dependent enzyme. Decreases in these two indices of the microsomal mixed-function oxidase system indicated that spaceflight may compromise the ability of liver to metabolize drugs and toxins. The higher HMG-CoA reductase correlated with elevated levels of serum cholestrol. Other changes included somewhat higher blood glucose, creatinine, SGOT, and much greater alkaline phosphatase and BUN. These results generally support the earlier observation of changes in these parameters (Merrill et al., Am. J. Physiol. 252:R22-R226, 1987). The importance of these alterations in liver function is not known; however, they have the potential to complicate long-term spaceflight.
In addition to nausea and vomiting, motion sickness involves slowing of brain waves, loss of performance, inhibition of gastric motility and the Sopite Syndrome. The therapeutic effects of antimotion sickness drugs on these reactions were evaluated. The subjects were rotated to the M-III end-point of motion sickness. Intramuscular (IM) medications were then administered. Side effects before and after rotation were reported on the Cornell Medical Index. Brain waves were recorded on a Grass Model 6 Electroencephalograph (EEG), and gastric emptying was studied after an oral dose of 1 mCi Technetium 99m DTPA in 10 oz. isotonic saline. An increase in dizziness and drowsiness was reported with placebo after rotation. This was not prevented by IM scopolamine 0.1 mg or ephedrine 25 mg. EEG recordings indicated a slowing of alpha waves with some thea and delta waves from the frontal areas after rotation. IM ephedine and dimenhydrinate counteracted the slowing while 0.3 mg scopolamine had an additive effect. Alterations of performance on the pursuit meter correlated with the brain wave changes. Gastric emptying was restored by IM metoclopramide. Ephedrine IM but not scopolamine is effective for some of the secondary effects of motion sickness after it is established.
The drag data on the Lageos satellite collected between 1976 and 1987 are analyzed, and the cause of fluctuations observed at times when the orbit intersects the earth's shadow is investigated. The average drag on the Lageos consists of three types of drag: the Yarkovsky thermal drag, which accounts for about 70 percent of the observed drag; the neutral particle drug, accounting for about 14 percent of the drag for a hydrogen number density of 5 x 10 to the 9th/cu m; and the charged particle drag, which accounts for 12 percent of average drag at a number density of 3 x 10 to the 9th and a temperature of 5000 K in the plasmasphere for a satellite potential of -1 V. The observed drag agrees with the particle environment at the Lageos altitude and the drag models. However, the fluctuations in Lageos's along-track acceleration when the orbit intersects the earth's shadow are still not well understood.
The effects of four weekly treatments with scopolamine (1.0 mg) and d-amphetamine (10 mg), separately or in combination, on human performance were investigated in 16 subjects undergoing nine performance tests from a menu of microcomputer-based tests administered after the treatment. It was d-amphetamine treatment that enhanced the results of motor and perceptual speed tests, while scopolamine had no effect on these tests. Two of the five cognitive tests showed reductions with scopolamine. The effects of scopolamine in this and other studies are considered in terms of a model which implies that the magnitude of the performance deficit depends on the performance type and the dosage level of the drug.
The headward shift of body fluid and increase in stress-related hormones that occur in hypogravity bring about a number of changes in metabolism and biochemistry of the human body. Such alterations may have important effects on health during flight and during a recovery period after return to earth. Body fluid and electrolytes are lost, and blood levels of several hormones that control metabolism are altered during space flight. Increased serum calcium may lead to an increased risk of renal stone formation during flight, and altered drug metabolism could influence the efficacy of therapeutic agents. Orthostatic intolerance and an increased risk of fracturing weakened bones are concerns at landing. It is important to understand biochemistry and metabolism in hypogravity so that clinically important developments can be anticipated and prevented or ameliorated.
The horizontally rotating fluid-filled, membrane oxygenated bioreactors developed at NASA Johnson for spacecraft applications provide a powerful tool for ground-based research. Three-dimensional aggregates formed by cells cultured on microcarrier beads are useful for study of cell-cell interactions and tissue development. By comparing electron micrographs of plant seedlings germinated during Shuttle flight 61-C and in an earth-based rotating bioreactor it is shown that some effects of microgravity are mimicked. Bioreactors used in the UAH Bioreactor Laboratory will make it possible to determine some of the effects of altered gravity at the cellular level. Bioreactors can be valuable for performing critical, preliminary-to-spaceflight experiments as well as medical investigations such as in vitro tumor cell growth and chemotherapeutic drug response; the enrichment of stem cells from bone marrow; and the effect of altered gravity on bone and muscle cell growth and function and immune response depression.
New class of compounds derived from polyethylene glycol (PEG's) namely, PEG-propionaldehydes, offers two important advantages over other classes of PEG aldehyde derivatives: compounds exhibit selective chemical reactivity toward amino groups and are stable in aqueous environment. PEG's and derivatives used to couple variety of other molecules, such as, to tether protein molecules to surfaces. Biotechnical and biomedical applications include partitioning of two phases in aqueous media; immobilization of such proteins as enzymes, antibodies, and antigens; modification of drugs; and preparation of protein-rejecting surfaces. In addition, surfaces coated with PEG's and derivatives used to control wetting and electroosmosis. Another potential application, coupling to aminated surfaces.
Scopolamine, fast-acting anticholinergic drug, formulated into drops administered intranasally. Formulation very useful for people who need immediate relief from motion sickness, and they can administer it to themselves. Also used in other clinical situations in which fast-acting anticholinergic medication required. Modified into such other forms as gel preparation, aqueous-base ointment, or aerosol spray or mist; also dispensed in metered-dose delivery system.
The purpose of this study was to gain experience with and validate the Heidelberg pH-telemetric methodology in order to determine if the pH-telemetric methodology would be a useful noninvasive measure of gastrointestinal transit time for future ground-based and in-flight drug evaluation studies. The Heidelberg pH metering system is a noninvasive, nonradioactive telemetric system that, following oral ingestion, continuously measures intraluminal pH of the stomach, duodenum, small bowel, ileocecal junction, and large bowel. Gastrointestinal motility profiles were obtained in normal volunteers using the lactulose breath-hydrogen and Heidelberg pH metering techniques. All profiles were obtained in the morning after an overnight fast. Heidelberg pH profiles were obtained in the fasting and fed states; lactulose breath-hydrogen profiles were obtained after a standard breakfast. Mouth-to-cecum transit time was measured as the interval from administration of lactulose (30 ml; 20 g) to a sustained increase in breath-hydrogen of 10 ppm or more. Gastric emptying time was measured as the interval from the administration of the Heidelberg capsule to a sustained increase in pH of three units or more.
Exposure of unprotected humans to altitudes above 63,000 ft results in ebullism. Ebullism occurs when the vapor pressure of tissues is less than the ambient pressure and the tissues spontaneously 'boil'. This may result in rapid unconsciousness, cardiac vaporlock, pulmonary collapse, cerebral anoxia, and sometimes even death. Potential places for this include EVA accidents in space, aircraft experiencing rapid decompression at high altitudes with cabin or pressure suit failure, and accidents during pressure suit training exercises. The pathophysiology of ebullism was studied in the 40's to 60's using animal models. There is one report of a prolonged, unprotected human exposure and several anecdotal of unprotected short term exposures to near vacuum. In addition to pulmonary and neurologic concerns, unprotected exposure of the head may result in freezing of the corneal surface of the eye. Surface eye freezing may impair vision and significantly impact mission completion. At this time, little data are available on the effectiveness of conventional treatment protocols, such as hyperbaric oxygen, for ebullism induced injuries. Research is needed to assess the efficacy of other adjunctive therapies such as high frequency ventilation and cerebral protective drugs that are still under development.