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NASA NTRS2014

Fibroblast Growth Factor-23 in Bed Rest and Spaceflight

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

Bokhari, R.↗
NASA NTRS1971

The measurement of radiation exposure of astronauts by radiochemical techniques

The concentrations of 23 major, minor, and trace elements in the fecal samples from the Apollo 12 and 13 astronauts are reported. Most elemental excretion rates are comparable to rates reported for earlier missions. Exceptions are noted for calcium, iron, and tin. Body calcium and iron losses appear to be reduced during the Apollo 12 and 13 missions such that losses now seem to be insignificant. Refined measurements of tin excretion rates agree with normal dietary intakes. Earlier reported tin values are in error. A new passive dosimetry canister was designed which contains foils of tantalum, copper, titanium, iron, cobalt, aluminum, and scandium. By measuring the concentrations of the various products of nuclear reactions in these metals after space exposure, the characteristics of the incident cosmic particles can be determined.

Brodzinski, R. L.↗
NASA NTRS1970

The Measurement of Radiation Exposure of Astronauts by Radiochemical Techniques

The principal gamma-ray-omitting radioisotopes produced in the body of astronauts by cosmic-ray bombardment which have half-lives long enough to be useful for radiation dose evaluation are Be-7, Na-22, and Na-24. The sodium isotopes were measured in the preflight and postflight urine and feces, and those feces specimens collected during the manned Apollo missions, by analysis of the urine salts and the raw feces in large crystal multidimensional gamma-ray spectrometers. The Be-7 was chemically separated, and its concentration measured in an all Na(T1), anticoincidence shielded, scintillation well crystal. The overall sensitivity of the experiment was reduced by almost all variables such as low concentrations of excreted cosmogenic radionuclides, high concentrations of injected radionuclides, low sample sizes, long delay periods before analysis, and uncertain excretion rates. The astronaut radiation dose in millirads, as determined by this technique, for the Apollo 7, 8, 9, 10, 11, 12, and 13 missions was 330, 160, 315, 870 ? 550, 31, 110, and 250 respectively. In view of these limitations this technique would be best applied to cases of unusually high exposures, such as that encountered from solar flares.

R L Brodzinski↗
NASA NTRS1974

Effects of an anti-G suit on the hemodynamic and renal responses to positive /+Gz/ acceleration

The effects of the currently used U.S. Air Force (CSU-12/P) anti-G suit on renal function during positive radial acceleration (+Gz) were assessed in seven normal male subjects in balance on a 200 meq sodium diet. Following suit inflation in the seated position, +2.0 Gz for 30 min resulted in a decrease in the rate of sodium excretion from 125 plus or minus 19 to 60 plus or minus 14 microeq/min, which persisted during a 25-min recovery period. Fractional excretion of sodium also decreased significantly during +Gz. The magnitude of the antinatriuresis was indistinguishable from that observed during +Gz without suit inflation. In contrast to the antinatriuresis observed during centrifugation without suit, however, the antinatriuresis with suit was mediated primarily by an enhanced tubular reabsorption of sodium.

Shubrooks, S. J., Jr.↗
NASA NTRS1974

The polyuria of paroxysmal atrial tachycardia

Two patients with paroxysmal atrial fibrillation and an associated polyuria were studied to delineate the mechanism of the increase in urine flow. A striking saluresis was noted in both patients. The increased sodium excretion was probably due to decreased sodium reabsorption, perhaps at proximal tubular nephron sites. This inhibition of sodium reabsorption could explain both the saluresis and some part or all of the polyuria. Re-evaluation of earlier case reports reveals patterns of concomitant salt and water excretion consistent with this mechanism. The saluresis cannot be explained by the previously favored hypothesis of antidiuretic hormone inhibition.

Kinney, M. J.↗
NASA NTRS1974

Biochemical responses of the Skylab crewman

The biochemical investigations of the Skylab crewmen were designed to study the physiological changes that were observed on flight crews returning from previous space flight missions as well as to study those changes expected to result from prolonged weightless exposure. These studies can be divided into two broad categories. One category included routine blood studies similar to those used in clinical medical practice. The second included research-type endocrine analyses used to investigate more thoroughly the metabolic/endocrine responses to the space flight environment. The premission control values indicated that all Skylab crewmen were healthy and were free from biochemical abnormalities. The routine results during and after flight showed slight but significant changes in electrolytes, glucose, total protein, osmolality, uric acid, cholesterol, and creatinine. Plasma hormal changes included adrenocorticotrophic hormone, cortisol, angiotensin I, aldosterone, insulin, and thyroxine. The 24-hour urine analyses results revealed increased excretion of cortisol, catecholamines, antidiuretic hormone, and aldosterone as well as excretion of significant electrolyte and uric acid during the Skylab flights.

Leach, C. S.↗
NASA NTRS1974

Total body calcium analysis

A technique to quantitate total body calcium in humans is developed. Total body neutron irradiation is utilized to produce argon 37. The radio argon, which diffuses into the blood stream and is excreted through the lungs, is recovered from the exhaled breath and counted inside a proportional detector. Emphasis is placed on: (1) measurement of the rate of excretion of radio argon following total body neutron irradiation; (2) the development of the radio argon collection, purification, and counting systems; and (3) development of a patient irradiation facility using a 14 MeV neutron generator. Results and applications are discussed in detail.

Lewellen, T. K.↗
NASA NTRS1974

Continued investigation of kinetic aspects of bone mineral metabolism

The total body calcium in humans was determined by measuring expired Ar-37 after neutron irradiation. The excretion of Ar-37 from humans was found to be much slower than the excretion from rats and dogs, and to be related to the age of a person. A study of the uniformity of the Ar-37 production throughout the thickness of the body was studied using phantoms. The results indicate that it should be possible to obtain a uniformity within plus or minus 3% for the production of Ar-37 per unit of calcium by using a bilateral irradiation. New low background, large volume proportional counters were developed and constructed, for more sensitive measurement of Ar-37 in the expired air from patients. A new irradiation enclosure was developed for measuring total body calcium in rats by the Ar-37 method. With this enclosure the Ar-37 production per gram of calcium is constant with a standard deviation of plus or minus 2.8% for any size rat between 100 and 500 grams. The use of Na-22 as measure of bone replacement in the fractured femur of a dog was not successful.

Palmer, H. E.↗
NASA NTRS1975

Fate in humans of the plasticizer, DI (2-ethylhexyl) phthalate, arising from transfusion of platelets stored in vinyl plastic bags

Platelet concentrates were shown to contain 18-38 mg/100 ml of a phthalate plasticizer (DEHP) which arose by migration from the vinyl plastic packs in which the plateletes were prepared and stored. Transfusion of these platelets into 6 adult patients with leukemia resulted in peak blood plasma levels of DEHP ranging from 0.34 - 0.83 mg/100 ml. The blood levels fell mono-exponentially with a mean rate of 2.83 percent per minute and a half-life of 28.0 minutes. Urine was assayed by a method that would measure unchanged DEHP as well as all phthalic acid-containing metabolities. In two patients, at most 60 and 90% of the infused dose, respectively, was excreted in the urine collected for 24 hours post-transfusion. These estimates, however, could be high due to the simultaneous excretion of DEHP remaining from previous transfusions or arising from uncontrolled environmental exposures.

Rubin, R. J.↗
NASA NTRS1975

Renal effects of continuous negative pressure breathing

Continuous negative pressure breathing (CNPB) was utilized to simulate the thoracic vascular distension of zero g or space, in 11 anesthetized rats. The animals underwent renal clearance and micropuncture renal nephron studies before, during, and after CNPB. Rats were pretreated with a high salt diet and I-M desoxycorticosterone (DOCA) in excess. None of these rats diuresed with CNPB. In contrast 5 of the 7 remaining rats increased the fraction of the filtered sodium excreted (C sub Na/GFR, p .05) and their urinary flow rate (V, p .05). Potassium excretion increased (U sub k V, p .05). End proximal tubular fluid specimen's TF/P inulin ratios were unchanged. Whole kidney and single nephron glomerular filtration rates fell 10%. CNPB, a mechanism for atrial distension, appears to cause, in rats, a decrease in distal tubular sodium, water and potassium reabsorption. Exogenous mineral-corticoid prevents the diuresis, saluresis, and kaluresis.

Kinney, M. J.↗
NASA NTRS1975

Control mechanisms of circadian rhythms in body composition: Implications for manned spaceflight

The mechanisms that underlie the circadian variations in electrolyte content in body fluid compartments were investigated, and the mechanisms that control the oscillations were studied in order to investigate what effects internal desynchronization in such a system would have during manned space flight. The studies were performed using volunteer human subjects and squirrel monkeys. The intercompartmental distribution of potassium was examined when dietary intake, activity, and posture are held constant throughout each 24-hour day. A net flux of potassium was observed out of the body cell mass during the day and a reverse flux from the extracellular fluid into the body cell mass during the night, counterbalanced by changes in urinary potassium excretion. Experiments with monkeys provided evidence for the synchronization of renal potassium excretion by the rhythm of cortisol secretion with the light-dark cycle. Three models of the circadian timing system were formalized.

Ede, M. C. M.↗
NASA NTRS1975

Circadian variation of intercompartmental potassium fluxes in man

Circadian rhythms of plasma potassium concentration and urinary potassium excretion persisted in three normal volunteers when diurnal variations in activity, posture, and dietary intake were eliminated for 3-10 days. Measurements of the arteriovenous difference in plasma potassium concentration across the resting forearm and of erythrocyte potassium concentration suggested that there is a net flux of potassium from ICF to ECF in the early morning and a reverse net flux later in the day. The total net ICF-ECF fluxes were estimated from the diurnal variations in extracellular potassium content corrected for dietary intake and urinary potassium loss. The net fluxes between ICF and ECF were found to be counterbalanced by the circadian rhythm in urinary potassium excretion. Desynchronization of these rhythms would result in marked fluctuations in extracellular potassium content. These findings suggest that some revision is required of the concept of basal state in potassium homeostasis.

Moore Ede, M. C.↗
NASA NTRS1975

Mineral and nitrogen balance study - Results of metabolic observations on Skylab II 28-day orbital mission

The prediction that various stresses of flight, particularly weightlessness, would bring about significant derangements in the metabolism of the musculoskeletal system has been based on various balance-study observations of long-term immobilized or inactive bed rest. The three astronauts of Skylab II consumed a planned dietary intake of major metabolic elements in mixed foods and beverages and provided virtually complete collections of excreta for 31 days preflight, 28 days inflight, and 17 days postflight. Analyses showed that, in varying degree among the crewmen, urinary calcium increased gradually during flight in a pattern similar to that observed in bed-rest studies. Fecal calcium excretion did not change significantly, but calcium balance, owing to the urinary calcium rise, became either negative or less positive than in preflight measurement. Increased excretion and negative nitrogen and phosphorus balances inflight indicated appreciable loss of muscle tissue in all three crewmen. Significant losses also occurred inflight in potassium, sodium, and magnesium. Based on the similarity in pattern and degree between these observations of calcium, phosphorus, and nitrogen loss, musculoskeletal integrity would not be threatened in space flights of up to at least 3 months. However, if similar changes occur in the planed Skylab flights for considerably more than 28 days, concern for capable musculoskeletal function should be serious for flights of very many months' duration.

Whedon, G. D.↗
NASA NTRS1975

Renal effects of continuous negative pressure breathing

Continuous negative pressure breathing (CNPB) was utilized to simulate the thoracic vascular distension of zero G in 11 anesthetized rats. The animals underwent renal clearance and micropuncture renal nephron studies before, during, and after CNPB. Four rats were pretreated with a high salt diet and I-M desoxycorticosterone (DOCA) in excess. None of these rats diuresed with CNPB. In contrast, five of the seven remaining rats increased the fraction of the filtered sodium excreted and their urinary flow rate. Potassium excretion increased. End proximal tubular fluid specimen's TF/P inulin ratios were unchanged. Whole kidney and single nephron glomerular filtration rates fell 10%. CNPB, a mechanism for atrial distension, appears to cause in the rat a decrease in distal tubular sodium and water reabsorption. Exogenous mineral-corticoid prevents the diuresis, saluresis, and kaluresis. The adequacy of other nonatrial volume control mechanisms in regulating renal salt and water conservation in opposition to the studied atrial-renal (Henry-Gauer) reflex of thoracic vascular distension is confirmed.

Kinney, M. J.↗
NASA NTRS1978

A review of the consequences of fluid and electrolyte shifts in weightlessness

This review describes the renal-endocrine mechanisms related to the early losses of fluid-electrolytes from the body during weightlessness as well as their contribution to longer term adaptation of fluid-electrolyte balance. The hypotheses presented were generated by a systematic analysis of body fluid and renal dynamics observed under conditions of actual and simulated spaceflight. These have increased our understanding of the effects of acute headward fluid shifts on renal excretion, the factors promoting excess sodium excretion and the regulation of extracellular fluid composition.

Leach, C. S.↗
NASA NTRS1977

Comparison of hormone and electrolyte circadian rhythms in male and female humans

Circadian rhythm characteristics in healthy male and female humans were studied at 4-hour intervals for urine volume, cortisol, 5-hydroxyindoleacetic acid (5-HIAA), Na, K, Na/K ratios in the urine, as well as plasma cortisol. While plasma and urinary cortisol rhythms were very similar in both sexes, the described rhythms in urine volume, electrolyte, and 5-HIAA excretion differ for the two sexes. The results suggest that sex differences exist in the circadian patterns of important hormone and metabolic functions and that the internal synchrony of circadian rhythms differs for the two sexes. The results seem to indicate that the rhythmical secretion of cortisol does not account for the pattern of Na and K excretion.

Vernikos-Danellis, J.↗
NASA NTRS1979

Experimental investigation of the role of thyrocalcitonin in the prophylaxis of disturbances in the water-salt and mineral metabolism during a 30-day hypokinesia

The effect of thyrocalcitonin (TCT) injections on the metabolism of water and electrolytes in free-moving and immobilized chinchilla hares is described. Calcium excretion from immobilized animals was elevated, but normalized in those also receiving TCT injections. TCT also normalized water content and excretion rates.

Shashkov, V. S.↗
NASA NTRS1979

Amino aciduria in weightlessness

Urinary excretion of amino acids by the 9 Skylab crewmen was studied as an indicator of the metabolic effects caused by exposure to the space flight environment. Intake was consistent in quality and quantity throughout the 28, 59 and 84-day flights for each of the crewmen and complete collections were accomplished. The results indicated an increased excretion in most amino acids during the first month of flight which remained elevated in the second and third months but to a lesser extent. Additional indications of change in muscle and skeletal metabolism were observed. These results point to the desirability of obtaining additional indices of alterations in protein synthetic processes in conjunction with future space flights.

Leach, C. S.↗