Up and Away: Five Decades of Urologic Investigation in Microgravity

Accepted Manuscript Title: Up and Away: Five Decades of Urologic Investigation in Microgravity Author: Michael S. Leapman, Jeffrey A. Jones, Karl Coutinho, Daniel Sagalovich, Maurice Garcia, Carl A. Olsson, Jeffrey Stock PII: DOI: Reference:

S0090-4295(17)30261-3 http://dx.doi.org/doi: 10.1016/j.urology.2017.03.012 URL 20340

To appear in:

Urology

Received date: Accepted date:

21-12-2016 8-3-2017

Please cite this article as: Michael S. Leapman, Jeffrey A. Jones, Karl Coutinho, Daniel Sagalovich, Maurice Garcia, Carl A. Olsson, Jeffrey Stock, Up and Away: Five Decades of Urologic Investigation in Microgravity, Urology (2017), http://dx.doi.org/doi: 10.1016/j.urology.2017.03.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Up and Away: Five Decades of Urologic Investigation in Microgravity Michael S. Leapman, MD1, Jeffrey A. Jones MD2, Karl Coutinho, MD3, Daniel Sagalovich MD3, Maurice Garcia MAS MD4, Carl A. Olsson, MD3, Jeffrey Stock, MD3 1

Department of Urology, Yale University School of Medicine, New Haven CT Department of Urology and Center for Space Medicine, Baylor College of Medicine, Houston Texas; 3The Icahn School of Medicine at Mount Sinai, New York; 4Department of Urology, University of California San Francisco 2

Corresponding Author: Michael S. Leapman, M.D. Assistant Professor Department of Urology Yale University School of Medicine New Haven, CT 06520 Tel: 203-785-3128 Fax: 203-785-4043 [email protected]

Manuscript Word Count: 2,982 Abstract Word Count: 100 Figures: 4

Keywords: Urology, Kidney Stones, Nephrolithiasis, Skylab, Space Medicine

The authors have no financial conflicts of interest relating to the publication of this manuscript.

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A renewed global interest in manned space-exploration has emerged, propelled by the challenge of reaching a new frontier: travel to the Red Planet, Mars. As the physiologic changes induced by microgravity bear direct relevance to the safety and viability of these goals, we provide a historical narrative of the urological investigations in space. We review the significant contributions to the understanding of the urologic consequences associated with exposure to microgravity, considerations for prolonged missions, and forward-looking efforts to manage emergent conditions remotely. Historic insights gleaned are poised to inform inter-planetary travel, where urologic pathology will remain an important practical consideration.

Space is open to us now; and our eagerness to share its meaning is not governed by the efforts of others. We go into space because whatever mankind must undertake, free men must fully share. -President John Fitzgerald Kennedy, May 25, 1961 Introduction The trajectory of manned spaceflight is aimed at the planet Mars. Initial efforts to achieve inter-planetary travel were articulated by President H.W. Bush’s Space Exploration Initiative, including the “90-Day Study” which estimated costs and logistics for a mission to the Red Planet. Later, the Constellation Program announced by George W. Bush aimed to return to the Moon, as well as a manned mission to Mars, but was ultimately cancelled in 2010 due to budgetary constraints. Recently, President Barack Obama expressed a focal imperative for the United States’ space program: “sending humans to Mars by the 2030s and returning them safely to Earth.” The enormity of this vision is considerable, evoking images of the early astronauts who braved uncertainty as they hurtled towards the moon. Though the technical and political landscapes of space travel have shifted dramatically in the decades since President Kennedy’s fateful speech before a special joint session of Congress, many similar challenges remain.

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Indeed, while the elements of the inaugural space program involved the tightly orchestrated effort of the National Aeronautics and Space Administration (NASA), forward-looking plans will draw from collaborative work including an increasing representation of the private sector, as well as the rich international partnerships that have been cultivated in the spirit of scientific endeavor. In contemplating the distances to be traversed by visiting our nearest neighboring planet—some 54.6 million kilometers from Earth—the urologic consequences associated with space travel will bear relevance to the safety and viability of such missions which are likely to be the longest ever in duration. To better anticipate the urologic challenges that may be experienced during space exploration, we provide a brief overview of the rich history relating to urologic investigation in space travel, the tangible scientific translational discoveries that have emerged from this work, and the contingency plans that have been devised to weather potential obstacles. Origins Early efforts to study the safety and viability of human space exploration have been an integral component of the early planning phases of the first manned missions, where early Russian and American programs proved survivability in microgravity environments. These included the Mercury Mission, the first human spaceflight program in the United States, initiated in 1958 and conducted until 1963. Subsequently, the Gemini Project (1961-1965) flew low Earth orbit missions, providing a framework for lunar missions (Figure 1). In parallel, Soviet developments offered early evidence regarding habitability, including the launch of Salyut 1, the first space station, in 1971,

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which achieved a 23-day manned docking with the ill-fated Soyuz 11 crew, who tragically perished during decompression at re-entry. Together, these polar ends of the ‘Space Race’ contributed tremendously to the early understanding of the rigor of extended duration orbits, as well as the mechanics of spaceflight that afforded future scientific inquiry. Skylab was founded in 1963 as a workshop overseen by the Office of Manned Space Flight, with the purpose of performing high-quality, reliable experiments in orbit (Figure 1). As the station took form as a “conceptual design study” investigators sought to acquire evidence to address questions raised by the Mercury and Gemini experience regarding the habitability of space, as well as to better characterize the physiologic implications of prolonged exposure to microgravity states2 3. Organizational responsibilities fell under the auspices of the Manned Spacecraft Center’s Medical Research and Operational Directorate, and in August of 1969, McDonnell-Douglas secured a contract to execute two stages of construction. The name “Skylab” formally emerged in 1970 as the result of an internal NASA contest.4 Skylab was launched on May 14, 1973 from Kennedy Space Station and flew three manned missions (SL-2, SL3 and SL-4). The results of these experiments demonstrated for the first time the ability to inhabit space for a prolonged period of time without major medical or psychological sequelae.5 While early theoretical investigations appeared to suggest that microgravitational states might contribute to derangements in bone mineral metabolism and potentially threaten the viability of long duration space missions, the Skylab missions were the first of their kind to enjoy a prolonged duration with little harm. Pragmatism in the Cosmos: The Space Toilet

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Safe and efficient storage of human waste in spaceflight has represented a unique engineering challenge given the need to provide sanitary disposal while facilitating accurate collection of samples with minimal handling. Two main considerations motivated the practical elements of the disposal system’s design: (1) the ability to conduct experiments of mineral, and (2) an overriding need for an easy and failure-proof system. The necessity for improvement became evident following the experience of Apollo astronauts who dreaded crude waste management systems, offering little more than thick plastic bags secured with adhesive. For the early space station incarnations seeking to reliably execute specimen collection, these requirements involved acquiring voided urine volumes with an accuracy of 1% in addition to a sampling of 10% volume to be dried and stored, with solid residues also collected daily. Additionally, the experimental design necessitated a mechanism to prevent any crosscontamination of individual crew member’s urine. The resulting disposal and collection systems incorporated fans generating vacuum suction that directed samples of both solid and liquid waste from astronaut to ampules for later study and transferred the remaining solid and liquid waste to storage vessels.6 The design allows astronauts to void into funneled urine receptacles that collect and transmit urine through a negative pressure chamber into collection bags. Similarly, solid waste may be collected by vacuum chamber, and filtered to allow dissipation of gas, resulting in sealed bags that can be frozen in waste storage drawers (Figure 2). Aside from a portion preserved for study, the vast majority (roughly 93%) of urine is recycled by means of distillation and filtration into potable water. While mechanisms for reclaiming water have long been invoked in spaceflight—including Russian efforts to recycle condensation—modern

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incarnations aboard the ISS include sophisticated urine processors. Seen from this context, the space toilet has represented more than simply a mundane fixture of waste disposal but, rather, a critical tool for specimen acquisition to better understand human physiology in microgravity. Nephrolithiasis in Space Early mineral balance experiments elucidated derangements associated with even limited exposures to microgravity. In rigorously conducted experiments drawing on the work of earth-orbital flights, Apollo astronauts were evaluated for baseline, in-flight, and post-flight bone mineral density, serum and urine electrolytes. The resulting findings, including the characterization of early bone resorption and hypercalciuria prompted increased attention to the consequences of rapid skeletal and bone turnover that occur during spaceflight.7 Among longer duration missions on the ISS, consistent rates of bone mass loss, muscle atrophy, and decreased oxygen consumption in space appear to offer insights regarding the challenges associated with the extended duration voyagers. These observations reflected the earliest clinical concern for potential kidney stone formation in space, and ushered in a rich field of space physiology that has relevance to present day space travel. Subsequent work was initiated focusing on bone demineralization and changes in dietary and fluid intake as causes of hypercalcuria, hyperuricosuria, hypocitraturia, and decreased urine pH, all of which have been seen in bedrest, spaceflight, and microgravity environments.8-11 Studies both on and off-earth at the International Space Station (ISS) have characterized the risk of renal calculi formation during spaceflight

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and have initiated pharmacologic, dietary, and behavioral modifications for prevention of nephrolithiasis in microgravity8,12,13. Specifically, the mechanisms that appear to confer greater risks of nephrolithiasis include the promotion of calcium resorption from bone resulting in hypercalciuria, as well as environmental factors and stresses including dehydration which act to promote conditions favoring crystallization. In the future, these considerations are poised to hold increasing relevance as commercial enterprises seek to expand the accessibility of space travel to highly-motivated civilians, many of whom may lack the intense physical conditioning and stamina required by NASA-vetted astronauts. Although rapid, measurable bone loss has been consistently observed in microgravity states, the precise mechanism underlying its onset remains incompletely understood. In simulated microgravity environments, in vitro studies have shown that absent gravitational forces appear to promote increases in bone resorption by osteoclasts, as well as a corresponding decrease in the osteoblast function. As a result, astronauts on contemporary missions routinely undergo intensive resistance exercise countermeasures including the use of the Advanced Resistive Exercise Device (ARED) which affords weight-bearing exercise in-flight, and has been associated with decreased bone loss, as well as gains in lean mass and decreases in fat mass (Figure 3).15 In addition, there is a growing interest in pharmacologic intervention to attenuate of bone resorption with bisphosphonates, acting to mitigate bone loss by the promotion of apoptosis in osteoclasts. In a joint U.S. and Japanese study of astronauts who were treated with 70mg of alendronate weekly before and during International Space Station (ISS) missions, the combination of ARED training with bisphosphonate therapy

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mitigated losses of bone density, as well as markers of bone resorption and urinary calcium.16 As gender differences in osteoporosis risk are well established, there has been an investigational interest in determining whether women face increased rates of bone demineralization in prolonged microgravity. In a study of 42 astronauts, including 33 men and 9 women, on missions between 2000 and 2012, all of whom had resistive exercise devices, NASA evaluated differences in bone mineral density as well as markers of bone and calcium metabolism before and after spaceflight. Despite differences in baseline values by gender, the bone density responses to spaceflight were similar, indicating that the rate of loss may not be increased for female astronauts, and also serves to highlight the successes of NASA’s refined spaceflight exercise programs.17 In addition to countermeasures aimed at reducing bone resorption mediated hypercalciuria, other pharmacologic interventions have been studied to reduce the risk of renal stone formation in microgravity.18 These have included a double-blinded, placebo-controlled trial of daily 20 mEq potassium citrate supplementation among 18 astronauts aboard the ISS. Astronauts randomized to receive supplementation had with decreased calcium excretion and increased urinary pH, resulting in lower calcium oxalate and uric acid supersaturation, resulting in a decreased risk of stone formation, although no stone episodes were observed in either arm19. An additional trial with full urine studies was conducted aboard the Space Shuttle Columbia during STS-107 in January of 2003; tragically, this study was never completed as damaged insulation resulted in disintegration of the shuttle at re-entry.

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Research into a putative microbial origin for nephrolithiasis has raised concerns for additional mechanisms underlying stone formation in microgravity, whereby gram negative atypical bacteria may lead to stone formation by producing carbonate apatite on their cell walls, resulting in early crystallization and accelerated stone formation. Ciftçioglu and colleagues at the NASA Universities Space Research Association evaluated this theory using a NASA-designed high aspect ratio vessel (HARV) rotation apparatus to simulate microgravity. Microbes cultured in this microgravity environment multiplied 4.6 times faster than stationary controls. This finding has fueled additional concern for apatite stone formation in astronauts with prolonged exposure to microgravity and has elucidated mechanisms for apatite formation in HARV culture conditions.20 In addition, studies of differential microbial growth in microgravity states has also led to speculation that the microbiome of astronauts may be altered during spaceflight which may impact their risk of urinary calculi as well as numerous other conditions.21

Fertility A long-speculated question relating to human space travel is whether a zero or low-gravity environment will impact fertility potential. Theoretical concerns have included the mechanical effects of weightlessness on gamete delivery and embryogenesis, deleterious effects of radiation, as well as psychological stress impacting the hormonal milieu. At the embryo level, it has also been postulated that fluid shifts experienced in low gravity could result in decreased plasma potassium which may, in turn, alter blastocyst development and resultant embryo size.22 In addition, studies have demonstrated significant changes in stress hormones during bedrest, spaceflight,

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parabolic flight, and microgravity conditions.23-26 Offered as a proxy for the physical stress associated with space missions, studies of endocrine function among distance runners have also shown transient reductions in serum testosterone and prolactin levels, implying a potential impact on sexual and reproductive function which may occur during prolonged space travel.27,28 Although the physical and environmental stresses have been shown to induce reproductive impairment and amenorrhea in women due to hypothalamic-pituitary-adrenal axis dysregulation, female astronauts have been noted to continue menstruation in space.29, 30 Early Soviet experiments examined whether the absence of gravity would interfere with mammalian reproduction, based on concerns that high energy particle radiation present in extra-atmospheric travel may result in gamete or embryological damage.31 Rats carried in flight by the Russian Kosmos 1129, an international biosatellite with an 18.5 days mission, demonstrated subsequent fertility potential on earth, however no living offspring occurred as the result of mating that occurred inflight.32 Contemporary in-vitro experiments have observed potential mechanisms for alterations in sperm physiology occurring in microgravity. These include changes in sperm and flagellate speed, as well as delayed response to egg chemotactic factors. For example, in experiments conducted on sea urchin eggs, Tash and colleagues al. noted decreased rates of fertilization, and sperm motility in low hyper-gravitational states simulating spaceflight.33,34 Should the direction of human space travel favor highly extended duration trips (including colonization), we anticipate the need for continued inquiry to address these potentially limiting considerations. Emergent Urologic Conditions in Space

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As the likely consequence of gravitational related hypercalciuria, the development of acute, symptomatic urinary calculi has been reported in one individual in-flight, and in 14 astronauts in the post-flight period.35,36,37,38 In his memoir, cosmonaut Valentin Lebdev describes his mission on the Salyut 7 space station in November 1982. One hundred and eighty days into their mission, engineer Lebdev found his mission commander Anatoly Berezovoy writhing in pain and clutching his left side. For two days the cosmonaut, stricken by colic, was unable to perform any tasks. Fearing the worst, a costly emergency Salyut 7 evacuation was planned; however just prior to its launch, Berezovoy passed a small calculus and his symptoms abated, allowing completion of the mission.39 Spaceflight may also present challenges for the treatment of urologic infections commonly encountered on Earth. These have included pseudomonas cysto-urethritis associated with prolonged condom catheter usage, as well as acute bacterial prostatitis resulting in prompt return to earth for an astronaut aboard the Mir space station. Early detection, and limited exposure periods to microgravity during active infections have resulted in resolution without issue, however several studies suggest that antibiotic efficacy may be altered by microgravity. These observations were first noted by the Cytos 2 experiment conducted aboard a joint French-Soviet flight in 1982 that evaluated antibiotic sensitivity during orbital missions. In-vitro bacterial colonies grown in space demonstrated increased antibiotic resistance as well as increased thickness of the cellular envelope.40,41 In more recent investigations with direct relevance to the treatment of common urologic pathogens, E. coli cultured under simulated microgravity conditions exhibited decreased sensitivity to ciprofloxacin, an effect which was reversed

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by return to normal gravity. It appears that varied sensitivity may be mediated by upregulation of antibiotic resistant efflux pump genes (acrAB-tolC) in microgravity.42 To date, no guidelines exist for distinct dosing or antibiotic selection, however these considerations may gain increasing attention in the planning of exploratory missions. Urologic interventions in space have already been required during manned missions. Flight surgeons have reported the onset of acute urinary retention in astronauts on multiple occasions. For example, one astronaut who received standard anti-cholinergic motion sickness prophylaxis experienced urinary retention immediately after entering orbit, and required management initially with clean intermittent catheterization and ultimately four days of indwelling catheter drainage.43 Contingency plans for the management of acute urinary retention in space, not amenable to urethral catheterization have also been developed. In 2007, NASA investigators reported on the successful performance of ultrasound-guided percutaneous catheterization of the urinary bladder in microgravity in an anesthetized porcine bladder using a 10.3 French pigtail catheter introducer.44 Medical intervention in space has relied on astute physical examination and clinical intuition, typically without the benefit of supporting radiologic studies. Recently, attempts have been made to incorporate imaging modalities in microgravity. Spaceflight ultrasonography with real time interpretation from on-earth observers has been reported with excellent clinical success in a trauma setting.45 In 2009 Jones et al. reported on the real-time acquisition of ultrasound images of the pelvis and retroperitoneum in microgravity performed by non-physicians on the ISS using a Philips ultrasound unit (Figure 4). The astronaut technicians, remotely guided by earth-based sonographers

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using continuous space-to-ground video, demonstrated the ability to perform high quality evaluations, suggesting a practical future tool for diagnosis of acute urologic conditions in microgravity.46 This followed an earlier report of simulated contingency placement of a ureteral stent in a porcine model on a reduced gravity aircraft (parabolic flight with periods of free fall) employing a flexible cystoscope and retroperitoneal ultrasonography with real-time telemedicine downlink.47 Just as space exploration has spurred innovation in medical discovery, the rapid pace of innovation in terrestrial surgery offers opportunities for translation to manned spaceflight. For example, the revolution in robotic-assisted urologic surgery on earth may translate to performing remote robotic procedures for emergent conditions that may occur in space. Such technology may permit the execution of skilled tasks such as ureteral stent placement, suprapubic cystotomy, or percutaneous nephrolithotomy by physicians on earth. Additionally, an opportunity exists to expand the use of real-time electronic monitoring of urine output and urine content, as well as increasingly sophisticated biosensors assessing drug levels, the presence of urine infection, bacterial resistance or urine mineral content.48 Conclusions: Human space travel has represented a remarkable engine for innovation and scientific discovery. These have included advancements to the understanding of urologic conditions including nephrolithiasis, reproductive physiology, as well as contributions to tele-medicine that may prepare future astronauts for the rigors of extended missions applied to space tourism or lofty plans for manned missions to Mars. As we look forward in these endeavors, a path towards continued success appears to

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be guided by an appreciation for the rich history of investigation that has paralleled the tremendous advances in contemporary space exploration.

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References 1.

Shepard AB, Slayton DK, Barbree J, et al: Moon shot: the inside story of America's race to the moon. Atlanta : Turner Pub. ; Kansas City, Mo. : Distributed by Andrews and McMeel; 1994.

2.

Compton WD and Benson CD: Living and working in space: a history of Skylab. NASA Special Publication 1983.

3.

Newkirk, Roland W., Ivan D. Ertel, and Courtney G. Brooks. 1977. Skylab: a chronology. Washington, D.C.: Scientific and Technical Information Office, National Aeronautics and Space Administration.

4.

Brooks CG, Grimwood JM and Swenson LS: Chariots for Apollo. Courier Corporation; 2012.

5.

Swenson LS Jr, Alexander CC and Grimwood JM: This New Ocean. A History of Project Mercury. By Loyd S. Swenson, Jr., James M. Grimwood, Charles C. Alexander.[Illustr.] - Washington. 1966. XV, 681 S. 4°. 1966.

6.

National Aeronautics Administration: Biomedical Results from Skylab. CreateSpace; 2014.

7.

Johnston RS, Dietlein LF, Berry CA, et al. Biomedical results of Apollo, Scientific and Technical Information Office, NASA Headquarters, Washington, D.C., 1975.

8.

Whitson PA, Pietrzyk RA and Pak CY: Renal stone risk assessment during Space Shuttle flights. J. Urol. 1997; 158: 2305–2310.

9.

Whitson PA, Pietrzyk RA, Morukov BV, et al: The risk of renal stone formation during and after long duration space flight. Nephron 2001; 89: 264–270.

10.

Hoyer JR, Pietrzyk RA, Liu H, et al: Effects of microgravity on urinary osteopontin. J. Am. Soc. Nephrol. 1999; 10 Suppl 14: S389–93.

11.

Smith SM, Zwart SR, Heer M, et al: Men and women in space: bone loss and kidney stone risk after long-duration spaceflight. J. Bone Miner. Res. 2014; 29: 1639–1645.

12.

Kumei Y, Shimokawa H, Katano H, et al: Microgravity induces prostaglandin E2 and interleukin-6 production in normal rat osteoblasts: role in bone demineralization. J. Biotechnol. 1996; 47: 313–324.

13.

Whitson PA, Pietrzyk RA, Pak CY, et al: Alterations in renal stone risk factors after space flight. J. Urol. 1993; 150: 803–807.

14.

Monga M, Macias B, Groppo E, et al: Renal stone risk in a simulated microgravity

Page 15 of 22

16

environment: impact of treadmill exercise with lower body negative pressure. J. Urol. 2006; 176: 127–131. 15.

Smith SM, Heer MA, Shackelford LC et al. Benefits for bone from resistance exercise

16.

Leblanc A, Matsumoto T, Jones J et al. Bisphosphonates as a supplement to exercise to protect bone during long-duration spaceflight. Osteoporos Int. 2013 Jul;24(7):2105-14.

17.

Smith SM, Zwart SR, Heer M et al. Men and women in space: bone loss and kidney stone risk after long-duration spaceflight. J Bone Miner Res. 2014 Jul;29(7):1639-45.

18.

Zerwekh JE, Odvina CV, Wuermser L-A, et al: Reduction of renal stone risk by potassium-magnesium citrate during 5 weeks of bed rest. J. Urol. 2007; 177: 2179–2184.

19.

Whitson PA, Pietrzyk RA, Jones JA, et al: Effect of potassium citrate therapy on the risk of renal stone formation during spaceflight. J. Urol. 2009; 182: 2490– 2496.

20.

Ciftçioglu N, Haddad RS, Golden DC, et al: A potential cause for kidney stone formation during space flights: enhanced growth of nanobacteria in microgravity. Kidney Int. 2005; 67: 483–491.

21.

Karouia F, Epperly MW, Jones J, et al. “Impact of Whole Body Irradiation on the Intestinal Microbiome Considerations for Space Flight, 40th COSPAR Scientific Assembly Abstract Bulletin, presented August, 2014 Moscow Russia. Manuscript under review, Radiation Research.

22.

Warren MP: Effects of space travel on reproduction. Obstet Gynecol Surv 1989; 44: 85–88.

23.

Strewe C, Feuerecker M, Nichiporuk I, et al: Effects of parabolic flight and spaceflight on the endocannabinoid system in humans. Rev Neurosci 2012; 23: 673–680.

24.

Stowe RP, Sams CF and Pierson DL: Adrenocortical and immune responses following short- and long-duration spaceflight. Aviat Space Environ Med 2011; 82: 627–634.

25.

Schneider S, Askew CD, Brümmer V, et al: The effect of parabolic flight on perceived physical, motivational and psychological state in men and women: correlation with neuroendocrine stress parameters and electrocortical activity. Stress 2009; 12: 336–349.

and nutrition in long-duration spaceflight: Evidence from biochemistry and densitometry. J Bone Miner Res. 2012 Sep;27(9):1896-906.

Page 16 of 22

17

26.

Schneider S, Brümmer V, Göbel S, et al: Parabolic flight experience is related to increased release of stress hormones. Eur J Appl Physiol 2007; 100: 301–308.

27.

Prior JC, Yuen BH, Clement P, et al: Reversible luteal phase changes and infertility associated with marathon training. Lancet 1982; 2: 269–270.

28.

Herod SM, Dettmer AM, Novak MA, et al: Sensitivity to stress-induced reproductive dysfunction is associated with a selective but not a generalized increase in activity of the adrenal axis. Am. J. Physiol. Endocrinol. Metab. 2011; 300: E28–36.

29.

Ryan KL, Loeppky JA, Kilgore DE Jr. A forgotten moment in physiology: the Lovelace Woman in Space Program (1960-1962). Adv Physiol Educ. 2009 Sep;33(3):157-64.

30.

NASA Johnson Space Center Oral History Project Edited Oral History Transcript: Sally K. Ride, interviewed by Rebecca Wright. http://www.jsc.nasa.gov/history/oral_histories/RideSK/RideSK_10-22-02.htm, Accessed 10/24/2016.

31.

Jones JA, Jennings R, Pietryzk R, et al: Genitourinary issues during spaceflight: a review. Int J Impot Res 2005; 17 Suppl 1: S64–S67.

32.

Souza, K., R. Hogan, and R. Ballard, eds. Life into Space: Space Life Sciences Experiments at Ames Research Center 1965-1990. NASA RP-1372, Washington, DC, 1995.

33.

Tash JS, Kim S, Schuber M, et al: Fertilization of sea urchin eggs and sperm motility are negatively impacted under low hypergravitational forces significant to space flight. Biol. Reprod. 2001; 65: 1224–1231.

34.

Tash JS and Bracho GE: Microgravity alters protein phosphorylation changes during initiation of sea urchin sperm motility. FASEB J. 1999; 13 Suppl: S43–54.

35.

Drinnan NR and de Juniac AB: The effects of microgravity on the urological system: a review. Journal of Clinical Urology 2013; 6: 391–394.

36.

Pietrzyk RA, Jones JA, Sams CF, et al: Renal stone formation among astronauts. Aviat Space Environ Med 2007; 78: A9–13.

37.

Risk of Renal Stone Formation Evidence Book. Human Research Program: Human Health Countermeasures Element (HRP-47060). National Aeronautics and Space Administration. March 2008. (Accessed online http://humanresearchroadmap.nasa.gov/evidence/reports/Renal%20Stone.pdf, date of access February 19, 2017).

38. Jones, Jeffrey A, Jennings, Richard T., Baker, Ellen S. “Genitourinary Health Issues for Space Shuttle Missions” In: STS Biomedical Results (published July

Page 17 of 22

18

2013) GPO 033-000-01363-9 ISBN:9780615866130 39.

Lebedev V. Diary of a cosmonaut: 211 days in space. New York, NY: Bantam Books; 1990.

40. Tixador R, Richoilley G, Gasset G et al. Preliminary results of Cytos 2 experiment. Acta Astronaut 1985 Feb;12(2):131-4. 41.

Tixador R, Richoilley G, Gasset G et al. Study of minimal inhibitory concentration of antibiotics on bacteria cultivated in vitro in space (Cytos 2 experiment). Aviat Space Environ Med. 1985 Aug;56(8):748-51).

42.

Xu B, Li C, Zheng Y et al. Simulated microgravity affects ciprofloxacin suspecptibility and expression of acrAB-tolC genes in E.coli ATCC25922. Int J Clin Exp Pathol. 2015 Jul 1;8(7):7945-52.

43.

Stepaniak PC, Ramchandani SR and Jones JA: Acute urinary retention among astronauts. Aviat Space Environ Med 2007; 78: A5–8.

44.

Jones JA, Kirkpatrick AW, Hamilton DR, et al: Percutaneous bladder catheterization in microgravity. Can J Urol 2007; 14: 3493–3498.

45.

Sargsyan AE, Hamilton DR, Jones JA, et al: FAST at MACH 20: clinical ultrasound aboard the International Space Station. J Trauma 2005; 58: 35–39.

46.

Jones JA, Sargsyan AE, Barr YR, et al: Diagnostic ultrasound at MACH 20: retroperitoneal and pelvic imaging in space. Ultrasound Med Biol 2009; 35: 1059– 1067.

47.

Liu T, Sin MLY, Pyne JD, et al: Electrokinetic stringency control in self-assembled monolayer-based biosensors for multiplex urinary tract infection diagnosis. Nanomedicine 2014; 10: 159–166.

48.

Jones JA, Johnston S, Campbell M et al. Endoscopic surgery and telemedicine in microgravity: developing contingency procedures for exploratory class spaceflight. Urology. 1999 May;53(5):892-7.

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Figure 1. Photographs of the early manned U.S. space missions. Image (A) depicts astronaut John Glenn entering the ‘Friendship 7’ capsule of the Mercury-Atlas 6 spacecraft to embark on the first manned orbital mission of the U.S. program. (B) The Project Gemini space capsule, NASA’s second human spaceflight program. (C) The Apollo 9 command module, the third manned mission of the American space program. (D) Image of Skylab 4, the United States’ first space station, and site for early transformative study regarding the habitability and effects of prolonged space travel. (Images courtesy NASA.gov).

Figure 2. Space toilet in the service module of the International Space Station, demonstrating vacuum funnel receptacle for liquid waste. (Image courtesy NASA: https://spaceflight.nasa.gov/gallery/images/station/crew-6/html/iss006e20909.html)

Figure 3. Use of the Advanced Resistive Exercise Device (ARED) by NASA astronaut Chris Cassidy aboard the International Space Station. Resistance exercise training is routinely undertaken by astronauts to offset the bone loss and risk of renal stone formation during Spaceflight. (Image courtesy NASA: https://www.nasa.gov/content/chris-cassidy-exercises-on-the-ared-0)

Figure 4. Photograph of (A) crewmember performing ultrasonography on the International Space Station generating dynamic sonographic images (B) of a distended bladder with visualization of left ureteral jet (reprint request Ultrasound Med Biol. 2009 Jul;35(7):1059-67)

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Editorial Comment Re: "Up and Away: Five Decades of Urologic Investigation in Microgravity" #URL-D-16-02536R1

Michael R. Barratt, M.D. Astronaut, National Aeronautics and Space Administration Lyndon B. Johnson Space Center Houston, Texas 77058 [email protected]

Urology Editorial It is difficult for many of us to comprehend that we have been flying in space for over 50 years, and except for a one-year gap between the Russian Mir Station and the International Space Stations (ISS), most of the past 28 years have seen a continual human presence in low earth orbit. Aside from the risks associated with leaving the planet and the remoteness of spacecraft, human health and performance in space is dominated by the condition of weightlessness. The removal of the gravity-driven hydrostatic gradient along with predictable anthropomorphic changes drives a set of global adaptive responses in nearly every physiologic system. Over these years we have developed an incomplete but serviceable knowledge of these adaptive responses1. Renal and urinary function have played a significant role in both the understanding and experience of human spaceflight. The piece by Leapman and colleagues in this issue introduces the fundamental urological issues associated with this novel environment. In my 212 days spent off the planet on the ISS, the US Space Shuttle, and the Russian Soyuz spacecraft, I have had the delightful and sometimes dubious opportunity to experience many of these first hand. The astronaut population is acutely aware of urologic issues, and these are debriefed and handed over to new flyers with great attention. Let’s begin with hardware. A spacecraft is a closed ecosystem built as precisely as possible with materials that must be light, power miserly, and reliable. The space toilet is no exception and serves may roles. Waste containment and management is a dodgy issue when gravity is not available to separate fluid and air, and the implications of failure (either of technique or plumbing) include embarrassment, unpleasant cleanup, and contamination of the cabin atmosphere. Directed airflow is used in lieu of gravity to

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channel urine into appropriate conduits, and centrifugal separation is required to sequester fluid. The toilet or sometimes dedicated urine collection device also becomes a sampling interface for important onboard science, assessing urinary markers of metabolism and physiologic changes, proteomics, and general hydration status to name a few2,3. Urine samples are routinely obtained and frozen aboard the ISS for later return to earth and batch analysis. Finally, the toilet becomes the upstream collection point for fluid to be processed and recycled into potable and hygiene water. This is critical in a closed environment where the vast majority of urine must be reclaimed to maintain a sustainable water balance. All these functions must be considered holistically, with knowledge of physiology and urine chemistry informing system design. The first urine reclamation system on the ISS was befuddled by the high urinary concentrations of calcium resulting from bone demineralization and urinary spillover that was not accounted for in the ground testing. The excess calcium complexed with the sulfuric acid treatment reagent and caused troublesome precipitation of CaSO4 salts in the system, decreasing efficiency and requiring changes in operation4. From a clinical standpoint, may urological issues have been encountered in human spaceflight, some of which have contributing risk factors directly attributed to weightlessness-induced changes and flight operations. These include nephrolithiasis, urinary retention, and urinary tract infections. All of these have driven the inclusion of inflight capabilities to support timely diagnosis and treatment. Minimal urinalysis in the form of chemical reagent sticks and direct visualization is routinely done for monitoring and diagnosis. Inflight ultrasound imagery performed by onboard crewmembers has been nicely developed over the years5, affording an elegant imagery capability for many urologic issues. Crewmembers have successfully performed catheterization to relieve urinary retention, and a suite of antibiotics is available to treat most urinary tract infections. However, the prospect of having to return a crewmember for a urologic issue beyond the onboard capabilities remains, and that concern is magnified for an exploration mission beyond Earth orbit where timely return is not an option. Prevention is an important aspect for spaceflight, including selecting out conditions that might predispose to urinary problems, periodic inflight monitoring, and encouraging good hydration status in an environment where the overhead of getting a drink is a little higher and thirst may be decreased. Looking toward the future with regard to urological issues in space flight, a major influence will be the prospect of leaving Earth vicinity for more remote venues, including the moon, Mars, asteroids, and other destinations of interest. Prevention of urologic problems where possible, by tighter screening or monitoring, takes on a more critical role. A more thorough understanding of spaceflight metabolism and renal function is required, including basic physiology, fluid regulation, and metabolism and clearance of pharmaceuticals or possible toxins. Without the ability to return samples to Earth, an enhanced diagnostic capability will imply onsite urine evaluation for chemistries, culture, and microscopic analysis to support both science and clinical practice. We should continue to develop imaging capabilities in tandem with minimally invasive procedures that can be accomplished by onboard crewmembers without real time communications with ground specialists due to the great distances involved. And we must deliberately

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and systematically record what we see to best characterize the human response to this extreme environment. Michael R. Barratt, M.D. Astronaut, National Aeronautics and Space Administration Lyndon B. Johnson Space Center Houston, Texas 77058

REFERENCES (1) Barratt M. Space Physiology and Medicine. In: Ernsting’s Aviation and Space Medicine, 5th edition. David Gradwell and David Rainford, editors. Chapter 18. CRC Press, Taylor and Francis Group, 2016 (2) Smith SM, Wastney ME, O'Brien KO, Morukov BV, Larina IM, Abrams SA, et al. Bone markers, calcium metabolism, and calcium kinetics during extendedduration space flight on the Mir space station. J Bone Miner Res. 2005 Feb;20(2):208-18. (3) Pastushkova LK, Kereev KI, Kononikhin AS, et al. Detection of Renal and Urinary Tract Proteins Before and After SPaceflgiht. Aviation Space Environ Med, Vol 84, No. 8. Aug 2013:859-63 (4) Carter L. Status of the Regenerative ECLSS Water Recovery System. 40th International Conference on Environmental Systems, 2010. AIAA 2010-6216 https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/20100033089.pdf, retrieved 6 mar 2017 (5) Sargsyan A. Medical Imaging. Chpt. 9 in Principles of Clinical Medicine for Space Flight. MR Barratt, SL Pool editors. Springer Verlag, New York 2009.

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