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M ARCH 2014, N O 5


Skye Bleu Skye Bleu is STEM Mascot at National Coalition of Aviation and Space Education, STEM Mascot at Think Global Flight and President and CEO at STEM Emissary. — Image Courtesy:Skye Bleu(with permission). Find Skye Bleu Here:

About ISOPTWPO International Space Flight & Operations - Personnel Recruitment, Training, Welfare, Protocol Programs Office (International Space Academy). It is a division of the ISA organization. Mr. Martin Cabaniss is director and Mr. Abhishek Kumar Sinha is Assistant Director of ISOPTWPO. — International Space Agency(ISA)

“Ad Astra! To The Stars! In Peace For all Mankind!

– Mr. Rick R. Dobson, Jr.(Veteran,US Navy)

The Impact of Sex and Gender on Adaptation to Space In order to ensure the health and safety of male and female astronauts during long duration space missions, it is imperative to examine and understand the physiological and psychological changes that occur during space flight.Data from space and ground-based studies and observations on the impact of sex and gender-based health during space flight and in terrestrial environments were analyzed by 6 work groups in the following areas: cardiovascular, musculoskeletal, neuro-vestibular, reproductive, immunological and behavioral. Following brief presentations highlighting key findings by the co-chairs from these work groups, audience participants will have an opportunity to ask questions. The Institute of Medicine defines "sex" as the classification of male or female according to an individual’s genetic make-up and "gender" refers to a person’s self representation as male or female based upon social interactions. Both significantly influence health on Earth and in Space and serve as a foundation for personalized medicine. Gender Differences in Mission and Demographic Information for Astronauts Transiting to the International Space Station (ISS) • Data obtained from publically-accessible government space agency and military websites for female and male astronauts from 1998-2013 (encompassing all missions to ISS) • N=129 US astronauts-26 females (20%) and 103 males (80%) • Females made fewer repeat transits to ISS than males (1.5 vs. 1.8 transits) • Greater % of males (72.8%) had military service background compared with females (38.5%) • Females had more doctoral degrees as males (i.e., 50% vs. 28%); males had more master’s degrees than females (85% vs. 58%) • Females had more bachelor’s degrees in biology; males had more bachelor’s and master’s degrees in engineering (though females had more doctoral degrees in engineering) • Females were younger than males for all transits to ISS (43.2y vs. 45.9y) • No differences in the % of male (76%) and female astronauts (69%) who were married • More males had at least one child (67% vs. 38%) and males had more children than females (on average, one more child) Terrestrial Medicine-Based Consensus of the Impact of Sex and Gender on Neurobehavioral and Psychosocial • No gender differences in neurobehavioral performance in response to sleep loss • Men gain more weight than women during chronic sleep restriction (CSR) • CSR induces greater increases in leptin and greater cellular immune activation of interleukin-6 and tumor necrosis factor-alpha in women than men • CSR decreases adiponectin levels in Caucasian women, but no changes in men • Gender differences in sleep in healthy young, middle-aged and elderly adults • Gender differences in chronotype and circadian rhythms • Gender and Behavioral Health on Earth: Anxiety and Depression • Anxiety disorders and major depressive disorder are about twice as prevalent in women than in men • Gender differences in symptoms, clinical course, co-morbidity and treatment response Gender and Stress

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• Women show heightened stress sensitivity • Women show an increased prevalence of stress-related affective disorders • Women display a greater physiological stress response axis than men: higher cortisol levels following stressors • Women more sensitive to effects of elevated adrenaline during stress activation as part of autonomic nervous system stress response • Individual life experiences and fluctuations in reproductive hormones in women affect magnitude of gender differences • Increased cortisol over extended periods produces cardiovascular and immune system effects and effects on learning, memory and mood Current Understanding of the Impact of Sex and Gender on Neurobehavioral and Psychosocial Factors in Space • Neurobehavioral and Sleep Measures from Astronauts on ISS • No gender differences identified to date in global performance score on Psychomotor Vigilance Test or selfratings of workload, tiredness and stress, or sleep quality in-flight or post-flight Medication Use to Promote Sleep and Wake in Astronauts • How sleep duration and quality on ISS and other analogs relate to medication use is unclear • While in spaceflight, an unknown number of astronauts use sleep medications and/or wakepromoting medications Relevance of Clinical Disorders to Space and Analog Environments • No evidence that female astronauts experience same risk for depression and anxiety disorders as their counterparts in the general population Behavioral Health in Analog Environments • Limited data on gender-based differences in behavioral health in isolated and confined extreme environments • Gender differences in behavioral health in Antarctica are unclear • No gender differences in personality characteristics in polar work groups or expedition teams • Women tend to assume a more cooperative and supportive role than men in their interactions with other members of polar work groups • Women have a somewhat more difficult interpersonal experience than men in polar work groups which may impact performance • Cultural influences may have an impact on gender-related group processes Behavioral Health in Spaceflight • Limited data on gender-based differences in behavioral health in space • Achievement most frequently mentioned value for male and female astronauts in their memoirs • The Journals Flight Experiment on ISS suggests slight differences between men and women in terms of netpositivity/negativity • Men exhibited greater positivity than women overall and particularly during the first and fourth quarters of ISS expeditions. Relevant entries of women fluctuated less than men ISOPTWPO Today Human Space Flight c International Space Agency(ISA)

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• Emotional stability among characteristics of successful adaptation and esteemed leadership in isolated and confined personnel, suggesting that any difference reflects successful adaptation by women to ISS Gender and Stress • Little research on gender differences in response to specific types of stressors found in space flight and microgravity • Head-down tilt long-term bed rest study in women found evidence for stress system activation and indications of "impairments in psychological states". No gender comparisons. • A 520-day simulated mission to Mars, conducted by Russian Institute of Biomedical Problems used an all-male crew of six. Majority of crewmembers developed sleep disturbances and other behavioral changes undesirable in prolonged space missions. Reference:The Impact of Sex & Gender on Adaptation to Space,Neurobehavioral and Psychosocial Factors Workgroup,JUNE 25, 2013.NASA-NSBRI VIRTUAL WORKSHOP

Reactivation of Latent Herpes Viruses in Cosmonauts During a Soyuz Taxi Mission Space flight causes anomalies in the human immune response. The physical and psychological conditions associated with space flight are likely to act as stressors, and stress is known to affect many aspects of the immune system, including the reactivation of latent viruses. Impairment of cellular immunity increases the incidence and duration of viral reactivation and the shedding of some viruses into body fluids. Herpes viruses are the most readily recognized of the latent viruses and are clinically important, being the cause of shingles, certain cancers, and other diseases, as well as the leading infectious cause of blindness in the U.S. Reactivation of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV) occurs in astronauts during short-term space flight. Because most astronauts (as well as the general population) harbor latent herpes viruses, herpes virus reactivation increases the health risks for crew members during short-term and long-term space flights. There are eight known human herpes viruses, and they are the most widely known latent viruses in humans. These viruses may be asymptomatic upon first exposure or cause a variety of primary diseases ranging from a sore throat to chickenpox. As the primary infection begins to subside, the viruses become latent in a variety of body tissues. Then during periods of decreased immunity, these viruses can reactivate, proliferate, and cause disease. Three of the eight human herpes viruses were routinely monitored in this study: 1) Epstein-Barr virus (EBV), 2) Cytomegalovirus (CMV), and 3) Varicella zoster (VZV). The primary technology used to detect and measure the extent of viral reactivation was the polymerase chain reaction (PCR). This molecular technology is sensitive, specific, and rapid. Viral plaque formation in tissue culture is the traditional method, but it is slow and some of the herpes viruses are difficult to culture. Culturing for viruses was used late in the study to demonstrate viable viruses. A detailed description of each virus studied is given below. Epstein-Barr virus (EBV): EBV becomes latent in B-cells and perhaps some other tissues. When it reactivates, it can cause infectious mononucleosis in young adults. In severe immuno-suppressed individuals, EBV can promote tumor formation. Cytomegalovirus (CMV): CMV is another herpes virus and it is shed in urine after reactivation. In addition to causing very serious congenital diseases in fetuses and newborns, it can lead to an infectious mononucleosis-type of disease in adults. This virus is found in the tissues of epithelial origin (i.e., kidney, liver, salivary glands, gut epithelium) and fibroblasts. Varicella zoster (VZV): VZV is the etiological agent of chickenpox (primary) and shingles. VZV becomes latent in human ganglia after primary infection. VZV reactivation occurs most frequently in elderly individuals, organ transplant recipients, and patients with cancer and AIDS, correlating with a specific decline in cell-mediated and humoral immunity to the virus. VZV can reactivate following the stress of surgery and also in response to various non-surgical stressors. ISOPTWPO Today Human Space Flight c International Space Agency(ISA)

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Virus reactivation can be detected by testing for viral DNA in body fluids and by testing blood samples for titer of antibodies to specific viruses. EBV DNA shedding in astronaut saliva samples was found at a greater frequency before space shuttle missions than during or after missions, but the number of EBV DNA copies in saliva was greatest during flight, when it was 10- fold greater than before or after flight. The titer of antibodies to two EBV antigens, viral capsid antigen (VCA) and early antigen (EA), was also measured in blood samples taken from astronauts at their annual medical exams (baseline), 10 days before launch, a few hours after landing, and 3 days after landing. Blood samples of all 32 astronauts tested contained antibodies to EBV antigens. The titer of anti-VCA antibodies was greater 10 days before and after launch than at baseline. The frequency of CMV DNA shedding in either preflight or postflight urine samples from 71 astronauts was significantly greater than that of the control population (P < 0.05). The titer of anti-CMV antibodies of the 15 astronauts who shed CMV DNA was significantly greater than their baseline values at all time points . VZV DNA was detected in 1% of preflight, 28% of in-flight, and 31% of postflight saliva samples from 8 astronauts. Result Of the 102 saliva samples collected from 3 crew members, 43 were collected before, 39 during, and 20 after flight. Compared to the samples from healthy controls, an overall increase was observed in the frequency of samples positive for the herpes viruses EBV, CMV, and VZV.

However, in an analysis that included all 3 viruses and all 3 phases, the frequency of positive samples was not significantly different for the different phases of the flight (before, during, and after flight), according to the ANOVA test performed. EBV, one of the most common herpes viruses of human adults, was found in 14% or more of the samples collected from the 3 crew members (Table 1). Compared with their numbers before flight, the number of copies of EBV DNA increased 9- fold during flight and 8-fold after flight.

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None of the saliva samples tested was positive for CMV, but CMV is not usually shed in saliva. Of the total of 6 urine samples, 2 were positive for CMV before flight and 1 was positive after flight. Because the number of samples was small, no statistical analysis could be performed on these data. VZV, a highly neurotropic alpha-herpesvirus that infects only humans, was found to have a significantly greater (P < 0.05) frequency, as well as number of copies, in the saliva samples collected during and after flight than in those collected before flight (Table 1). Fig. 1 shows the number of copies of VZV DNA before, during, and after the flight in all of the saliva samples from all 3 of the subjects studied.At no time did crew membersâ&#x20AC;&#x2122; antibody titers against EBV,CMV, or VZV antigens (Table 1) differ significantly from titers in blood samples from control subjects.Salivary and urinary cortisol had high intersubject variability and did not change significantly from one mission phase to another (Table 1). The frequency of positive samples and the large numbers of EBV DNA copies were consistent with EBV reactivation before, during, and after space flight. However, in other studies greater frequencies of EBV-positive saliva samples and greater numbers of copies of EBV DNA were found before and after flight. A study of 32 astronauts on Space Shuttle flights of 5 - 14 days showed that 29% of preflight, 16% of in-flight, and 16% of postflight samples were EBV-positive, and 10 times as many copies of EBV DNA were found in in-flight samples as were found in preflight and postflight samples . EBV reactivation has also been found to occur in subjects who spent the winter in Antarctica, another stressful environment. The frequency of EBV shedding increased significantly from 6% before the winter isolation to 13% during isolation. In a study of 71 Shuttle astronauts , shedding of CMV was detected in a smaller percentage of samples (10.6% of preflight urine samples) than were found in this study. The mean number of CMV copies in preflight samples was 202 copies/mL, considerably more than the 33 found in the present study. During and after spaceflight, 30% of saliva samples from 8 astronauts were positive for VZV DNA, about twice the ISOPTWPO Today Human Space Flight c International Space Agency(ISA)

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frequency found in the current study. This finding showed that subclinical reactivation of VZV occurred during spaceflight. In other studies of astronauts, the titers of antibodies to all 3 of these herpesviruses have changed before and/or after spaceflight. Anti-VCA (EBV) antibodies before launch, at landing, and after landing were significantly greater than baseline values determined 5 to 24 months before flight . A slight increase in antibodies to early antigen (EA) was also found after spaceflight compared to the preflight titer; baseline values were not available for EA. Of 15 astronauts shedding CMV, anti-CMV antibody titer was found to increase significantly before flight, at landing, and 3 days after landing compared to baseline values. Anti-VZV antibody titers were measured in 6 astronauts in another study. There was no significant difference between preflight and postflight values. The apparent lack of spaceflight effect on anti-herpesvirus antibody titers in the present study brings up the question of whether an immune response is necessary for reactivation of latent viruses. The stress of spaceflight may have had a direct effect on viral shedding . Increased concentrations of cortisol, especially urinary cortisol, are usually found after spaceflight , but the small number of samples in this study and their high variability probably made it unlikely that a spaceflight-associated change could be found. Also, baseline values were not available, so that values obtained during the stressful prelaunch period had to be used for comparison with postflight values. Other than herpes simplex virus lesions, no health effects of herpesvirus reactivation have been observed during or after spaceflight, but the limited data available suggest that a greater number of copies of EBV DNA may be shed on longer flights. Missions of 3 months or more are expected to become more frequent in the future, so the potential exists for reactivation of latent viruses to affect astronaut health. Reference:Satish K. Mehta and Duane L. Pierson: Reactivation of Latent Herpes Viruses in Cosmonauts During a Soyuz Taxi Mission

Reactivation and Shedding of Cytomegalovirus in Astronauts during Spaceflight Microgravity is a unique and unfamiliar environment for human beings.The sudden gravitational changes in spaceflight (e.g., launch acceleration followed by microgravity) may therefore be expected to elicit a stress response.Indeed, previous studies have shown increased levels of urinary cortisol and interleukin-6 on the first day of spaceflight.The psychological and physical stressors associated with spaceflight may lead to the down-regulation of some aspects of the immune response. Latent Epstein-Barr virus (EBV) reactivation in astronauts as a model for viral reactivation and found increased frequency of EBV shedding by astronauts before spaceflight.Eight-fold or greater increases in anti-EBV antibodies were observed after spaceflight. Previous ground-based studies conducted in the Antarctic demonstrated that EBV shedding increased, while cellular immunity diminished, during long periods of isolation. These studies suggested that decreased cellular immune function results in reactivation and shedding of potentially infectious viruses. Another latent herpesvirus, human cytomegalovirus (CMV), may pose a similar kind of risk to the health of astronauts during spaceflight. CMV infection is usually acquired asymptomatically during childhood. However, in individuals whose immune system is either immature or compromised, CMV can cause a number of serious diseases, such as encephalitis, gastroenteritis, pneumonia, and chorioretinitis. Moreover, CMV infection may contribute to preexisting immunosuppression by directly infecting leukocytes and hematopoietic cells. We examined the effect of spaceflight on CMV reactivation to begin the process of assessing the health consequences of latent viruses during spaceflights of long duration. Subjects Urine samples were obtained from 71 crew members 10 (L - 10) and 3 (L - 3) days before launch and 2 - 3 h after landing (R+0). The mean ages of the 58 male and 13 female astronauts were 43.1 Âą6 and 39.9Âą0.8 years, respectively. Spaceflight constraints allowed us to obtain in-flight urine samples collected on spaceflight days 2 - 4 from only 4 crew members. Urine samples were stored frozen until processed. Plasma for measurement of virus antibody titers and stress hormones was obtained from 71 astronauts at L-10, R+0, and 3 days after landing (R+3) and was stored at -70 degree until processed. Sixty - one healthy age-matched adults served as control subjects. One urine

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sample was obtained from each of these control subjects. Only 11 of the 61 control subjects, whose availability was limited, provided blood samples; additional urine samples were obtained from these 11 control subjects 7 and 22 days after the first urine sample. This collection schedule closely approximates the prespaceflight and postspaceflight collection schedule of a 12 - day spaceflight. Results CMV in urine Shedding of CMV in urine was detected by PCR at least once for 15 (21%) of 71 astronauts studied during the mission-monitoring period (L-10, L-3, and R+0). By contrast, only 1 (1.6%) of 61 control subjects shed CMV during 1 sampling period. In general, shedding by astronauts was more prevalent before spaceflight than during or after spaceflight, with 10 subjects shedding at L-10, 5 at L-3, and 4 at R+0. These included 1 subject shedding at all 3 time points and 3 shedding at 2 of the 3 time points. Of 71 astronauts, 55 (77%) were seropositive for CMV. CMV DNA was detected in 23 of 177 urine samples from the 55 seropositive astronauts, whereas only 1 of 33 samples from the control group was positive for CMV. No CMV was detected in urine of the 16 seronegative astronauts at any time. Overall, shedding was observed in 15 (10.6%) of 142 prespaceflight urine samples from the astronauts, compared with only 1 (1.2%) of 82 urine samples from control subjects. In astronaut prespaceflight samples in which shedding occurred, copy numbers ranged from 56 to 896 copies/mL (mean, 202 copies/mL). The 1 control subject sample in which shedding had occurred had 45 copies/mL. Even allowing for the fact that multiple urine samples from some subjects were analyzed, the differencebetween the 2 groups was statistically significant (P < .0001). At the same time, we found no significant difference between pre- and postspaceflight distributions of CMV copy numbers for the 15 astronauts. The postspaceflight number of CMV copies ranged from 68 to 251 copies/mL (mean, 140 copies/mL). In-flight measurements were available for only 4 astronauts, 2 of whom shed CMV at least once during that time. In urine samples from astronaut 15, CMV was detected on L-10 (259 copies/mL) and spaceflight days 2 (388 copies/mL) and 3 (447 copies/mL); CMV was not detected on spaceflight day 4 or R+0. Urine samples fromastronaut 16 had no detectable levels of CMV before or after spaceflight, but this subject shed in 2 of the 3 in-flight samples that were obtained on spaceflight days 2 (421 copies/mL) and 3 (242 copies/mL). CMV antibody titer No significant changes in CMV antibody titer occurred before or after spaceflight within the group of 55 seropositive astronauts. However, when these subjects were divided into 40 nonshedders and 15 CMV shedders, an interesting difference was found. No significant changes from baseline were found in CMV IgG antibody titer at any time for nonshedders (Figure 1.A). In contrast, CMV antibody titers of the 15 shedders were significantly increased (P < .001) over their baseline values at all time points (L - 10, R + 0, and R + 3). In addition, antibody was significantly increased at R13, compared with that at L - 10 (P < .001). No significant change was observed in the measles IgG antibody titer at R10 or R13, compared with that at L - 10 (data not shown), and no changes in CMV IgG antibody titer from 11 CMVseropositive control subjects were found across 3 sampling times. These CMV antibody titers of the control subjects did not differ from the baseline levels of astronauts. In 11 of the 15 astronauts who shed CMV in urine, anti- CMV antibody titer was increased â&#x2030;¤ 4 - fold at L - 10 versus their baseline values. In 3 of the 15 subjects (data from 2 are shown in figures 1B and 1C), a further increase (4 - fold) inCMV antibody titer was observed at R + 3, compared with that at R + 0. In the remaining 12 subjects, no significant postspaceflight (R + 3) changes in CMV antibody titer were found. Stress hormones Plasma cortisol, adrenocorticotropic hormone, and human growth hormone of 48 of the 55 CMVseropositive astronauts were measured at 3 time points (L - 10, R + 0, and R + 3); the only statistically significant difference at landing (R + 0) or R + 3, compared with that before spaceflight (L - 10), was a decrease in plasma cortisol (P < .05; table 1). However, 24-h levels of urinary cortisol and catecholamines (epinephrine and norepinephrine) were significantly elevated at landing, compared with levels at L - 10 (P < .05). Further analysis of samples from the 15 astronauts who shed CMV in urine showed no detectable difference in stress hormone levels, compared with those of the 40 nonshedders.

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Orthostatic heart rate responses after prolonged space flights Many astronauts experience orthostatic symptoms after returning to earth.Orthostatic symptoms may be explained in part by cardiovascular autonomic deconditioning. These observations have raised concerns regarding the cardiovascular safety of long-term space flights. Moreover, they created much enthusiasm among autonomic scientists because space flight induced postural orthostatic tachycardia (POTS) may serve as a model for the postural tachycardia syndrome in earthlings . Indeed, astronauts may feature changes in cardiovascular autonomic regulation that have been previously observed in POTS patients . Cardiovascular deconditioning was not a major health problem during the long-term missions on board the Russian space station MIR. Furthermore, in a small set of astronauts, we observed little POTS after long-term space flights . However, data on orthostatic heart rate and blood pressure regulation after short and prolonged space missions are controversial. Therefore, we determined orthostatic heart rate and blood pressure responses in cosmonauts before and after long-term missions on board the International Space Station (ISS). Methods We assessed supine and upright heart rate regulation in 18 male astronauts (aged 43 ± 2 years, BMI 26 ± 1 kg/m2) 60 and 30 days before and 3 - 5 days after longterm missions with flight duration ranging between 162 and 196 days. A 24 h daily schedule with alternating sleep - wake and work cycles was maintained during the flight. The daily routine included time for exercise for up to 2 h. Three exercise days were followed by 1 day without exercise. The astronauts did not exercise during the first days after landing. Results Before space flight, all astronauts completed the standing test without symptoms. One astronaut showed more than 30 beats per min heart rate increase while standing before flight, which is the diagnostic cutoff value for diagnosing POTS. He did not report orthostatic symptoms (Fig. 1, top). None of the astronauts showed orthostatic hypotension during pre-flight testing defined as ≥ 20/10 mmHg reduction in blood pressure after 3 min standing (Fig. 1, middle and bottom). After their return to earth, 3 out of 18 astronauts reported moderate orthostatic symptoms like lightheadedness and headache. Yet, all astronauts completed 10 min standing without presyncope or overt syncope at 3 - 5 days after landing. Mean blood pressure changes during orthostatic testing were 4 ± 2/8 ± 2 mmHg 60 days before flight, 5 ± 2/8 ± 2 mmHg 30 days before flight and 6 ± 2/ 11 ± 2 mmHg at 3 - 5 days after landing. None of the astronauts showed significant orthostatic hypotension during post - flight testing. Supine heart rate was 58 ± 2 bpm at 60 days before flight, 60 ± 2 bpm at 30 days before flight, and 68 ± 2 bpm at 3 - 5 days after return to earth (p < 0.05, compared to pre-flight supine heart rate). Standing heart rate was 72 ± 3 bpm at 60 days before flight, 74 ± 3 bpm at 30 days before flight, and 90 ± 2 bpm at 3 - 5 days after return to earth (p < 0.05, compared to preflight upright heart rate). One astronaut exhibited an increased heart rate greater than 30 bpm (4 HR = 31 bpm). He declined undergoing orthostatic testing on post-flight day 6. None of the astronauts had an upright heart rate of 120 bpm or greater.

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Table 1 shows HRV data obtained during pre-flight and post-flight orthostatic testing. Increased supine HR 3 - 5 days after space flight was accompanied by decreased HRV in the time domain, decreased power in the high frequency band, and by an increased LF to HF ratio. The absolute power of HRV in the low frequency range was unchanged. Upright HRV in the time and in the frequency domain was reduced 3 - 5 days after landing compared to pre-flight values.

Reference:Orthostatic heart rate responses after prolonged space flights,Baevsky

Digestive Organs during Long Spaceflight Multiple changes in the digestive system of cosmonauts were revealed upon completion of long spaceflights, including gastric hypersecretion, hypofunction of the exocrine and endocrine pancreas, dysfunction of the bile - excreting system, decreased hydrolytic potential of the intestine and its evacuatory function, and the development of dysbacteriosis (bacterial overgrowth).In addition, data on the special conditions of functioning of the digestive system during weightlessness because of the plethoric state of veins and changes in the hemodynamics of the abdominal organs were later obtained. To study the relationship between the structural and functional changes in the abdominal organs and the state of regional hemodynamics, a glucose tolerance test with a simultaneous milk intake (a glucose - milk loading) was

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carried out during missions of different durations. In addition to the glycemic profile, this test allows the functional state of the gallbladder, pancreas, and stomach to be assessed with the ultrasonic method, which extends the possibilities of studying the digestive system during spaceflight. The cosmonaut physician on board the Mir space station performed this combined test to assess he state of his own and those of other digestive system crew members during two long-term missions, including the longest manned spaceflight in the history of astronautics, which lasted for almost 15 months. The main objective of the study was to assess ultrasonically the state of the digestive organs and the regional hemodynamics under conditions of long spaceflight and to test simultaneously glucose tolerance and the functional state of the gallbladder, the pancreas, and the stomach during a glucose - milk load (GML). Methods The examination was started every morning on an empty stomach. The glucose, amylase, bilirubin, glutamate oxalacetate transferase, glutamate pyruvate transferase, and Îł-glutamyl transferase concentrations were measured in the capillary (finger-prick) blood using an onboard Reflotron analyzer (Bochringer Mannheim). After determination of the basal glycose level and a baseline echographic examination, the cosmonauts ingested a glucose - milk mixture (56 g of glucose, 200 ml of tea, and 200 ml of 3.2% milk), subsequently biochemical analysis of the capillary (fingerprick) blood and ultrasonic examination of the abdominal organs was performed every 30 min for 2 h. In addition to the assessment of glucose tolerance, the use of milk with tea in the loading test allowed us to evaluate echographically the gallbladder contractility, the pancreas reactivity, and the gastric evacuatory function. The ingestion of 400 ml of fluid improved imaging of the stomach and the descending division of the duodenum, which facilitated the assessment of the state of these organs. The ultrasonic examination of the abdominal organs and vessels was performed by the crew physician with an onboard echograph (France) using standard ultrasonic biometric techniques. The echographic data obtained during each session were videotaped for subsequent processing and analysis on earth.The studies were conducted in the preflight period (30 days before the start) simultaneously with training of the cosmonauts and on days 70 - 370 of the flight, as well as on days 1 and 5 - 9 after completion of the mission.The in-flight studies were conducted by the cosmonauts under the supervision of Mission control specialists. Eight cosmonauts (mission duration, 132 - 438 days) participated in 11 study sessions and were examined on board the Mir station. In addition, four cosmonauts were examined only before and after the flight. Results Studies in the preflight period In the preflight period, the biochemical composition of the capillary blood was always within normal limits. The maximal rise in the glucose concentration was observed 30 min after, and, at 90 min, the glycemic level returned to the baseline values, which is characteristic of the response of a healthy individual (Fig. 1). The ultrasonic examination showed that the size of the liver, spleen, pancreas, and other organs, as well as the diameter of the great vessels, was within normal limits. The echostructure of the organs was characterized by organ specificity. The echogenicity of the pancreas was higher than that of the liver, and the echogenicities of the liver and the spleen were higher than that of the renal cortex. The gallbladder had a welldefined contour against the background of the hepatic tissue; its walls were smooth and not thicker than 1 mm. The bile ducts were normally no more than 2 mm in diameter. The stomach appeared as a narrow cavity, with the wall thickness not exceeding 3 mm in most cases. An empty stomach revealed a very small amount of fluid (up to 15 ml). After the GML intake, the gastric cavity increased in all directions. After 15 min, the calculated gastric volume was about 350 ml, and at 30 min it decreased by an average of 60% (Fig. 2). The volume returned to the initial values at 90 min, which corresponded to the normal rate of evacuation of fluid from the stomach. After the GML, the gallbladder volume decreased by an average of 60% by 30 min and returned to the baseline values by 90 min, which suggested its normotonic and normokinetic state (Fig. 3). Thirty minutes after the GML, we observed dilatation of the bile ducts, which did not change thereafter during the load. Additionally, after the GML, the size of the pancreas increased and its echogenicity decreased; the duct was dilated up to 3 mm,

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which was a normal physiological response caused by a working level of blood filling of the gland and the activation of its secretion.

Studies under spaceflight conditions The biochemical tests of capillary blood under spaceflight conditions did not usually reveal any significant changes (table); only in individual cases did the bilirubin and glucose concentrations increase, which may reflect functional stress in the state of the digestive system. In-flight ultrasonic examinations performed after fasting showed dilatation of the large veins of the abdominal cavity, an increase in the size of the parenchymatous organs, and a decrease in their echogenicity, as well as thickening of the walls of the hollow organs as compared to the preflight values. These results are likely to reflect the changes in the abdominal organs and vessels caused by venous congestion and redistribution of blood and other body fluids during weightlessness. A relatively large amount of homogeneous fluid (up to 100 ml) was revealed in the stomach in all cosmonauts after fasting, and the stomach walls were uniformly thickened up to 6 mm on average. In most cases, dilatation of the cavity of the proximal division of the duodenum and thickening of its walls were noticed. After a GML in weightlessness, the calculated volume of the content of the gastric cavity (after 15 min) ISOPTWPO Today Human Space Flight c International Space Agency(ISA)

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usually constituted about 300 ml. The size of the stomach decreased by only 30% 30 min after the load and returned to the initial value only after 120 min, suggesting that the evacuatory activity of the stomach was low under these conditions (Fig. 2). After overnight fasting, the gallbladder was usually smaller than in the preflight period, which may indicate its increased tone. The walls of the gallbladder were thickened and triple in places (stratification). The bile ducts, as compared to in the preflight period, were dilated up to 3 - 5 mm, and their ultrasonic pattern was similar to that observed before the flight in the process of active secretion after a GML. During the flight, because of its initial contraction, the gallbladder did not show any detectable response to the GML, which is indicative of the hypokinetic state of this organ (Fig. 3). In most cases, the transverse dimensions of the pancreatic head, body, and tail were increased after fasting; the echostructure of the gland became more uniform; and its echogenicity decreased to that of the liver. The pancreatic duct after fasting was dilated up to 3 - 4 mm (in the preflight period, to no more than 1 mm). The ultrasonic pattern of the pancreas was similar to that observed in the preflight period after the GML, when it reflected a working level of blood filling of the gland and the secretory activity of the organ. The pancreas response was also minimal, because the initial venous blood filling of the organ masked its changes during work and an increase in its secretory activity during weightlessness. The results obtained show that the modification of the functional activity of the digestive organs during weightlessness occurs against the background of their large venous capacity. Similar functional changes with signs of venous congestion in the abdominal vessels and organs were also repeatedly observed in experimental hypokinesia under conditions of long-term bed rest in the antiorthostatic position.

The course of the glycemic curves after the glucose tolerance test is an integrative index of the state of carbohydrate hydrolysis, transport, and utilization. To assess the state of carbohydrate metabolism and the function of the pancreas, the glucose tolerance test was first used in the Russian cosmonauts piloting the Salyut space station, and the changes revealed were regarded as signs of decreased carbohydrate tolerance . In this study, the cosmonautsâ&#x20AC;&#x2122; in - flight glycemic curves after the GML were flattened, with, in most cases, a smaller rise in glycemia at 30 min and higher glucose concentrations at 90 - 120 min than on earth. Such a flattened curve and prolonged restoration of the baseline glycemic level might have been the consequence of delayed glucose absorption and/or a higher blood insulin level (hypoglycemic effect), which, incidentally, was repeatedly revealed after flights and during model experiments with hypokinesia.

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Studies in the postflight period When ultrasonic examinations of the abdominal cavity organs were performed immediately after completion of spaceflights (during the first day), the changes revealed were similar to those observed during the spaceflight. Venous dilatation and a high level of blood filling of the abdominal organs, with signs of increased secretion and delayed evacuation from the stomach, pancreas, and biliary tract, were observed. This ultrasonic pattern is consistent with the results of biochemical investigations carried out in this period. On a day when a GML was performed, namely, after overnight fasting on days 5 - 9 after the flights, a relatively large amount of fluid (up to 100 ml) and wall thickening were observed, which implies a persistent hypersecretory state of the stomach. Increased gallbladder tone and dilatation of the common bile duct also persisted. In most cases, the pancreas size returned to the preflight values, but the gland remained hypoechogenic with a dilated duct, which was indicative of its active secretion after fasting. With a GML, the dynamics of the stomach, pancreas, bile ducts, and gallbladder was similar to the preflight dynamics. After the longest missions, the glycemic profile after a GML still resembled that observed in flight. The fasting glucose concentration at 90 - 120 also remained min than in the preflight period. This course of the glycemic curve is typical of hyperinsulinemia, which was repeatedly observed in the postflight period . In individual cases, glycemic curves with slow restoration were obtained, which are characteristic of a transient carbohydrate metabolism disorder. Thus, the results of a comprehensive investigation of the digestive organs under conditions of long spaceflight showed a tendency for the blood bilirubin and glucose concentrations to increase, as well as characteristic changes in the glycemic profile after a GML. The glycemic curves were flattened and returned more slowly to the baseline level than in the preflight period, suggesting that glucose was utilized at a lower rate; however, no signs of deficiency of the insulin apparatus were revealed. In most cases, dilatation of the pancreatic duct and the hepatic bile ducts and increases in the gallbladder tone and the fluid content of the stomach were noticed after fasting, which indicates an increase in the secretory activity of these organs. Moreover, the GML was associated with a decrease in the pancreatic activity, inhibition of the evacuatory function of the stomach, and decreased contractility of the gallbladder. These functional shifts occurred against the background of structural changes in the abdominal organs caused by venous overfilling in the splanchnic area. Dilatation of veins, an enlargement of the parenchymatous organs (liver, pancreas, spleen), a decrease in their echogenicity, and thickening of the walls of the hollow organs (stomach, gallbladder, duodenum) were observed. It should be emphasized that the markedness of these changes in the digestive system was not connected with the duration of exposure to weightlessness (for durations shorter than six months). The changes revealed were reversible and disappeared in most cases two weeks after completion of the missions. Reference:The State of the Digestive Organs during Long Spaceflight,AFONIN et al.

ISOPTWPO Today Human Space Flight c International Space Agency(ISA)

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ISOPTWPO Today March 2014 No.5

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