Endothelial dysfunction markers and immune response indices in cosmonauts' blood after long-duration space flights.

Space flight factors are known to cause a malfunction in the human immune system and lead to damage to blood vessels. The hemostatic function of endothelium during space missions and its interaction with human immunity has not been determined so far. In this work, we investigated the markers of endothelial activation and damage (plasma concentrations of soluble thrombomodulin fraction (sTM), von Willebrand factor (vWF), highly sensitive C-reactive protein (hs-CRP)), as well as the level of D-dimer and compared them to the immunological parameters characterizing the state of human humoral and cellular immunity. The immune status of long-duration ISS crewmembers was assessed by whole-blood testing, and comprehensive postflight immune assessment included the analysis of leukocyte distribution. Flow cytometry was applied to determine the absolute counts and the percentage of lymphocyte subsets: B cells (CD19+), T cells (CD3+, CD3+CD4+, CD3+CD8+), NK cells (CD3-CD16+CD56+, CD11b+CD56+), and activated subsets (CD3+CD25+ and CD3+HLA-DR+). The in vitro basal cytokine production was investigated in whole blood cell culture. The cytokines IFN-gamma, IL-1-beta, IL-4, IL-6, IL-10, IL-18, and TNF-alpha were measured in plasma and the 24-h supernatants by a sensitive enzyme-linked immunosorbent assay. A significant increase in the plasma levels of vWF and hs-CRP and a decrease in the concentration of sTM after spaceflights were detected. Divergent changes in the parameters characterizing the state of the immune system were observed. We propose that the changes revealed may lead to an increase in the procoagulant activity of blood plasma, suppression of protein C activation and thrombin inhibition, as well as to an increase in the adhesive-aggregate potential of platelets, especially in case of changes in the rheological characteristics of blood flow during re-adaptation to ground conditions. We also speculate that the immune system might play an important role in vessel damage during long-duration missions.

Body composition and metabolic changes during a 520-day mission simulation to Mars.

PURPOSE: The "Mars-500 project" allowed to evaluate the changes in psychological/physiological adaptation over a prolonged confinement, in order to gather information for future missions. Here, we evaluated the impact of confinement and isolation on body composition, glucose metabolism/insulin resistance and adipokine levels. METHODS: The "Mars-500 project" consisted of 520 consecutive days of confinement from June 3, 2010 to Nov 4, 2011. The crew was composed of six male subjects (three Russians, two Europeans, and one Chinese) with a median age of 31 years (range 27-38 years). RESULTS: During the 520-day confinement, total body mass and BMI progressively decreased, reaching a significant difference at the end (417 days) of the observation period (- 9.2 and - 5.5%, respectively). Fat mass remained unchanged. A progressive and significant increase of fasting plasma glucose was observed between 249 and 417 days (+ 10/+ 17% vs baseline), with a further increase at the end of confinement (up to + 30%). Median plasma insulin showed a non-significant early increment (60 days; + 86%). Total adiponectin halved (- 47%) 60 days after hatch closure, remaining at this nadir (- 51%) level for a further 60 days. High molecular weight adiponectin remained significantly lower from 60 to 168 days. CONCLUSIONS: Based on these data, countermeasures may be envisioned to balance the potentially harmful effects of prolonged confinement, including a better exercise program, with accurate monitoring of (1) the individual activity and (2) the relationship between body composition and metabolic derangement.

[Human body composition during extended stay in microgravity].

According to the Sprut-2 protocol, bio-impedancemetry of ISS cosmonauts was performed once a month and also before and after mission. Multiple non-invasive body measurements were carried out in 15 cosmonauts in real time. Relocation of extracellular liquid along the body axis led to its reduction in legs and, on the contrary, an increase in the abdomen. Volumes of total body liquid as well as intra- and extracellular liquids decreased in comparison with pre-flight levels. Lean body mass also became less in microgravity, whereas fat mass showed an increase.

Functional changes in neutrophils and psychoneuroendocrine responses during 105 days of confinement.

The innate immune system as one key element of immunity and a prerequisite for an adequate host defense is of emerging interest in space research to ensure crew health and thus mission success. In ground-based studies, spaceflight-associated specifics such as confinement caused altered immune functions paralleled by changes in stress hormone levels. In this study, six men were confined for 105 days to a space module of ~500 m(3) mimicking conditions of a long-term space mission. Psychic stress was surveyed by different questionnaires. Blood, saliva, and urine samples were taken before, during, and after confinement to determine quantitative and qualitative immune responses by analyzing enumerative assays and quantifying microbicide and phagocytic functions. Additionally, expression and shedding of L-selectin (CD62L) on granulocytes and different plasma cytokine levels were measured. Cortisol and catecholamine levels were analyzed in saliva and urine. Psychic stress or an activation of the psychoneuroendocrine system could not be testified. White blood cell counts were not significantly altered, but innate immune functions showed increased cytotoxic and reduced microbicide capabilities. Furthermore, a significantly enhanced shedding of CD62L might be a hint at increased migratory capabilities. However, this was observed in the absence of any acute inflammatory state, and no rise in plasma cytokine levels was detected. In summary, confinement for 105 days caused changes in innate immune functions. Whether these changes result from an alert immune state in preparation for further immune challenges or from a normal adaptive process during confinement remains to be clarified in future research.

520-d Isolation and confinement simulating a flight to Mars reveals heightened immune responses and alterations of leukocyte phenotype.

During interplanetary exploration, chronic stress caused by long term isolation and confinement in the spacecraft is one of the major concerns of physical and psychological health of space travelers. And for human on Earth, more and more people live in an isolated condition, which has become a common social problem in modern western society. Collective evidences have indicated prolonged chronic stress could bring big influence to human immune function, which may lead to a variety of health problems. However, to what extent long-term isolation can affect the immune system still remains largely unknow. A simulated 520-d Mars mission provided an extraordinary chance to study the effect of prolonged isolation. Six healthy males participated in this mission and their active neuroendocrine and immune conditions were studied with saliva and blood samples from all participants on chosen time points during the isolation period. As a typical neuroendocrine parameter, stress hormone cortisol was measured in the morning saliva samples. Immune phenotype changes were monitored through peripheral leukocyte phenotype analysis. Using an ex vivo viral infection simulation assay we assessed the immune response changes characterized by the ability to produce representative endogenous pro-inflammatory cytokines. The results of this study revealed elevated cortisol levels, increased lymphocyte amount and heightened immune responses, suggesting that prolonged isolation acting as chronic stressors are able to trigger leukocyte phenotype changes and poorly controlled immune responses.

[Shifts in metabolism and its regulation under the effect of spaceflight factors].

The review deals with the results of studying the adaptive changes in metabolism and its neuroendocrine regulation in humans and animals under the effect of spaceflight factors and ground-based simulation of the gravitational unloading. The majority of the investigations were concerned with the water-electrolyte and mineral turnover, as well as protein, lipid and carbohydrates metabolism. Biochemical measurements of the body liquids (blood, urine and saliva) before, in and after space flight or in ground simulation experiments were used as indictors of the status of sympathoadrenal, hypothalamo-pituitary-adrenal and other systems involved in systemic regulation of metabolism, and also strength of stress-reaction to adversities. The authors generalized data on the interrelation and interaction of the neuroendocrine and psychophysiological status both in the real and simulated conditions of space flight.

[Features of the psychophysiological status of men with different levels of vestibuloautonomic resistance and their interrelation with motion sickness' etiology and pathogenesis].

The results of more than 600 observations of 200 healthy male-volunteers of 23-45 years old including parameters of electroencephalogram, sensorimotor reactions, and questionnaires of Cattell, Strelau and Taylor were analyzed. Division into groups with high, moderate and low vestibuloautonomic resistance (VAR) was done on base of endurance of rotary test with interrupted cumulation of Coriolis accelerations. It is shown, that VAR degree along with distinctions in sensitivity of peripheral compartment of a vestibular analyzer and other sensory systems is appreciably defined by the distinctions in force, lability, activity and dynamism of a nervous system, equilibrium and mobility of processes of excitation-inhibition. VAR is also defined by the distinctions of the initial psychophysiological status characterizing psychomotor reactivity, features of personality, temperament and cognitive abilities, while expressiveness ofvestibuloautonomic disorders in susceptible to motion sickness men is essentially intensified by the influence of their psychoemotional condition during vestibular stimulation-suibjective sensation "lost in space", manifestation of mental discomfort and anxiety, accompanied by autonomic and neurohormonal reactions which extreme form can be characterized as the "syndrome of a threatened state".

[Dynamics of blood concentration of neurospecific proteins and risk of neuropathy development in the conditions of 105-day confinement].

Six male volunteers (aged 25 to 40 years) were subjects in all-round psychophysiological, hormonal and immunological studies before, in and after 105-day isolation and confinement. Blood was drawn and the 16-factorial Cattell personality inventory was filled out every 30 days. Concentrations of blood hormones, neurospecific proteins and cytokines point to a close interrelation between antibody titers to myelin-associated glycoprotein and changes in the parameters of metabolism and reproduction-related hormones, as well as cytokines and individual psychophysiology (extra-introversion, dominance, intropunitiveness, social contact selectivity, etc.), and suggest a minimum risk of demyelinizing neuropathy due to exposure to the conditions of isolation and confinement.

[Dynamics of the body composition, neurohumoral and psychophysiological status of humans in the conditions of 105-day isolation and confinement].

Before, in and after the experiment with 105-day isolation and confinement, 6 male volunteers from 25 to 40 years of age rationed NaCl and performed integral impedancimetric, psychological and hormonal investigations. Every 30 days blood collection for hormonal measurements was combined with filling of Cattell's 16 personal factor questionnaire. Parameters of total body fluid, body mass, basic exchange, specific hydration and basic exchange were determined. The results showed that the experimental conditions did not affect significantly body composition, metabolism or neurohumoral regulation; the metabolic variations were largely associated with motivation for and value orientation in accommodation, to the permissible extent, of the controlled diet and work/rest schedule to personal needs. In addition, it was found that evolution of the psychophysiological status of humans in isolation and confinement is governed primnarily by personality characteristics and, to a less degree, specifics and length of exposure to the artificial environment; thus, in the opinion of the volunteers normoxic, normobaric and slightly hypercapnic (0.15-0.65% CO2) atmosphere was comfortable and harmless to health. Analysis of the whole data array verified the expressed interrelation of neuroendocrine and psychophysiological parameters as well as shifts in body basic exchange and mass, salt intake and hydration rate in the conditions of isolation and confinement.

[Psychophysiological adaptation and communication behavior of human operator during 105-day isolation].

Purpose of the study was to assess effects of 105-d isolation on language behavior and psychophysiological status of volunteered subjects. Software NOOJ was used to determine frequency of mentioning in written reports notions falling into the categories of "Needs", "Activity", "Negation" and "Social regulation". Well-being, activity and mood were assessed with the SAN questionnaire and urine cortisol measurement. Correlation of the content-analysis results with phases of adaptation to extended isolation and confinement made it possible to elicit specific features of language behavior of the small group members, at the time of simulated autonomy, specifically. Besides, the computerized content-analysis enabled a quantitative description of communication strategy as a function of psychophysiological adaptation to stressful factors of the simulation experiment.

[Analysis of the relationships between the psychophysiological status and system of adaptive immunity in the conditions of 5-day dry immersion].

Relationships of the T- and B-components of adaptive immunity and the psychophysiological status were studied in 14 volunteers for the experiment with 5-d dry immersion (DI) w/o countermeasures. Comparison of frequency of deviations in immunity parameters of psychologically different subjects demonstrated the highest frequency in non-anxious and extravert individuals on day-5 in DI. These differences in immune reactions as a function of psychological type and temperament point to existence of a neuroimmune typology and, therefore, the necessity of concurrent immunologic and psychological investigations in order to develop separate measures of rehabilitation from and prevention of stress in people with polar psychological status.

[Evaluation of synthetic antidiuretic hormone as a corrective substance following head-down tilt].

Effects of synthesized desmopressin, analog of antidiuretic hormone, and water-salt supplement on the renal function and orthostatic stability were studied in 6 normal male subjects after 12-hr. head-down tilt (12 degrees). The combination of water-salt homeostasis normalizing methods was effective in retaining excessive liquid and salts. Moreover, tolerance of the standard 20-min. passive standing test improved significantly. Hence, it was demonstrated that intake of synthetic vasopressin analog combined with WSS counteracted hypohydration of organism due to HDT and improved orthostatic tolerance.

[Desmopressin effect on water-salt homeostasis and orthostatic tolerance during head-down tilting].

Effects of desmopressin, a synthetic analog of antidiuretic hormone (ADH), on water-salt metabolism and orthostatic tolerance were evaluated in human subjects during 24-hr HDT (-15 degrees). Consumption of the preparation was found to dampen losses in total body and extracellular liquids and to slow down diuresis as well as establishment of a positive water balance as compared with control series without ADH. In addition, tolerance of the standard standing test improved noticeably. To conclude, desmopressin precluded hypohydration of the tilted subjects and, consequently, prevented loss of orthostatic tolerance.

[Analysis of interdependence of temperament, neuroendocrine control and psychophysiological status during dry immersion].

Interdependence of temperament, hormonal and psychophysiological status was investigated in 8 young volunteers for 7-d dry immersion (DI). Blood levels of insulin, sex, steroid, thyroid hormones and psychomotor parameters were determined on DI days 3 and 7, and on day 7 of recovery. Before DI, the volunteers filled in the Kettelle personality questionnaire. During DI, anxious subjects spent less time to compare visual patterns demonstrating high and stable speed of reactions but made a bit more errors. Extraverts showed high speed of reactions and stability of psychomotor parameters and did not increase the number of errors. Easy-tempered and introvert subjects preserved inherently high insulin concentrations in DI. Support deprivation was attended by drop of the levels of triiodothyronine and cortisol and rise of prolactin and thyroxin. Results of multiple correlation analysis led to the conclusion that DI accentuates the role of original extra-introversion and dampens origin anxiety. Successfulness can be attained by adequate alteration of the levels of steroid and thyroid hormones with effectively balanced vagoinsulin-sympathoadrenal neuroendocrine control and monoaminergic CNV activity.

[Dynamics of the body liquids and composition in long-duration space flight (bio-impedance analysis)].

Bio-impedancemetiy was used to study dynamics of the human hydration status and body composition aboard the International space station (ISS). Body liquids in 12 Russian crewmembers were found reduced in different periods of space flight: the total, intra- and extracellular liquid volumes became less by 5.2 to 10.4% on the group average as compared with baseline values. In-flight changes in body composition also displayed a consistent pattern. While the lean mass loss was insignificant averaging 1.9-4.0%, the fatty mass gain averaged 4.6 to 8.2% in the initial three months on flight. We conclude that the human body hydration status falls along with the muscular mass reduction and fatty mass gain during long-duration space flight.

[State of the abdominal organs and vessels on the background of simulated venous plethora in the splanchnic vascular system].

Ultrasonic investigations of the abdominal organs and splanchnic veins were performed in essentially healthy subjects tilted at 12 degrees and 15 degrees for the period of 12 hrs. and 24 hrs. Tilting produced typical redistribution of venous blood and body liquids toward the cranial end. In its turn, blood redistribution caused excessive venous plethora and abdominal stasis. These were succeeded by expansion of large veins in the abdomen, enlargement of parenchymal organs and contraction of their echogenicity, and thickening of the hollow organs walls. Changes in the gastrointestinal functions before meal included elevated gastric, hepatic and pancreatic secretion, and an increased amount of intestinal content. The investigations demonstrated that stasis of the splanchnic veins altered functioning of the digestive organs in tilted human subjects.

[Investigations of human body liquids in long-duration space flight].

The hydration status of a Russian member on a six-month ISS mission was evaluated by bio-impedancemetry during monthly sessions of experiment Sprut (Octopus). Body liquids tended to diminish gradually and measured minimum values on the landing day. By the end of mission the total volume of liquids reduced by 18.9 %; the intracellular and extracellular portions lost 19.0 and 20.4 %, respectively. Time history of specific body liquids was identical in flight. Reductions in the body mass and lean mass (according to impedancemetry) reached 6.9 % and 8.0 %, respectively. These results point to a decrease in the human body hydration status during long-duration space flight concurrent to losses in the muscle mass. In two weeks after landing there was an implicit trend toward regaining the pre-flight hydration status and body mass; yet, both parameters were still below pre-flight values.

Hormonal changes during long-term isolation.

Confinement and inactivity induce considerable psychological and physiological modifications through social and sensory deprivation. The aim of the SFINCSS-99 experiment was to determine the cardiovascular and hormonal pattern of blood volume regulation during long-term isolation and confinement. Simulation experiments were performed in pressurized chambers similar in size to the volumes of modern space vehicles. Group I consisted of four Russian male volunteers, who spent 240 days in a 100-m(3 )chamber. Group II included four males (one German and three Russians) who spent 110 days in isolation (200-m(3) module). The blood samples, taken before, during and after the isolation period, were used to determine haematocrit (Ht), growth hormone (GH), active renin, aldosterone, and osmolality levels. From the urine samples, electrolytes, osmolality, nitrites, nitrates, cortisol, antidiuretic hormone (ADH), aldosterone, normetanephrine and metanephrine levels were determined. The increase in plasma volume (PV) that is associated with a tendency for a decrease in plasma active renin is likely to be due to decreased sympathetic activity, and concords with the changes in urinary catecholamine levels during confinement. Urinary catecholamine levels were significantly higher during the recovery period than during confinement. This suggests that the sympathoadrenal system was activated, and concords with the increase in heart rate. Vascular resistance is determined by not only the vasoconstrictor but also vasodilator systems. The ratio of nitrite/nitrate in urine, as an indicator of nitric oxide release, did not reveal any significant changes. Analysis of data suggests that the duration of the isolation was a main factor involved in the regulation of hormones.