Severe Spaceflight-Associated Neuro-Ocular Syndrome in an Astronaut With 2 Predisposing Factors.

Importance: Understanding potential predisposing factors associated with spaceflight-associated neuro-ocular syndrome (SANS) may influence its management. Objective: To describe a severe case of SANS associated with 2 potentially predisposing factors. Design, Setting, and Participants: Ocular testing of and blood collections from a female astronaut were completed preflight, inflight, and postflight in the setting of the International Space Station (ISS). Exposure: Weightlessness throughout an approximately 6-month ISS mission. Mean carbon dioxide (CO2) partial pressure decreased from 2.6 to 1.3 mm Hg weeks before the astronaut's flight day (FD) 154 optical coherence tomography (OCT) session. In response to SANS, 4 B-vitamin supplements (vitamin B6, 100 mg; L-methylfolate, 5 mg; vitamin B12, 1000 µg; and riboflavin, 400 mg) were deployed, unpacked on FD153, consumed daily through FD169, and then discontinued due to gastrointestinal discomfort. Main Outcomes and Measures: Refraction, distance visual acuity (DVA), optic nerve, and macular assessment on OCT. Results: Cycloplegic refraction was -1.00 diopter in both eyes preflight and +0.50 - 0.25 × 015 in the right eye and +1.00 diopter in the left eye 3 days postflight. Uncorrected DVA was 20/30 OU preflight, 20/16 or better by FD90, and 20/15 OU 3 days postflight. Inflight peripapillary total retinal thickness (TRT) peaked between FD84 and FD126 (right eye, 401 µm preflight, 613 µm on FD84; left eye, 404 µm preflight, 636 µm on FD126), then decreased. Peripapillary choroidal folds, quantified by surface roughness, peaked at 12.7 µm in the right eye on FD154 and 15.0 µm in the left eye on FD126, then decreased. Mean choroidal thickness increased throughout the mission. Genetic analyses revealed 2 minor alleles for MTRR 66 and 2 major alleles for SHMT1 1420 (ie, 4 of 4 SANS risk alleles). One-week postflight, lumbar puncture opening pressure was normal, at 19.4 cm H2O. Conclusions and Relevance: To the authors' knowledge, no other report of SANS documented as large of a change in peripapillary TRT or hyperopic shift during a mission as in this astronaut, and this was only 1 of 4 astronauts to experience chorioretinal folds approaching the fovea. This case showed substantial inflight improvement greater than the sensitivity of the measure, possibly associated with B-vitamin supplementation and/or reduction in cabin CO2. However, as a single report, such improvement could be coincidental to these interventions, warranting further evaluation.

Integrating Cultural Humility into Medical Education Using a Structured and Interactive Workshop.

Background: Cultural humility is a lifelong commitment to self-evaluation, redressing power imbalances in patient-physician relationships and developing mutually trusting beneficial partnerships. Objective: The objective of this study was to determine the feasibility and efficacy of cultural humility training. Methods: From July 2020-March 2021, 90-minute educational workshops attended by 133 medical students, resident physicians and medical education faculty included 1) pre- and post- intervention surveys; 2) interactive presentation on equity and cultural humility principles; 3) participants explored sociocultural identities and power; and 4) reflective group discussions. Results: There were significant increases from pre to post intervention assessments for perception scores (3.89 [SEM= 0.04] versus 4.22 [0.08], p<0.001) and knowledge scores (0.52 [0.02] versus 0.67 [0.02], p<0.001). Commonest identities participants recognized as changing over time were personality = 40%, appearance = 36%, and age =35%. Commonest identities experienced as oppressed/subjugated were race/ethnicity = 54%, gender = 40% and religion = 28%; whilst commonest identities experienced as privileged were gender= 49%, race/ethnicity = 42% and appearance= 25%. Male participants assigned mean power score of 73% to gender identity compared to mean power score of -8% by female participants (P<0.001). Non-Hispanic Whites had mean power score for race identity of 62% compared to 13% for non-white participants (p<0.001). English as a second language was only acknowledged as an oppressed/subjugated identity by those born outside the United States (p<0.001). Conclusion: An interactive educational workshop can increase participants' knowledge and perceptions regarding cultural humility. Participants can self-reflect to recognize sociocultural identities that are oppressed/subjugated or privileged.

Reduced fibrous capsule elastic fibers from biologic ECM-enveloped CIEDs in minipigs, supported with a novel compression mechanics model.

BACKGROUND: Fibrous capsules (Fb) in response to cardiovascular implantable electronic devices (CIEDs), including a pacemaker (P) system, can produce patient discomfort and difficulties in revision surgery due partially to their increased compressive strength, previously linked to elevated tissue fibers. OBJECTIVE: A preliminary study to quantify structural proteins, determine if biologic extracellular matrix-enveloped CIEDs (PECM) caused differential Fb properties, and to implement a realistic mechanical model. METHODS: Retrieved Fb (-P and -PECM) from minipigs were subjected to biomechanical (shear oscillation and uniaxial compression) and histological (collagen I and elastin) analyses. RESULTS: Fb-PECM showed significant decreases compared to Fb-P in: low strain-loss modulus (390 vs. 541 Pa) across angular frequencies, high strain-compressive elastic modulus (1043 vs. 2042 kPa), and elastic fiber content (1.92 vs. 3.15 µg/mg tissue). Decreases in elastin were particularly noted closer to the implant's surface (Fb-PECM = 71% vs. Fb-P = 143% relative to dermal elastin at mid-tangential sections) and verified with a solid mechanics hyperelasticity with direction-dependent fiber viscoelasticity compression simulation (r2 ≥ 98.9%). CONCLUSIONS: The biologic envelope composed of decellularized porcine small intestine submucosa ECM for CIEDs promoted fibrous tissues with less elastic fibers. Novel compression modeling analyses directly correlated this singular reduction to more desirable subcutaneous tissue mechanics.

Countermeasures-based Improvements in Stress, Immune System Dysregulation and Latent Herpesvirus Reactivation onboard the International Space Station - Relevance for Deep Space Missions and Terrestrial Medicine.

The International Space Station (ISS) has continued to evolve from an operational perspective and multiple studies have monitored both stress and the immune system of ISS astronauts. Alterations were ascribed to a potentially synergistic array of factors, including microgravity, radiation, psychological stress, and circadian misalignment. Comparing similar data across 12 years of ISS construction and operations, we report that immunity, stress, and the reactivation of latent herpesviruses have all improved in ISS astronauts. Major physiological improvements seem to have initiated approximately 2012, a period coinciding with improvements onboard ISS including cargo delivery and resupply frequency, personal communication, exercise equipment and protocols, food quality and variety, nutritional supplementation, and schedule management. We conclude that spaceflight associated immune dysregulation has been positively influenced by operational improvements and biomedical countermeasures onboard ISS. Although an operational challenge, agencies should therefore incorporate, within vehicle design limitations, these dietary, operational, and stress-relieving countermeasures into deep space mission planning. Specific countermeasures that have benefited astronauts could serve as a therapy augment for terrestrial acquired immunodeficiency patients.

The influence of spaceflight on the astronaut salivary microbiome and the search for a microbiome biomarker for viral reactivation.

BACKGROUND: Spaceflight impacts astronauts in many ways but little is known on how spaceflight affects the salivary microbiome and the consequences of these changes on astronaut health, such as viral reactivation. In order to understand this, the salivary microbiome was analyzed with 16S rRNA gene amplicon sequencing, and saliva viral titers were analyzed with quantitative polymerase chain reaction (qPCR) with primers specific for Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV) from 10 astronauts pre-flight, in-flight, and post-flight. RESULTS: Streptococcus was the most abundant organism in the saliva, making up 8% of the total organisms detected, and their diversity decreased during spaceflight. Other organisms that had statistically significant changes were Proteobacteria and Fusobacteria which increased during flight and Actinobacteria which decreased during flight. At the genus level, Catonella, Megasphera, and Actinobacillus were absent in more than half of saliva samples collected pre-flight but were then detected during flight. In those subjects that already had these genera pre-flight, their relative abundances increased during flight. Correlation analyses between the microbiome and viral titers revealed a positive correlation with Gracilibacteria, Absconditabacteria, and Abiotrophia and a negative correlation between Oribacterium, Veillonella, and Haemophilus. There was also a significant positive correlation between microbiome richness and EBV viral titers. CONCLUSIONS: This is the first study to look at how the salivary microbiome changes as a result of spaceflight and the search for bacterial biomarkers for viral reactivation. Further studies examining the role of specific organisms that were shown to be correlative and predictive in viral reactivation, a serious problem in astronauts during spaceflight, could lead to mitigation strategies to help prevent disease during both short and long duration space missions. Video abstract.

Immune sensitization during 1 year in the Antarctic high-altitude Concordia Environment.

BACKGROUND: Antarctica is a challenging environment for humans. It serves as a spaceflight ground analog, reflecting some conditions of long-duration exploration class space missions. The French-Italian Concordia station in interior Antarctica is a high-fidelity analog, located 1000 km from the coast, at an altitude of 3232 m. The aim of this field study was to characterize the extent, dynamics, and key mechanisms of the immune adaptation in humans overwintering at Concordia for 1 year. METHODS: This study assessed immune functions in fourteen crewmembers. Quantitative and phenotypic analyses from human blood were performed using onsite flow cytometry together with specific tests on receptor-dependent and receptor-independent functional innate and adaptive immune responses. Transcriptome analyses and quantitative identification of key response genes were assessed. RESULTS: Dynamic immune activation and a two-step escalation/activation pattern were observed. The early phase was characterized by moderately sensitized global immune responses, while after 3-4 months, immune responses were highly upregulated. The cytokine responses to an ex vivo stimulation were markedly raised above baseline levels. These functional observations were reflected at the gene transcriptional level in particular through the modulation of hypoxia-driven pathways. CONCLUSIONS: This study revealed unique insights into the extent, dynamics, and genetics of immune dysfunctions in humans exposed for 1 year to the Antarctic environment at the Concordia station. The scale of immune function was imbalanced toward a sensitizing of inflammatory pathways.

Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions.

Recent studies have established that dysregulation of the human immune system and the reactivation of latent herpesviruses persists for the duration of a 6-month orbital spaceflight. It appears certain aspects of adaptive immunity are dysregulated during flight, yet some aspects of innate immunity are heightened. Interaction between adaptive and innate immunity also seems to be altered. Some crews experience persistent hypersensitivity reactions during flight. This phenomenon may, in synergy with extended duration and galactic radiation exposure, increase specific crew clinical risks during deep space exploration missions. The clinical challenge is based upon both the frequency of these phenomena in multiple crewmembers during low earth orbit missions and the inability to predict which specific individual crewmembers will experience these changes. Thus, a general countermeasure approach that offers the broadest possible coverage is needed. The vehicles, architecture, and mission profiles to enable such voyages are now under development. These include deployment and use of a cis-Lunar station (mid 2020s) with possible Moon surface operations, to be followed by multiple Mars flyby missions, and eventual human Mars surface exploration. Current ISS studies will continue to characterize physiological dysregulation associated with prolonged orbital spaceflight. However, sufficient information exists to begin consideration of both the need for, and nature of, specific immune countermeasures to ensure astronaut health. This article will review relevant in-place operational countermeasures onboard ISS and discuss a myriad of potential immune countermeasures for exploration missions. Discussion points include nutritional supplementation and functional foods, exercise and immunity, pharmacological options, the relationship between bone and immune countermeasures, and vaccination to mitigate herpes (and possibly other) virus risks. As the immune system has sentinel connectivity within every other physiological system, translational effects must be considered for all potential immune countermeasures. Finally, we shall discuss immune countermeasures in the context of their individualized implementation or precision medicine, based on crewmember specific immunological biases.

Alterations in hematologic indices during long-duration spaceflight.

BACKGROUND: Although a state of anemia is perceived to be associated with spaceflight, to date a peripheral blood hematologic assessment of red blood cell (RBC) indices has not been performed during long-duration space missions. METHODS: This investigation collected whole blood samples from astronauts participating in up to 6-months orbital spaceflight, and returned those samples (ambient storage) to Earth for analysis. As samples were always collected near undock of a returning vehicle, the delay from collection to analysis never exceeded 48 h. As a subset of a larger immunologic investigation, a complete blood count was performed. A parallel stability study of the effect of a 48 h delay on these parameters assisted interpretation of the in-flight data. RESULTS: We report that the RBC and hemoglobin were significantly elevated during flight, both parameters deemed stable through the delay of sample return. Although the stability data showed hematocrit to be mildly elevated at +48 h, there was an in-flight increase in hematocrit that was ~3-fold higher in magnitude than the anticipated increase due to the delay in processing. CONCLUSIONS: While susceptible to the possible influence of dehydration or plasma volume alterations, these results suggest astronauts do not develop persistent anemia during spaceflight.

Latent virus reactivation in astronauts on the international space station.

Reactivation of latent herpes viruses was measured in 23 astronauts (18 male and 5 female) before, during, and after long-duration (up to 180 days) spaceflight onboard the international space station . Twenty age-matched and sex-matched healthy ground-based subjects were included as a control group. Blood, urine, and saliva samples were collected before, during, and after spaceflight. Saliva was analyzed for Epstein-Barr virus, varicella-zoster virus, and herpes simplex virus type 1. Urine was analyzed for cytomegalovirus. One astronaut did not shed any targeted virus in samples collected during the three mission phases. Shedding of Epstein-Barr virus, varicella-zoster virus, and cytomegalovirus was detected in 8 of the 23 astronauts. These viruses reactivated independently of each other. Reactivation of Epstein-Barr virus, varicella-zoster virus, and cytomegalovirus increased in frequency, duration, and amplitude (viral copy numbers) when compared to short duration (10 to 16 days) space shuttle missions. No evidence of reactivation of herpes simplex virus type 1, herpes simplex virus type 2, or human herpes virus 6 was found. The mean diurnal trajectory of salivary cortisol changed significantly during flight as compared to before flight (P = 0.010). There was no statistically significant difference in levels of plasma cortisol or dehydoepiandosterone concentrations among time points before, during, and after flight for these international space station crew members, although observed cortisol levels were lower at the mid and late-flight time points. The data confirm that astronauts undertaking long-duration spaceflight experience both increased latent viral reactivation and changes in diurnal trajectory of salivary cortisol concentrations.

Three-dimensional organotypic co-culture model of intestinal epithelial cells and macrophages to study Salmonella enterica colonization patterns.

Three-dimensional models of human intestinal epithelium mimic the differentiated form and function of parental tissues often not exhibited by two-dimensional monolayers and respond to Salmonella in key ways that reflect in vivo infections. To further enhance the physiological relevance of three-dimensional models to more closely approximate in vivo intestinal microenvironments encountered by Salmonella, we developed and validated a novel three-dimensional co-culture infection model of colonic epithelial cells and macrophages using the NASA Rotating Wall Vessel bioreactor. First, U937 cells were activated upon collagen-coated scaffolds. HT-29 epithelial cells were then added and the three-dimensional model was cultured in the bioreactor until optimal differentiation was reached, as assessed by immunohistochemical profiling and bead uptake assays. The new co-culture model exhibited in vivo-like structural and phenotypic characteristics, including three-dimensional architecture, apical-basolateral polarity, well-formed tight/adherens junctions, mucin, multiple epithelial cell types, and functional macrophages. Phagocytic activity of macrophages was confirmed by uptake of inert, bacteria-sized beads. Contribution of macrophages to infection was assessed by colonization studies of Salmonella pathovars with different host adaptations and disease phenotypes (Typhimurium ST19 strain SL1344 and ST313 strain D23580; Typhi Ty2). In addition, Salmonella were cultured aerobically or microaerobically, recapitulating environments encountered prior to and during intestinal infection, respectively. All Salmonella strains exhibited decreased colonization in co-culture (HT-29-U937) relative to epithelial (HT-29) models, indicating antimicrobial function of macrophages. Interestingly, D23580 exhibited enhanced replication/survival in both models following invasion. Pathovar-specific differences in colonization and intracellular co-localization patterns were observed. These findings emphasize the power of incorporating a series of related three-dimensional models within a study to identify microenvironmental factors important for regulating infection.

Incidence of clinical symptoms during long-duration orbital spaceflight.

BACKGROUND: The environment of spaceflight may elevate an astronaut's clinical risk for specific diseases. The purpose of this study was to derive, as accurately as currently possible, an assessment of in-flight clinical "incidence" data, based on observed clinical symptoms in astronauts on board the International Space Station (ISS). METHODS: Electronic medical records were examined from 46 long-duration ISS crew members, each serving approximately a 6-month mission on board the ISS, constituting 20.57 total flight years. Incidence for immunological-related adverse health events or relevant clinical symptoms was tabulated in a non-identifiable fashion. Event categories included infectious diseases, allergies, and rashes/hypersensitivities. A subsequent re-evaluation of more notable events, either of prolonged duration or unresponsive to treatment, was performed. RESULTS: For the disease/symptom categories used in this evaluation, the ISS incidence rate was 3.40 events per flight year. Skin rashes were the most reported event (1.12/flight year) followed by upper respiratory symptoms (0.97/flight year) and various other (non-respiratory) infectious processes. During flight, 46% of crew members reported an event deemed "notable". Among the notable events, 40% were classified as rashes/hypersensitivities. Characterization of on-orbit rashes manifested as redness with irritation, and could present on a variety of body locations. CONCLUSION: Based on reported symptoms, astronauts experience adverse medical events of varying severity during long-duration spaceflights. The data suggests caution, from both a vehicle design and biomedical countermeasures perspective, as space agencies plan for prolonged deep space exploration missions.

Decreases in thymopoiesis of astronauts returning from space flight.

Following the advent of molecular assays that measure T cell receptor excision circles (TRECs) present in recent thymic emigrants, it has been conclusively shown that thymopoiesis persists in most adults, but that functional output decreases with age, influencing the maintenance of a diverse and functional T cell receptor (TCR) repertoire. Space flight has been shown to result in a variety of phenotypic and functional changes in human T cells and in the reactivation of latent viruses. While space flight has been shown to influence thymic architecture in rodents, thymopoiesis has not previously been assessed in astronauts. Here, we assessed thymopoiesis longitudinally over a 1-year period prior to and after long-term space flight (median duration, 184 days) in 16 astronauts. While preflight assessments of thymopoiesis remained quite stable in individual astronauts, we detected significant suppression of thymopoiesis in all subjects upon return from space flight. We also found significant increases in urine and plasma levels of endogenous glucocorticoids coincident with the suppression of thymopoiesis. The glucocorticoid induction and thymopoiesis suppression were transient, and they normalized shortly after return to Earth. This is the first report to our knowledge to prospectively demonstrate a significant change in thymopoiesis in healthy individuals in association with a defined physiologic emotional and physical stress event. These results suggest that suppression of thymopoiesis has the potential to influence the maintenance of the TCR repertoire during extended space travel. Further studies of thymopoiesis and endogenous glucocorticoids in other stress states, including illness, are warranted.

Evaluation of techniques for performing cellular isolation and preservation during microgravity conditions.

Genomic and epigenomic studies require the precise transfer of microliter volumes among different types of tubes in order to purify DNA, RNA, or protein from biological samples and subsequently perform analyses of DNA methylation, RNA expression, and chromatin modifications on a genome-wide scale. Epigenomic and transcriptional analyses of human blood cells, for example, require separation of purified cell types to avoid confounding contributions of altered cellular proportions, and long-term preservation of these cells requires their isolation and transfer into appropriate freezing media. There are currently no protocols for these cellular isolation procedures on the International Space Station (ISS). Currently human blood samples are either frozen as mixed cell populations (within the CPT collection tubes) with poor yield of viable cells required for cell-type isolations, or returned under ambient conditions, which requires timing with Soyuz missions. Here we evaluate the feasibility of translating terrestrial cell purification techniques to the ISS. Our evaluations were performed in microgravity conditions during parabolic atmospheric flight. The pipetting of open liquids in microgravity was evaluated using analog-blood fluids and several types of pipette hardware. The best-performing pipettors were used to evaluate the pipetting steps required for peripheral blood mononuclear cell (PBMC) isolation following terrestrial density-gradient centrifugation. Evaluation of actual blood products was performed for both the overlay of diluted blood, and the transfer of isolated PBMCs. We also validated magnetic purification of cells. We found that positive-displacement pipettors avoided air bubbles, and the tips allowed the strong surface tension of water, glycerol, and blood to maintain a patent meniscus and withstand robust pipetting in microgravity. These procedures will greatly increase the breadth of research that can be performed on board the ISS, and allow improvised experimentation by astronauts on extraterrestrial missions.

Post-Spaceflight (STS-135) Mouse Splenocytes Demonstrate Altered Activation Properties and Surface Molecule Expression.

Alterations in immune function have been documented during or post-spaceflight and in ground based models of microgravity. Identification of immune parameters that are dysregulated during spaceflight is an important step in mitigating crew health risks during deep space missions. The in vitro analysis of leukocyte activity post-spaceflight in both human and animal species is primarily focused on lymphocytic function. This report completes a broader spectrum analysis of mouse lymphocyte and monocyte changes post 13 days orbital flight (mission STS-135). Analysis includes an examination in surface markers for cell activation, and antigen presentation and co-stimulatory molecules. Cytokine production was measured after stimulation with T-cell mitogen or TLR-2, TLR-4, or TLR-5 agonists. Splenocyte surface marker analysis immediate post-spaceflight and after in vitro culture demonstrated unique changes in phenotypic populations between the flight mice and matched treatment ground controls. Post-spaceflight splenocytes (flight splenocytes) had lower expression intensity of CD4+CD25+ and CD8+CD25+ cells, lower percentage of CD11c+MHC II+ cells, and higher percentage of CD11c+MHC I+ populations compared to ground controls. The flight splenocytes demonstrated an increase in phagocytic activity. Stimulation with ConA led to decrease in CD4+ population but increased CD4+CD25+ cells compared to ground controls. Culturing with TLR agonists led to a decrease in CD11c+ population in splenocytes isolated from flight mice compared to ground controls. Consequently, flight splenocytes with or without TLR-agonist stimulation showed a decrease in CD11c+MHC I+, CD11c+MHC II+, and CD11c+CD86+ cells compared to ground controls. Production of IFN-γ was decreased and IL-2 was increased from ConA stimulated flight splenocytes. This study demonstrated that expression of surface molecules can be affected by conditions of spaceflight and impaired responsiveness persists under culture conditions in vitro.

Alterations in adaptive immunity persist during long-duration spaceflight.

BACKGROUND: It is currently unknown whether immune system alterations persist during long-duration spaceflight. In this study various adaptive immune parameters were assessed in astronauts at three intervals during 6-month spaceflight on board the International Space Station (ISS). AIMS: To assess phenotypic and functional immune system alterations in astronauts participating in 6-month orbital spaceflight. METHODS: Blood was collected before, during, and after flight from 23 astronauts participating in 6-month ISS expeditions. In-flight samples were returned to Earth within 48 h of collection for immediate analysis. Assays included peripheral leukocyte distribution, T-cell function, virus-specific immunity, and mitogen-stimulated cytokine production profiles. RESULTS: Redistribution of leukocyte subsets occurred during flight, including an elevated white blood cell (WBC) count and alterations in CD8+ T-cell maturation. A reduction in general T-cell function (both CD4+ and CD8+) persisted for the duration of the 6-month spaceflights, with differential responses between mitogens suggesting an activation threshold shift. The percentage of CD4+ T cells capable of producing IL-2 was depressed after landing. Significant reductions in mitogen-stimulated production of IFNγ, IL-10, IL-5, TNFα, and IL-6 persisted during spaceflight. Following lipopolysaccharide (LPS) stimulation, production of IL-10 was reduced, whereas IL-8 production was increased during flight. CONCLUSIONS: The data indicated that immune alterations persist during long-duration spaceflight. This phenomenon, in the absence of appropriate countermeasures, has the potential to increase specific clinical risks for crewmembers during exploration-class deep space missions.

Early adaption to the antarctic environment at dome C: consequences on stress-sensitive innate immune functions.

UNLABELLED: Abstract Feuerecker, Matthias, Brian Crucian, Alex P. Salam, Ales Rybka, Ines Kaufmann, Marjan Moreels, Roel Quintens, Gustav Schelling, Manfred Thiel, Sarah Baatout, Clarence Sams, and Alexander Choukèr. Early adaption in the Antarctic environment at Dome C: Consequences on stress-sensitive innate immune functions. High Alt Med Biol 15:341-348, 2014.-Purpose/Aims: Medical reports of Antarctic expeditions indicate that health is affected under these extreme conditions. The present study at CONCORDIA-Station (Dome C, 3233 m) seeks to investigate the early consequences of confinement and hypobaric hypoxia on the human organism. METHODS: Nine healthy male participants were included in this study. Data collection occurred before traveling to Antarctica (baseline), and at 1 week and 1 month upon arrival. Investigated parameters included basic physiological variables, psychological stress tests, cell blood count, stress hormones, and markers of innate immune functions in resting and stimulated immune cells. By testing for the hydrogen peroxide (H2O2) production of stimulated polymorphonuclear leukocytes (PMNs), the effects of the hypoxia-adenosine-sensitive immune modulatory pathways were examined. RESULTS: As compared to baseline data, reduced oxygen saturation, hemoconcentration, and an increase of secreted catecholamines was observed, whereas no psychological stress was seen. Upon stimulation, the activity of PMNs and L-selectin shedding was mitigated after 1 week. Endogenous adenosine concentration was elevated during the early phase. In summary, living conditions at high altitude influence the innate immune system's response. After 1 month, some of the early effects on the human organism were restored. CONCLUSION: As this early adaptation is not related to psychological stress, the changes observed are likely to be induced by environmental stressors, especially hypoxia. As hypoxia is triggering ATP-catabolism, leading to elevated endogenous adenosine concentrations, this and the increased catecholamine concentration might contribute to the early, but reversible downregulation of innate immune functions. This indicates the slope of innate immune adaptation to hypoxia.

Plasma cytokine concentrations indicate that in vivo hormonal regulation of immunity is altered during long-duration spaceflight.

Aspects of immune system dysregulation associated with long-duration spaceflight have yet to be fully characterized and may represent a clinical risk to crewmembers during deep space missions. Plasma cytokine concentration may serve as an indicator of in vivo physiological changes or immune system mobilization. The plasma concentrations of 22 cytokines were monitored in 28 astronauts during long-duration spaceflight onboard the International Space Station. Blood samples were collected 3 times before flight, 3-5 times during flight (depending on mission duration), at landing, and 30 days after landing. Analysis was performed by bead array immunoassay. With few exceptions, minimal detectable mean plasma concentrations were observed at baseline (launch minus 180) for innate inflammatory cytokines or adaptive regulatory cytokines; however, interleukin (IL)-1ra and several chemokines and growth factors were constitutively present. An increase in the plasma concentration, tumor necrosis factor-α (TNFα), IL-8, IL-1ra, thrombopoietin (Tpo), vascular endothelial growth factor (VEGF), C-C motif chemokine ligand 2 (CCL2), chemokine ligand 4/macrophage inhibitory protein 1b (CCL4), and C-X-C motif chemokine 5/epithelial neutrophil-activating protein 78 (CXCL5) was observed associated with spaceflight. No significant alterations were observed during or following spaceflight for the inflammatory or adaptive/T-regulatory cytokines: IL-1α, IL-1ß, IL-2, interferon-gamma (IFN-γ), IL-17, IL-4, IL-5, IL-10, G-CSF, GM-CSF, FGF basic, CCL3, or CCL5. This pattern of cytokine dysregulation suggests multiple physiological adaptations persist during flight, including inflammation, leukocyte recruitment, angiogenesis, and thrombocyte regulation.

Terrestrial stress analogs for spaceflight associated immune system dysregulation.

Recent data indicates that dysregulation of the immune system occurs and persists during spaceflight. Impairment of immunity, especially in conjunction with elevated radiation exposure and limited clinical care, may increase certain health risks during exploration-class deep space missions (i.e. to an asteroid or Mars). Research must thoroughly characterize immune dysregulation in astronauts to enable development of a monitoring strategy and validate any necessary countermeasures. Although the International Space Station affords an excellent platform for on-orbit research, access may be constrained by technical, logistical vehicle or funding limitations. Therefore, terrestrial spaceflight analogs will continue to serve as lower cost, easier access platforms to enable basic human physiology studies. Analog work can triage potential in-flight experiments and thus result in more focused on-orbit studies, enhancing overall research efficiency. Terrestrial space analogs generally replicate some of the physiological or psychological stress responses associated with spaceflight. These include the use of human test subjects in a laboratory setting (i.e. exercise, bed rest, confinement, circadian misalignment) and human remote deployment analogs (Antarctica winterover, undersea, etc.) that incorporate confinement, isolation, extreme environment, physiological mission stress and disrupted circadian rhythms. While bed rest has been used to examine the effects of physical deconditioning, radiation and microgravity may only be simulated in animal or microgravity cell culture (clinorotation) analogs. This article will characterize the array of terrestrial analogs for spaceflight immune dysregulation, the current evidence base for each, and interpret the analog catalog in the context of acute and chronic stress.