AUGUST 2014, N O 10
ISOPTWPO Today
Sally Kristen Ride,NASA ASTRONAUT (1951 - 2012) Sally Ride, the first American woman in space, started Sally Ride Science in 2001 to inspire young people-especially girls-to stick with their interest in science and to consider pursuing careers in science and engineering. She served as CEO of Sally Ride Science until her death on July 23, 2012, after a 17-month battle with pancreatic cancer.
Sally was finishing her Ph.D. in physics at Stanford University in 1977 when she answered a NASA newspaper ad seeking astronaut candidates. When she blasted off aboard the space shuttle Challenger on June 18, 1983, she became the first American woman-and, at 32, the youngest American-in space. Sally’s historic flight made her a symbol of the ability of women to break barriers and a hero to generations of adventurous young girls. She flew on Challenger again in 1984 and later was the only person to serve on both panels investigating the nation’s space shuttle disasters-the Challenger explosion in 1986 and the breakup of the shuttle Columbia on reentry in 2003. After retiring from NASA, Sally became a physics professor and an award-winning author of science books for children. She used her high profile to champion a cause she cared about passionately-igniting students’ enthusiasm for science and piquing their interest in careers in science, technology, engineering, and math. At Sally Ride Science, she guided the creation of innovative classroom programs, classroom materials, and professional development programs for teachers and students. — Image Credit:NASA
Human Space Flight Edition
Reactivation of latent viruses in Astronaut Decreased immunity has been observed in astronauts during short duration missions, as evident by the reactivation of latent herpes viruses.For many years, conclusions of immune status have been largely based on measurements taken before and after spaceflight and not during the flight phase itself, thus making it difficult to ascertain the effects of spaceflight independently from the stressors associated with landing and re-adaptation to the 1G environment. More recently, saliva sampling on orbit has made it possible to document latent viral reactivation as marker of systemic immune function during the flight phase.
During periods of reduced immunity, latent herpes viruses reactivate and shed in body fluids. Epstein-Barr virus (EBV), varicella-zoster virus (VZV) , and some other herpes viruses are released into saliva upon reactivation, while cytomegalovirus (CMV) is shed in urine following reactivation. A primary (first) CMV infection can cause serious disease in immunocompromised persons (meaning people with weakened immune systems), such as • Organ and bone marrow transplant recipients • Cancer patients • Patients receiving immunosuppressive drugs • HIV-infected patients Once a person has had a CMV infection, the virus stays in their body for life. The virus stays dormant (inactive) most of the time, but it can reactivate (become active again) and cause illness. Reactivation of a previous CMV infection is a more common problem for persons with weakened immune systems than primary infection since the majority of people are infected with CMV by the time they are 40 years old. Reactivation of these viruses has been largely asymptomatic, but clinical symptoms have resulted from VZV and herpes simplex virus type 1 reactivation. Increases in viral reactivation that are similar to spaceflight but smaller in magnitude have also been described in Antarctic expeditioners, aquanauts in an undersea habitat, and in other ground-based spaceflight analogs. Reactivation of viruses in Antarctica expeditioners The immune system is one of the major thrust areas in understanding the effects of adverse climatic conditions on human health. Exposure to the Antarctic environment, such as isolation, cold, UV radiations, magnetic field, blizzards, circadian biorhythms, and fear of the unknown, modify various components of the immune system. The study was performed on winter team members of the 28th Indian Scientific Expedition. In this study, different immunological parameters, which mainly include cytokines (TNF-a, IFN-γ, TGF-β, and IL-4), chemokine MIP-1a, immunoglobulins (IgA, IgM and IgG), cortisol and netrin-1, were assayed in sera by ELISA. Twenty-two members (all males) of the wintering team of the 28th Indian Scientific Expedition to Antarctica volunteered to participate in this study. Ages ranged from 25 to 60 years, with a mean age of 36 years. All had undergone predeparture clinical, psychological and laboratory examinations to ensure a healthy population for the isolation during the Antarctic stay. The study was conducted at the Indian Maitri research base, Antarctica. Blood was drawn from the expeditioners in October 2008 before leaving India to Antarctica, and in March, May, August and November 2009. None of the subjects had any signs or symptoms indicative of infection at the time of the study, nor had they used drugs that could significantly affect the immunological parameters. Informed consent was obtained from each of the subjects involved in the study.
Result Serum Cytokines TNF- α Levels Analysis of serum TNF-α in wintering expeditioners revealed that the mean baseline control level was 1.51 ± 1.5 pg/ml (Fig. 1a). After reaching Antarctica, the level significantly increased to 76 ± 6.4 pg/ml in March compared ISOPTWPO Today c International Space Agency(ISA)
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Human Space Flight Edition with the baseline level (p < 0.001). In May, it decreased to 66 ± 5.5 pg/ml but was significantly increased compared with the control level (p < 0.001). In August, the TNF-α level significantly decreased to 20 ± 3.4 pg/ml compared with March (p < 0.005) and May (p < 0.005) but remained significantly increased compared with the control level (p < 0.001). The level further significantly decreased to 7.32 ± 3.20 pg/ml in November compared with March (p < 0.001), May (p < 0.005) and August (p < 0.05).
Fig. 1. Sequential variation in serum TNF-α (a), IFN-γ (b) and TGF-β (c) levels in Indian Antarctic expeditioners before leaving India (control) and during their stay at Maitri, Antarctica, in March, May, August and November. Data are presented as means ± SEs. aa p < 0.005 March vs. August, b p < 0.001 March vs. November, c p < 0.001 control vs. March, d p < 0.001 control vs. May, e p < 0.005 May vs. August, f p < 0.005 May vs. November, g p < 0.001 control vs. August, and h p < 0.05 August vs. November. ba p < 0.005 control vs. March, b p < 0.001 March vs. August, c p < 0.001 March vs. November, d p < 0.005 control vs. May, e p < 0.001 May vs. August, f p < 0.001 May vs. November, g p < 0.05 control vs. August, and h p < 0.001 control vs. November. ca p < 0.005 March vs. May, b p < 0.05 March vs. August, c p < 0.01 control vs. May, d p < 0.01 control vs. August, e p < 0.05 May vs. August, f p < 0.05 control vs. November, g p < 0.005 May vs. November, and h p < 0.05 August vs. November. FN- γ Levels IFN- γ, a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control, was measured in the serum of expeditioners. The baseline control level of serum IFN- γ was 54 ± 5.2 pg/ml (Fig. 1b). The IFN- γ level was significantly increased to 92 ± 6.5 pg/ml in March (p < 0.005) compared with the control level. Further, in May, the level decreased to 83 ± 6 pg/ml compared with March but remained significantly higher than the control level (p < 0.005). However, in August, the IFN- γ level dramatically decreased to 18 ± 2.3 pg/ml, a significant decrease compared with the control level (p < 0.05), and the levels in March (p < 0.001) and May (p < 0.001). The level further decreased to 3.69 ± 2.12 pg/ml in November, a significant decrease compared with the control level (p < 0.001), and the levels in March (p < 0.001) and May (p < 0.001). IL-4 Levels The signature cytokine for Th2 immunity is IL-4; it was not detected at any time point of sampling in Indian Antarctic expeditioners (data not shown). TGF- β Levels The TGF- β level was 322 ± 32 pg/ml in the baseline control samples and was significantly decreased at each time point of sampling during the entire period of isolation (fig. 1c). In March, the level was 236 ± 16 pg/ml
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Human Space Flight Edition (p < 0.05 vs. control) and was further decreased to 63 ± 13 pg/ml in May (p < 0.001 vs. control, p < 0.005 vs. March). However, the level was significantly increased to 137 ± 21 pg/ml in August compared with May (p < 0.05) but it was significantly lower compared with March (p < 0.05). Furthermore, the level increased to 212 ± 33 pg/ml in November compared with August (p < 0.05) and May (p < 0.05). MIP-1α Levels MIP-1α, a chemokine generally involved in acute inflammatory states, was measured in the serum samples of Antarctic wintering personnel (Fig. 2). The baseline control level was 2.5 ± 1 pg/ml. It was observed that after reaching Antarctica, the levels initially increased significantly to 189 ± 16 pg/ml in March (p < 0.001) compared with the control level and then gradually decreased to 162 ± 16 pg/ml in May, but the level remained significantly higher compared with the control level (p < 0.001); the level further significantly decreased to 82 ± 10 pg/ml in August compared with March (p < 0.01) and May (p < 0.01) but remained significantly high compared with the control level (p < 0.01). Further, the levels were drastically reduced to 18 ± 7 pg/ml in November compared with March (p < 0.005), May (p < 0.005) and August (p < 0.005).
Fig. 2. MIP-1α level in Indian Antarctic expeditioners before leaving India (control) and during their stay at Maitri, Antarctica, in March, May, August and November. Data are presented as means ± SEs. a p < 0.001 control vs. March, b p < 0.01 March vs. August, c p < 0.005 March vs. November, d p < 0.001 control vs. May, e p < 0.01 May vs. August, f p < 0.005 May vs. November, g p < 0.01 control vs. August, h p < 0.05 August vs. November. Serum Immunoglobulins IgA Levels The concentrations of serum IgA at various time points are shown in Fig 3 a. It was observed that after reaching Antarctica, the IgA levels were significantly increased at all time points compared with baseline. The baseline control level of IgA, which was 607 ± 26 mg/dl, was significantly increased to 999 ± 29 mg/dl (p < 0.001) in March. It was further significantly increased to 1,188 ± 65 mg/dl (p < 0.001 vs. control) in May. However, the IgA level was decreased to 1,005 ± 41 mg/dl in August but remained significantly high compared with the control level (p < 0.001). It was further significantly decreased to 859 ± 25 mg/dl in November compared with March (p < 0.05), May (p < 0.05) and August (p < 0.05) but was significantly increased compared with the control level (p < 0.001). IgM Levels The concentrations of serum IgM were measured at different time points in Antarctic wintering personnel as shown in Fig3 b. No significant alteration was observed at any time point before leaving or during the Antarctic isolation. IgG Levels ISOPTWPO Today c International Space Agency(ISA)
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Human Space Flight Edition The concentrations of serum IgG at various time points are shown in Fig 3 c. The baseline value of IgG was 1,953 ± 54 mg/dl. It increased to 1,995 ± 46 and 2,046 ± 53 mg/dl in March and May, respectively. The IgG level significantly decreased to 1,830 ± 282 mg/dl in August compared with May (p < 0.05) and March. The level was further increased to 1,954 ± 28 mg/dl in November.
Fig. 3. Serum IgA ( a ), IgM ( b ) and IgG ( c ) levels in Indian Antarctic expeditioners before leaving India (control) and during their stay at Maitri, Antarctica, in March, May, August and November.Data are presented as means ± SEs. aa p < 0.001 control vs. March, b p < 0.05 March vs. November, c p < 0.001 control vs. May, d p < 0.05 May vs. November, e p < 0.001 control vs. August, f p < 0.05 August vs. November, g p < 0.001 control vs. November, and h p < 0.05 May vs. November. ca p < 0.05 May vs. August. Cortisol Level Cortisol, usually referred as ’stress hormone’, was measured in the serum samples of Antarctic wintering personnel at different time points ( Fig. 4 a). The baseline level of cortisol was 14.3 ± 1.24 µ g/dl and increased to 18.6 ± 2.4 and 19.6 ± 2.4 µ g/dl in March and May, respectively. The level further increased to 24 8 2 µ g/dl in August; this increase was significant compared with the control level (p < 0.05). However, in November, the level significantly decreased to 16.5 8 2.2 µ g/dl compared with August (p < 0.05). Netrin-1 Level Netrin-1, an anti-inflammatory neuronal guide molecule, was measured in the serum samples of Antarctic wintering personnel at different time points as shown in Fig 4 b. No significant alteration was observed at any time point. The netrin-1 level in the baseline control sample was 779 ± 101 pg/ml and decreased to 614 ± 100 pg/ml in March. This level increased to 742 ± 102 pg/ml in May and then decreased to 566 ± 80 pg/ml in August and increased to 821 ± 134 pg/ml in November. The level of the anti-inflammatory molecule netrin-1 was not significantly altered during the entire isolation period in Antarctica.
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Human Space Flight Edition
Fig. 4. Sequential variation in serum cortisol ( a ) and netrin-1 ( b ) levels in Indian Antarctic expeditioners before leaving India (control) and during their stay at Maitri, Antarctica, in March, May, August and November. Data are presented as means Âą SEs. aa p < 0.05 August vs. control, b p < 0.05 November vs. August. NASA 14 Day Undersea Missions: A Short-Duration Spaceflight Analog for Immune System Dysregulation
Spaceflight-associated immune dysregulation occurs during spaceflight and may represent specific clinical risks for exploration-class missions. An appropriate ground analog for spaceflight-associated immune dysregulation would offer a platform for ground evaluation of various potential countermeasures. This study evaluated the NASA Extreme Environment Mission Operations (NEEMO), consisting of 14 day undersea deployment at the Aquarius station, as an analog for SAID. Sixteen Aquanauts from missions NEEMO-12, 13 and 14 participated in the study. RESULTS Mid-mission alterations leukocyte distribution occured,including granulocytosis,elevated memeory T cells,CD8+ Tcells subsets,constitutively activated T cells(Figure 2). General T cell function was reduced during NEEMO mission in roughly 50% of subjects.Although the percentage of T cells secreting IFNg rose,the bulk production decline by MD11 . Production of several inflammatory cytokines rose during NEEMO missions(Figure 2).
Assuming R+7 to be the appropriate baseline: T cell production of IFNg,IL-5,IL-10,IL-2, TNFa and IL-6 were all reduced before and during the mission. Conversely,monocyte production of TNFa,IL-10,IL-6,IL-1b and IL-8 were elevated during mission,more so at the MD-14 time point(data not shown).
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Human Space Flight Edition Granulocyte adhesion molecule expression(e.g.CD11b,CD62L) as assessed in NEEMO-14 indicated high activation during mission(data not shown).
Antibodies to Epstein-Barr virus(EBV) viral capsid antigen and early antigen were increased in approximately 40 % of the subjects (Figure 4).
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Human Space Flight Edition
Changes in EBV tetramer-positive CD8+ T-cells exhibited a variable pattern.Antibodies against Cytomegalovirus(CMV) were marginally increased during the mission (Figure 4). Herpesvirus reactivation was determined by PCR.EBV viral load was generally elevated at L-6(Figure 4). Higher levels of EBV reactivation were found before and during the NEEMO mission (Figure 5),VZV reactivation occured in 2 NEEMO cremembers,no CMV reactivation was observed in any of the NEEMO mission or control samples (Table 1). Plasma cortisol was elevated at L-6.
Latent viral reactivation has been shown to occur prior to spaceflight, it is likely that increased hypothalamicpituitary-adrenocortical(HPA)-axis and the sympathetic nervous system (SNS) activity, and the resulting release of catecholamines and cortisol, compromise immune elements responsible for maintaining herpes viruses in a latent state. Schematic representation of the hypothalamic-pituitary-adrenal (HPA) axis. Hypophysiotropic neurons localized in the paraventricular nucleus (PVN) of the hypothalamus synthesize corticotropin-releasing factor (CRF) and vasopressin (AVP). In response to stress, CRF is released into hypophysial portal vessels that access the anterior pituitary ISOPTWPO Today c International Space Agency(ISA)
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Human Space Flight Edition gland. Binding of CRF to the CRF type 1 receptor (CRFR1) on pituitary corticotropes activates cyclic adenosine monophosphate (cAMP) pathway events that induce the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. In the presence of CRF, AVP elicits synergistic effects on ACTH release that are mediated through the vasopressin V1b receptor. Circulating ACTH binds to the melanocortin type 2 receptor (MC2-R) in the adrenal cortex where it stimulates glucocorticoid synthesis and secretion into the systemic circulation. Glucocorticoids regulate physiological events and inhibit further HPA axis activation (red lines) through intracellular receptors that are widely distributed throughout the brain and peripheral tissues. IP3, inositol triphosphate; DAG, diacylglycerol.
Cytokines are cell-signaling protein molecules that are critical to the development of both pro- and anti-inflammatory immune responses following infection or injury. Th1 immune responses involve the action of cytokines such as IL-2, IFN Îł, IL-12, and IL-17 that mostly stimulate cellular immunity and the involvement of CD4+ and CD8+ T-cells. Cytokines such as IL-4, IL-5, IL-10, and IL-13 are mostly responsible for stimulating Th2 humoral immune responses and the activation of antibody producing effector B-cells. Blood T-cells stimulated after spaceflight were found to have a lower IFN Îł:IL10 secretion ratio compared to pre-flight samples indicating that spaceflight is associated with a Th2 cytokine shift. However, it is not known if this cytokine shift compromises astronaut immunity or if it is associated with latent viral reactivation during flight. Seventeen astronauts (14 M, 3F) ranging in age from 36-59 and 10 age-matched healthy control subjects (6 M, ISOPTWPO Today c International Space Agency(ISA)
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Human Space Flight Edition 4F) were included in the study. The astronauts participated on a Space Shuttle mission of 9-14 days’ duration. Eight different shuttle missions were utilized to acquire the 17 participants. Ten healthy, age and gender matched subjects from the NASA Test Subject Facility were selected for ’controls’. All human study protocols used were approved by the Committee for the Protection of Human Subjects of the Johnson Space Center, Houston, TX, and informed consent was obtained from all subjects. All subjects included in the study were seropositive for EBV, VZV, and CMV. Results Latent virus reactivation Nine of 17 astronauts (virus shedders) shed one or more of the target viruses EBV, VZV, or CMV in their saliva (EBV and VZV) or urine (CMV) samples during, or after spaceflight (Table 2). In four of the nine virus shedding astronauts, a greater number of EBV copies (206-321 copies/ml saliva) was found in their saliva during spaceflight than after spaceflight (data not given in Table 2) . Varicella-zoster virus (VZV) was detected in saliva of five astronauts at R + 0 and in three astronauts by R + 3. CMV DNA was detected in the urine of two astronauts only at the R + 3 time point. None of the healthy controls shed CMV in their urine or VZV in saliva. EBV did not exceed basal levels (<40 copies/ml, as reported earlier in the healthy controls. The healthy controls were all considered ’non-virus shedding’ (data not shown). The eight astronauts who did not shed any of the three target viruses were designated ’non-virus shedders’.
Plasma cytokine levels Cytokines were analyzed in the categories of inflammatory cytokines( IL-1 α, IL-1 β, TNF α, IL-6, IL-8), lymphoid growth factors (IL-2,IL-7, IL-15), Th1/17 cytokines (IFN γ, IL-12, IL-17), Th2 cytokines (IL-4, IL-5, IL-10, IL-13), myeloid growth factors (G-CSF, GM-CSF), and chemokines (eotaxin, MCP-1, M1P1 α,IP-10). Mean values of plasma cytokines of astronauts at 120 days after landing (R + 120) did not differ from healthy, low-stress control subjects. The R + 120 values were designated as ’baseline’ values and were used for comparisons of all cytokines studied. Compared to baseline values, astronauts displayed significant increases in plasma IL-1 α , IL-6,IL-8, IFN γ, IL-4, eotaxin, and IP-10 at L-10 (Fig. 6). Of these, IL-6, IL-8, IL-4, eotaxin, and IP-10 also increased at R + 0 (p < 0.01). Plasma IL-4 was elevated 35-fold and 21-fold at L-10 and R + 0, respectively, whereas IFN γ was elevated only 2.7and 2.1-fold, respectively, over baseline values. These cytokines, except for IL-1α and IFN γ, also increased at R + 0. By R + 3 only IL-4, eotaxin, and IP-10 remained elevated.
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Human Space Flight Edition
At R + 120, all cytokines, except IL-4, continued to decrease to values not statistically different from the control subject values. Plasma cytokine levels of all 17 astronauts were also analyzed in the context of virus shedding: nine crew members shed one or more of the target viruses EBV, CMV, and VZV upon landing whereas the other eight crew members shed no virus. Since most of the viral shedding occurred only after flight at R + 0, cytokine levels at this time point were compared in shedders and non-shedders. In the shedding crew members, at R + 0 ten cytokines (IL-1 α , IL-6, IL-8, IFN γ , IL-12p70, IL-4, IL-10, IL-13, eotaxin, and IP-10) were significantly elevated (Fig. 7). An additional seven cytokines (IL β , IL-2, IL- 7, IL-15, G-CSF, GM-CSF, M1P-1α) were at least 2-fold (but not statistically significantly and not shown in Fig. 7) elevated in the virusshedding astronauts.
The single largest cytokine elevations in the virus-shedding crew members were IL-4 (21-fold increase) and IL-6 (33-fold increase). In non-shedding astronauts, at R + 0 only IL-4 and IP-10 levels were elevated over the control values. To document Th1-Th2 shift, the ratio of IFN γ : IL-4 was plotted (Fig. 8). There was a significant decrease in IFN γ: IL-4 in shedders compared to nonshedders. In addition, the cytokines that showed increase at R + 0 were also elevated at L-10 in shedders as compared to non-shedders. ISOPTWPO Today c International Space Agency(ISA)
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Human Space Flight Edition
Nine out of 17 astronauts shed at least one of the targeted herpes viruses (CMV, EBV or VZV) in response to flight (’shedders’) and also demonstrated greater elevations in 10 plasma cytokines (IL-1 α, IL-6, IL-8, IFN γ, IL-4, IL-10, IL-12, IL-13, eotaxin, and IP-10) compared to the non-shedders, who only exhibited elevations in IL-4 and IP-10 (Fig. 7). In virus shedders,plasma IL-4 (a Th2 cytokine) was elevated 21-fold at R + 0, whereas IFN γ (a Th1 cytokine) was elevated only 2-fold indicating a Th2 shift in response to spaceflight that was amplified in astronauts with a latent viral reactivation. The decrease in the ratio of IFN γ and IL-4 and was greater than the non-shedders emphasizing Th2 shift (Fig. 8). A Th1-Th2 cytokine shift has been previously reported in astronauts in both long and short-duration spaceflight missions . The shifts in plasma cytokines could be due to the aforementioned stressors associated with the spaceflight environment. Indeed, acute psychological stressors can directly provoke transient increases in circulating cytokines and are reported to cause a shift from a Th1 to a Th2 response associated with chronic stressors such as care giving . The stressors associated with the spaceflight environment could be responsible for the apparent Th2 shift observed in the astronauts. Moreover, because a reduction in the IFN-γ:IL-4 ratio was observed even before launch, acute and chronic stress levels may be the major contributing factors to spaceflight-induced immune dysfunction, at least during shortduration missions to Earth’s orbit. Reactivation of herpes simplex virus (HSV) type 1, EBV, VZV, and CMV is a frequent occurrence during and after short-duration spaceflight . Although the precise molecular mechanism for reactivation of latent herpes viruses is unknown, numerous studies have demonstrated that reactivation commonly follows stress-related reductions in immunity . The viral and immunological findings associated with spaceflight best fits the model of reduced activity of cytotoxic T-cells due to stress induced activation of the HPA-axis and the SNS. Many substances can activate the stress response and IL-1, TNF-alpha and IL-6 are among the most important. They can act independently or in concert. The 33-fold increase in IL-6 levels of virus shedders along with substantially increased IL-1 likely exhibited strong stimulation of HPA-axis and SNS. Indeed, it has been shown previously that elevations in plasma IL-6 are accompanied with human herpes virus-6 reactivation in transplant recipients, indicating that IL-6 may be involved in the pathogenesis of latent viral reactivation. The precise molecular mechanism of virus reactivation is not known. However, the reactivation of HSV-1, EBV, CMV, and VZV in astronauts is consistent with the classic HPA-axis and SNS pathways for processing stress. The unique ISOPTWPO Today c International Space Agency(ISA)
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Human Space Flight Edition stressors associated with human spaceflight results in activation of the HPA axis and the SNS resulting in the release of glucocorticoids and catecholamines into circulation. The higher levels of stress hormones reduce immune elements responsible for controlling latency resulting in virus reactivation. The reactivation of latent viruses during spaceflight is most likely due to alterations in CD8+ T-cell and regulatory T-cell function responsible for maintaining viral latency. Latent viral reactivation in astronauts is associated with shifts toward a Th-2 cytokine balance in response to shortduration spaceflight missions.
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Human Space Flight Edition Reference: 1.Pierson DL, Mehta SK, Stowe RP. Reactivation of latent herpes viruses in astronauts. Psychoneuroimmunology 2007;4 E II:851-68. 2.Pierson DL, Stowe RP, Phillips TM, Lugg DJ, Mehta SK. Epstein-Barr virus shedding by astronauts during space flight. Brain Behav Immun 2005;19:235-42. 3.Mehta SK, Cohrs RJ, Forghani B, Zerbe G, Gilden DH, Pierson DL. Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J Med Virol 2004;72:174-9. 4.Mehta SK, Stowe RP, Feiveson AH, Tyring SK, Pierson DL. Reactivation and shedding of cytomegalovirus in astronauts during spaceflight. J Infect Dis 2000;182:1761-4. 5.Mehta SK, Crucian B, Pierson DL, Sams C, Stowe RP. Monitoring immune system function and reactivation of latent viruses in the artificial gravity pilot study. J Gravit Physiol 2007;14:P21-25. 6.Mehta SK, Pierson DL, Cooley H, Dubow R, Lugg D. Epstein-Barr virus reactivation associated with diminished cellmediated immunity in antarctic expeditioners. J Med Virol 2000;61:235-40. 7.Grigorâ&#x20AC;&#x2122;ev, A.I., Noskov, V.B., Polyakov, V.V., et al., Dynamics of the Reactivity of the System of Hormonal Regulation on Exposure to ODNT during a Long-Term Space Flight, Aviakosmich. Ekol. Med., 1998, no. 3, p. 18. 8.Anand Prakash Yadav, Kamla Prasad Mishra, Lilly Ganju, Shashi Bala Singh.Wintering in Antarctica: Impact on Immune Response of Indian Expeditioners.Neuroimmunomodulation 2012;19:327-333. 9.B. E. Crucian, R. P. Stowe, S. K. Mehta, M. Feuerecker, A. Choukèr, H. Quiriarte,D. L. Pierson and C. F. Sams.NASA 14 Day Undersea Missions: A Short-Duration Spaceflight Analog for Immune System Dysregulation.18th IAA Humans in Space Symposium (2011). 10.Pierson DL, Stowe RP, Phillips TM, Lugg DJ, Mehta SK. Epstein-Barr virus shedding by astronauts during space flight. Brain Behav Immun 2005;19:235-42. 11.S.K. Mehta , B.E. Crucian , R.P. Stowe , R.J. Simpson , C.M. Ott , C.F. Sams , D.L. Pierson.Reactivation of latent viruses is associated with increased plasma cytokines in astronauts.Cytokine 61 (2013).
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ISOPTWPO The ISOPTWPO is 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. Ad Astra ! To The Stars! In Peace For All Mankind ! Mr. Rick R. Dobson, Jr.(Veteran U.S Navy) â&#x20AC;&#x201D; International Space Agency (ISA)
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