Early immune anergy towards recall antigens and mitogens in patients at onset of septic shock

The pathology of sepsis is typically characterized by an infection and excessive initial inflammation including a cytokine storm, followed by a state of immune suppression or paralysis. This classical view of a two peak kinetic immune response is currently controversially discussed. This study was a sub-study of the randomized clinical Trial SISPCT registered with www. clinicaltrials. gov (NCT00832039, Registration date: 29/01/2009). Blood samples from 76 patients with severe sepsis and septic shock were incubated for 48 h at 37 degrees C in vitro with bacterial or fungal recall-antigens or specific mitogen antigens within 24 hours of sepsis onset. Recall-antigen stimulation led to a severe dampening of normal cytokine release. This immunologic anergy was similarly observed after mitogen stimulation. Moreover, patients under hydrocortisone therapy or with lowered arterial oxygen tension had further reductions in cytokine levels upon B- and T-cell mitogen stimulation. This investigation reveals an early onset of immunoparalysis during sepsis. This immune incompetence in mounting an adequate response to further infections includes previously sensitized pathogens, as seen with recall- antigens. Also, the immune-suppressive role of hydrocortisone and low PaO2 is highlighted. Aside from early broad-spectrum antimicrobial therapy, our findings reinforce the need for maximal immunological support and protection against further infections at the onset of sepsis

Cells' Flow and Immune Cell Priming under alternating g-forces in Parabolic Flight

Gravitational stress in general and microgravity (mu g) in particular are regarded as major stress factors responsible for immune system dysfunction in space. To assess the effects of alternating mu g and hypergravity (hyper-g) on immune cells, the attachment of peripheral blood mononuclear cells (PBMCs) to adhesion molecules under flow conditions and the antigen-induced immune activation in whole blood were investigated in parabolic flight (PF). In contrast to hyper-g (1.8 g) and control conditions (1 g), flow and rolling speed of PBMCs were moderately accelerated during mu g-periods which were accompanied by a clear reduction in rolling rate. Whole blood analyses revealed a "primed" state of monocytes after PF with potentiated antigen-induced pro-inflammatory cytokine responses. At the same time, concentrations of anti-inflammatory cytokines were increased and monocytes displayed a surface molecule pattern that indicated immunosuppression. The results suggest an immunologic counterbalance to avoid disproportionate immune responses. Understanding the interrelation of immune system impairing and enhancing effects under different gravitational conditions may support the design of countermeasures to mitigate immune deficiencies in space

Human Factors Engineering Activities for Past, Present and Future Manned Space Habitats

Space is an extreme and hostile environment for human life and launching the man out of the Earth’s gravity, keeping him safe and functional in space, entails a lot of work and money. Human spaceflights represent a techno-logical challenge and the design and implementation of manned space habitats and work environment require knowledge and expertise to create habitats for mission scenarios that, for the future space missions, are not currently well known. The present International Space Station (ISS) is born on the experiences matured on the heritage of past space stations (Salyut, Skylab, Mir). The design solutions implemented on the ISS are therefore based on Human Factors Engineering (HFE) requirements developed from past experiences. From late eighties as of today, Thales Alenia Space in Italy has developed about fifty percent of the pressurized volume of the ISS, providing the permanent modules Node 2, Node 3, Cupola, Permanent Multipurpose Module (PMM), Columbus and the logistic Multi-Purpose Logistics Modules (MPLM), Automated Transfer Vehicles (ATV), Cygnus. In all these modules Thales Alenia Space in Italy implemented HFE activities based on a human-centered design approach (driving the design, providing analysis, evaluation and usability verification of crew interfaces for work areas and equipment) aimed to guarantee a safe performance of all the on board crew operations, including displays and controls, workstation systems or evaluation of the entire spacecraft cabin or module habitable volume. The future of space exploration will passes through: (1) the extension of life of the ISS until 2024, exploiting it as test bench for future exploration missions and then as private and commercial orbital infrastructures; (2) the Chinese Space Station, that started its life in 2011 and will reach its full operability around 2022; (3) new commercial and independent stations in Low Earth Orbit (LEO) and then from LEO to (4) Cislunar and deep space stations, including planetary outposts (Moon and Mars). This paper describes how the HFE activities have been performed for the ISS manned modules orbiting around the Earth and, thanks to the experience gained on the ISS, how they may be developed to physically and psychologically counteract the effects of a long stay period in space to suit future long duration spaceflights

PlanHab study: assessment of psycho-neuroendocrine function in male subjects during 21 d of normobaric hypoxia and bed rest

Immobilization and hypoxemia are conditions often seen in patients suffering from severe heart insufficiency or primary pulmonary diseases (e.g. fibrosis, emphysema). In future planned long-duration and exploration class space missions (including habitats on the moon and Mars), healthy individuals will encounter such a combination of reduced physical activity and oxygen tension by way of technical reasons and the reduced gravitational forces. These overall unconventional extraterrestrial conditions can result in yet unknown consequences for the regulation of stress-permissive, psycho-neuroendocrine responses, which warrant appropriate measures in order to mitigate foreseeable risks. The Planetary Habitat Simulation Study (PlanHab) investigated these two space-related conditions: bed rest as model of reduced gravity and normobaric hypoxia, with the aim of examining their influence on psycho-neuroendocrine responses. We hypothesized that both conditions independently increase measures of psychological stress and enhance neuroendocrine markers of stress, and that these effects would be exacerbated by combined treatment. The cross-over study composed of three interventions (NBR, normobaric normoxic horizontal bed rest; HBR, normobaric hypoxic horizontal bed rest; HAMB, normobaric hypoxic ambulatory confinement) with 14 male subjects during three sequential campaigns separated by 4 months. The psychological state was determined through three questionnaires and principal neuroendocrine responses were evaluated by measuring cortisol in saliva, catecholamine in urine, and endocannabinoids in blood. The results revealed no effects after 3 weeks of normobaric hypoxia on psycho-neuroendocrine responses. Conversely, bed rest induced neuroendocrine alterations that were not influenced by hypoxia

Habitability Issues in Long Duration Space Missions Far from Earth

Living in space today means to stay at an altitude of about 400 km above the Earth surface, on the orbital International Space Station (ISS). In the ‘70s the man reached the Moon but a manned space exploration mission, beyond low Earth orbit and cislunar space, might significantly increase adverse psychophysical effects on human wellbeing. Nowadays, a manned mission to deeper space, such as for example to Mars, is one of the greatest psychological challenge that has never been faced by the humankind. Due to the enormous distance between Earth and Mars, astronauts sent to Mars will be the first human beings who will lose a direct visual link with their Home Planet. Human responses to this and other extreme conditions that might be encountered during long duration missions into deep space are still unknown. In addition, the acute and long term effects of altered gravitational input on the central nervous system and their impact on sensorimotor and cognitive functions need to be clarified to assure maximum performance capabilities during spaceflight and planetary explorations. Our current knowledge on psychological and cognitive effects of orbital spaceflights or analogue environments is not sufficient to reliably assess the specific risks of human mission into outer space. New psychological challenges of mission to Mars will be analyzed with respect to three different areas: individual response and small crew interactions in isolated, confined, and extreme environments (ICE); human adaptation and performance in different gravity environments; concept and methods of psychological countermeasures. The needs of crew members to effectively and safely live and work in space are now referred to missions orbiting around the Earth and have been managed through specific human factors requirements applicable to the ISS. Future manned exploration missions need to reinforce these requirements to design an environment suitable for a safe stay during manned space missions far from Earth. The recommendations of astronauts who have experienced long term stays in space are collected and analyzed to be translated into requirements to be implemented in future space habitats. The analysis of what we have now and what is thought to be relevant to ensure crew wellbeing and performance during long term stays in space is a critical step to assure the success of deep space human missions

Sex differences in stress and immune responses during confinement in Antarctica

Abstract Background Antarctica challenges human explorers by its extreme environment. The effects of these unique conditions on the human physiology need to be understood to best mitigate health problems in Antarctic expedition crews. Moreover, Antarctica is an adequate Earth-bound analogue for long-term space missions. To date, its effects on human physiology have been studied mainly in male cohorts though more female expeditioners and applicants in astronaut training programs are selected. Therefore, the identification of sex differences in stress and immune reactions are becoming an even more essential aim to provide a more individualized risk management. Methods Ten female and 16 male subjects participated in three 1-year expeditions to the German Antarctic Research Station Neumayer III. Blood, saliva, and urine samples were taken 1–2 months prior to departure, subsequently every month during their expedition, and 3–4 months after return from Antarctica. Analyses included cortisol, catecholamine and endocannabinoid measurements; psychological evaluation; differential blood count; and recall antigen- and mitogen-stimulated cytokine profiles. Results Cortisol showed significantly higher concentrations in females than males during winter whereas no enhanced psychological stress was detected in both sexes. Catecholamine excretion was higher in males than females but never showed significant increases compared to baseline. Endocannabinoids and N-acylethanolamides increased significantly in both sexes and stayed consistently elevated during the confinement. Cytokine profiles after in vitro stimulation revealed no sex differences but resulted in significant time-dependent changes. Hemoglobin and hematocrit were significantly higher in males than females, and hemoglobin increased significantly in both sexes compared to baseline. Platelet counts were significantly higher in females than males. Leukocytes and granulocyte concentrations increased during confinement with a dip for both sexes in winter whereas lymphocytes were significantly elevated in both sexes during the confinement. Conclusions The extreme environment of Antarctica seems to trigger some distinct stress and immune responses but—with the exception of cortisol and blood cell counts—without any major relevant sex-specific differences. Stated sex differences were shown to be independent of enhanced psychological stress and seem to be related to the environmental conditions. However, sources and consequences of these sex differences have to be further elucidated

Five days of head-down-tilt bed rest induces noninflammatory shedding of L-selectin

Head-down-tilt bed rest (HDTBR) is a popular model, simulating alterations of gravitation during space missions. The aim of this study was to obtain a better insight into the complexly orchestrated regulations of HDTBR-induced immunological responses, hypothesizing that artificial gravity can mitigate these HDTBR-related physiological effects. This crossover-designed 5 days of HDTBR study included three protocols with no, or daily 30 min of centrifugation or 6 X 5 min of centrifugation. Twelve healthy, male participants donated blood pre-HDTBR, post-HDTBR, and twice during HDTBR. Cellular immune changes were assessed either by enumerative and immune cell phenotyping assays or by functional testing of responses to either recall antigens or receptor-dependent activation by chemotactic agents N-formyl-methionyl-leucyl-phenylalanine (fMLP) and with TNF-alpha. The expression of the adhesion molecule L-selectin (CD62L) on the surface of granulocytes and its shedding into plasma samples were measured. In parallel, other humoral factor, such as interleukin-6 and interleukin-8, parameters of endothelial damage (glycocalyx) were determined. Hematocrit and hemoglobin were significantly increased during HDTBR. Although immune functional tests did not indicate a change in the immune performance, the expression of CD62L on resting granulocytes was significantly shed by 50% during HDTBR. Although the latter is normally associated to an activation of inflammatory innate immune responses and during interaction of granulocytes with the endothelium, CD62L shedding was, however, not related either to a systemic inflammatory alteration or to shedding of the endothelial glycocalyx during bed rest. This suggests a noninflammatory or "mechanical" shedding related to fluid shifts during head-down intervention and not to an acute inflammatory process

Cells' Flow and Immune Cell Priming under alternating g-forces in Parabolic Flight

Gravitational stress in general and microgravity (mu g) in particular are regarded as major stress factors responsible for immune system dysfunction in space. To assess the effects of alternating mu g and hypergravity (hyper-g) on immune cells, the attachment of peripheral blood mononuclear cells (PBMCs) to adhesion molecules under flow conditions and the antigen-induced immune activation in whole blood were investigated in parabolic flight (PF). In contrast to hyper-g (1.8 g) and control conditions (1 g), flow and rolling speed of PBMCs were moderately accelerated during mu g-periods which were accompanied by a clear reduction in rolling rate. Whole blood analyses revealed a &quot;primed&quot; state of monocytes after PF with potentiated antigen-induced pro-inflammatory cytokine responses. At the same time, concentrations of anti-inflammatory cytokines were increased and monocytes displayed a surface molecule pattern that indicated immunosuppression. The results suggest an immunologic counterbalance to avoid disproportionate immune responses. Understanding the interrelation of immune system impairing and enhancing effects under different gravitational conditions may support the design of countermeasures to mitigate immune deficiencies in space.</p