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.

Psychoneuroendocrine alterations during 5 days of head-down tilt bed rest and artificial gravity interventions.

This study aimed to investigate psychological stress and endocrine responses during 5 days of head-down tilt bed rest (HDTBR) with or without the impact of artificial gravity (AG). Participants were assigned to one of three bed-rest-protocols either with (i) no centrifugation, (ii) continuous 30 min (AG1) or (iii) discontinuous 6 × 5 min (AG2) centrifugation periods at 1G in the center of mass periods. Centrifugations were performed daily in one session. Questionnaires for assessing psychological stress and the corresponding biological sample collection were performed before, during and after HDTBR or centrifugation. Overall, questionnaires showed no significant changes of anxiety or emotional stress during HDTBR. In the AG1-group, salivary cortisol levels were significantly higher after centrifugation irrespective of the progress of the HDTBR and day of intervention. The AG2-group showed higher cortisol concentrations after centrifugation only on the first days of head-down tilt but no more on day 5 of HDTBR. During bed rest, urine epinephrine excretion increased in all groups, but showed the highest day concentrations in the AG1-group, which were also significantly higher when compared with AG2. These results indicate that 5 days of HDT alone is not a major stressor and accordingly resulted only in moderate changes of neuroendocrine responses over time. However, daily centrifugation for a continuous duration of 30 min induced a significant neuroendocrine response, which was not subject to a habituation as compared with daily but intermittent centrifugation for 6 × 5 min. Discontinuous centrifugation is better tolerated and associated with lower adrenocortical stress responses during HDTBR.

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

Gravitational stress in general and microgravity (µg) in particular are regarded as major stress factors responsible for immune system dysfunction in space. To assess the effects of alternating µg 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 µg-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.

PlanHab Study: Consequences of combined normobaric hypoxia and bed rest on adenosine kinetics.

Adenosine plays a role in the energy supply of cells and provokes differential, hormone-like functions in circulating cells and various tissues. Its release is importantly regulated by oxygen tension. This renders adenosine and its kinetics interesting to investigate in humans subjected to low oxygen conditions. Especially for space exploration scenarios, hypoxic conditions - together with reduced gravity - represent two foreseen living conditions when planning manned long-duration space missions or planetary habitats. The PlanHab study investigated microgravity through inactivity in bed rest and normobaric hypoxia to examine their independent or combined effect on adenosine and its kinetics. Healthy male subjects (n = 14) completed three 21-day interventions: hypoxic bed rest (HBR); hypoxic ambulatory confinement (HAMB); normoxic bed rest (NBR). The interventions were separated by 4 months. Our hypothesis of a hypoxia-triggered increase in adenosine was confirmed in HAMB but unexpectedly also in NBR. However, the highest adenosine levels were noted following HBR. Furthermore, the percentage of hemolysis was elevated in HBR whereas endothelial integrity markers stayed low in all three interventions. In summary, these data suggest that neocytolysis accounts for these effects while we could reduce evidence for microcirculatory changes.

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 × 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-α. 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.

Physician referrals in a competitive environment. An estimate of the economic impact of a referral.

Beyond offering optimum care for individual patients, physician referrals have a cumulative economic impact on many components of the broader medical care system. This article offers an approximation of the magnitude of that impact. By retrospectively reviewing financial records associated with 225 referrals from fee-for-service, rural family practice sites to university-based specialist colleagues, we found that the average referral generated $2944 in combined hospital charges and professional fees within a six-month period after referral. Almost half (110/225, or 49%) of those referrals resulted in a hospital admission and 72% of all revenue associated with referral accrued to the hospital. A second and more detailed study of 97 referrals showed that only 18% of total revenue resulting from referrals accrued to the physician to which the patient was initially referred. We argue that control over volume and destination of referrals, historically the referring physician's prerogative, is susceptible to change in our rapidly restructuring medical care system. In the future, no economic entity that benefits from physician referrals should take for granted those referrals or their impact.