Immobilization induces a very rapid increase in osteoclast activity

We studied in a randomized, strictly controlled cross-over design, the effects of 6 days 6 degrees head-down tilt bed rest (HDT) in eight male healthy subjects in our metabolic ward. The study consisted of two periods (phases) of 11 days each in order to allow for the test subjects being their own controls. Both study phases were identical with respect to environmental conditions, study protocol and diet. Two days before arriving in the metabolic ward the subjects started with a diet. The diet was continued in the metabolic ward. The metabolic ward period (1l days) was divided into three parts: 4 ambulatory days, 6 days either HDT or control and 1 recovery day. Continuous urine collection started on the first day in the metabolic ward to analyze calcium excretion and bone resorption markers. On the 2nd ambulatory day in the metabolic ward and on the 5th day in HDT or control blood was drawn to analyze serum calcium, parathyroid hormone, and bone formation markers. Urinary calcium excretion was, as early as the first day in immobilization, increased (p<0.01). CTX- and NTX-excretion stayed unchanged in the first 24 h in HDT compared to the control. But already on the 2nd day of immobilization, both bone resorption markers significantly increased. We conclude from these results--pronounced rise of bone resorption markers--that already 24 h of immobilization induce a significant rise in osteoclast activity in healthy subjects. Thus, it appears possible to use short-term bed rest studies as a first step for the development of countermeasures to immobilization.     

Effect of a venotonic agent on the main arteries and veins during a 5 day HDT.

Objective: To evaluate the cardiac, arterial and venous effect of a venotonic drug (Cirkan "Ck") administrated orally daily to 6 subjects in HDT position during 5 days. These subjects underwent a second 5d HDT without Ck treatment one month later. Pre and post HDT the subjects were submitted to a stand test. Method: The cardiovascular parameters were measured by echography and Doppler. Results and discussion: The Cirkan treatment contributed to reduce the increase in cerebral resistance, and to maintain the lower limb resistance at a higher level than on controls. It reduces the vein section at the extremities (Jugular, femoral) and in the central vein system connected to the right heart (sub hepatics). On the other hand it increases the portal vein section which means that the blood stagnation at the splanchnic level is increased. Despite these arterial and venous significant modifications the clinical and ECG and Blood pressure response to the Stand test was similar in both groups.     

Dynamic change of ERPs related to selective attention to signals from left and right visual field during head-down tilt

To study further the effect of head-down tilt (HDT) on slow positive potential in the event-related potentials (ERPs), the temporal and spatial features of visual ERPs changes during 2 hour HDT (-10 degrees) were compared with that during HUT (+20 degrees) in 15 normal subjects. The stimuli were consisted of two color LED flashes appeared randomly in left or right visual field (LVF or RVF) with same probability. The subjects were asked to make switch response to target signals (T) differentially: switching to left for T in LVF and to right for T in RVF, ignoring non-target signals(N). Five sets of tests were made during HUT and HDT. ERPs were obtained from 9 locations on scalp. The mean value of the ERPs in the period from 0.32-0.55 s was taken as the amplitude of slow positive potential(P400). The main results were as follows. 1) The mean amplitude of P400 decreased during HDT which was more significant at the 2nd, 3rd and 5th set of tests; 2) spatially, the reduction of mean P400 amplitude during HDT was more significant for signals from RVF and was more significant at posterior and central brain regions than that on frontal locations. As that the positive potential probably reflects the active inhibition activity in the brain during attention process, these data provide further evidence showing that the higher brain function was affected by the simulated weightlessness and that this effect was not only transient but also with interesting spatial characteristics.     

Efficacy of periodic centrifugation of primates during 4-week head-down tilt.

Creation of artificial force of gravity (AFG) to counteract the negative consequences of microgravity in manned space missions of extended duration is one of the high-priority problems of space biology and medicine. However, there are a number of especial effects of AFG (namely, structural changes in muscles and bones, and some other system) which need implantation of electrodes and sensors and are possible only with animals. That is why it is of particular interest to make studies with monkeys whose reactions to changed gravity bear much resemblance with human. The purpose of the investigation was development of a protocol of periodic gravity loads as a counter-measure against the hypokinetic syndrome in Macaca mulatta. Two series of experiments were performed. In the series, animals were split into two groups of 6 species each who were motor restrained with the head end tilted downward at 5 degrees (HDT) for 28 days. Monkeys of group-2 were periodically subjected to centrifugation (HDT+G). During the first series of experiments rotation was conducted in the +Gz direction at g-loads from 1.2 to 1.6 units for 30-40 minutes 4-5 times a week. In the second series, g-load was equal to 1.2 units and the animals were rotated 30 min. 2-3 time a week. The criterion of Y-training protocol efficacy was a test +Gz run at 3 units for 30 s. during which functioning of the cardiovascular systems and its controls was evaluated. The test run was performed prior to and after HDT. Following HDT the animals of group HDT+G were more resistant to the test than their counterparts who had not been trained on the centrifuge. Data of the investigation imply that following HDT and HDT+G alike reduced the amount of total bodily fluids (by approximately 5%), the intracellular component (approximately 4%), and plasma volume (by 6-7%). Yet, there are radical differences between the groups in the levels of reduction in extracellular fluids (by 11% and 6.5%, respectively, P<0.05) and the interstitial component (by 11.5% and 6.5, respectively, P<0.05). Prophylactic centrifugation during HDT was also positive to the muscular blood flow in lower extremities.     

Gender differences in organ density in a rat simulated microgravity model

Research investigating the physiological effects of microgravity on the human body has demonstrated a shift of body fluids in actual spaceflight and in simulated Earth-based microgravity models in both males and females, possibly causing many deleterious physiological effects. Twenty-five anatomically normal female (NF) and 20 ovariectomized (OE) Fischer 344 rats were randomly selected to be in an experimental (1 h of 45 degrees head-down tilt, 45HDT) or control (1 h of prone position) group. At the end of the hour experimental period, the density of the brain, lungs, heart, liver, and left and right kidneys were measured using spiral computed tomography (SCT) while the rats remained in their experimental positions. A sub-group of OE rats (N=6) was administered estrogen replacement therapy on a daily basis (5 micrograms/kg body weight, s.c.) for 4 days and then underwent 1 h of 45HDT and SCT analysis at one day, 2 days, and 5 days to determine if estrogen replacement therapy would alter organ densities. Our data demonstrate that 1 h of 45HDT produced significant increases (p<0.05) in the organ densities of the brain, liver, left kidney, and lung of the OE female group compared to their prone controls. However, only the brain density was significantly increased in the NF group. Estrogen replacement therapy caused a significant decrease in brain organ density at the 5 day time point compared to the 24 h time point. We conclude that estrogen plays a role in fluid distribution in a rat 45HDT model.     

Effect on the cardiac function of repeated LBNP during a 1-month head down tilt

Cardiovascular assessment by ultrasound methods was performed during two long duration (1 month) Head Down Tilt (HDT) on 6 healthy volunteers. On a first 1 month HDT session, 3 of the 6 subjects (A, B, C) had daily several lower body negative pressure tests (LBNP), whereas the 3 subjects remaining (D, E, F) rested without LBNP. On a second 1 month HDT session subjects D, E, and F had daily LBNP tests and the A, B and C subjects did not. The cardiac function was assessed by Echocardiography, (B mode, TM mode). On all the "6 non LBNP" subjects the left ventricule diastolic volume (LVDV), the stroke volume (SV) and the cardiac output (CO) increase (+10%, -15%) after HDT then decrease and remain inferior (-5%, -5%) or equal to the basal value during the HDT. Immediately after the end of the HDT the heart rate (HR) increase (+10%, +30%) whereas the cardiac parameters decrease weakly (-5%, -10%) and normalize after 3 days of recovery. On the "6 LBNP" subjects the LVDV, SV and CO increase (+10%, 15%) after 1 h HDT as in the previous group then decrease but remain superior (+5%, +15%) or equal to the basal value. After the HDT session, the HR is markedly increased (+20%, +40%) the LVDV and SV decrease (-15%, -20%) whereas the CO increases or decreases depending on the amplitude of the HR variations. These parameters do not completely normalize after 3 day's recovery. Repeated LBNP sessions have a significant effect on the cardiovascular function as it maintains all cardiac parameters above the basal value. The LBNP manoeuvre can be considered as an efficient countermeasure to prevent cardiac disadaptation induced by HDT position and probably microgravity.     

Effects of 12 days exposure to simulated microgravity on central circulatory hemodynamics in the rhesus monkey

Central circulatory hemodynamic responses were measured before and during the initial 9 days of a 12-day 10 degrees head-down tilt (HDT) in 4 flight-sized juvenile rhesus monkeys who were surgically instrumented with a variety of intrathoracic catheters and blood flow sensors to assess the effects of simulated microgravity on central circulatory hemodynamics. Each subject underwent measurements of aortic and left ventricular pressures, and aortic flow before and during HDT as well as during a passive head-up postural test before and after HDT. Heart rate, stroke volume, cardiac output, and left ventricular end-diastolic pressure were measured, and dP/dt and left ventricular elastance was calculated from hemodynamic measurements. The postural test consisted of 5 min of supine baseline control followed by 5 minutes of 90 degrees upright tilt (HUT). Heart rate, stroke volume, cardiac output, and left ventricular end-diastolic pressure showed no consistent alterations during HDT. Left ventricular elastance was reduced in all animals throughout HDT, indicating that cardiac compliance was increased. HDT did not consistently alter left ventricular +dP/dt, indicating no change in cardiac contractility. Heart rate during the post-HDT HUT postural test was elevated compared to pre-HDT while post-HDT cardiac output was decreased by 52% as a result of a 54% reduction in stroke volume throughout HUT. Results from this study using an instrumented rhesus monkey suggest that exposure to microgravity may increase ventricular compliance without alternating cardiac contractility. Our project supported the notion that an invasively-instrumented animal model should be viable for use in spaceflight cardiovascular experiments to assess potential changes in myocardial function and cardiac compliance.     

Changes in organ perfusion and weight ratios in post-simulated microgravity recovery

Head-down tilt models have been used as ground-based simulations of microgravity. Our previous animal research has demonstrated that there are significant changes in fluid distribution within 2 h after placement in a 45 degrees head-down tilt (45HDT) position and these changes in fluid distribution were still present after 14 days of 45HDT. Consequently, we investigated changes in fluid distribution during recovery from 16 days of 45HDT. Changes in radioactive tracer distribution and organ/body weight ratio were examined in rats randomly assigned to a 45HDT or prone control group. The 45HDT rats were suspended for 16 days and then allowed to recover at the prone position 0, 77, 101, or 125 h post-suspension. Animals were injected with technetium-labeled diethylenetriamine pentaacetate (99mTcDTPA, MW=492 amu, physical half-life of 6.02 h) and then killed 30 min post-injection. Lungs, heart, liver, spleen, kidneys, and brain were harvested, weighed, and measured for radioactive counts. Statistical analyses included two-way analysis of variance (ANOVA) that compared 45HDT versus controls at the four experimental time points. The organ weight divided by the body weight ratio for the brain, heart, kidneys and liver in the 45HDT rats was significantly different than the control rats, regardless of time (treatment). There was no difference between the different time points (time). The average 99mTcDTPA count divided by the organ weight ratio values for the heart, liver, and spleen were significantly higher in the 45HDT group than the control group. The average counts for the heart and spleen were significantly higher at 77, 101, and 125 h than at time zero. We conclude that the major organs have different recovery patterns after 45HDT for 16 days in the rat.     

Impaired T-wave amplitude adaptation to heart-rate induced by cardiac deconditioning after 5-days of head-down bed-rest

The study of QT/RR relationship is important for the clinical evaluation of possible risk of acquired or congenital ventricular tachyarrhythmias. In the hypothesis that microgravity exposure could induce changes in the repolarization mechanisms, our aim was to test if a short 5-days strict 6° head-down bed-rest (HDBR) could induce alterations in the QT/RR relationship and spatial repolarization heterogeneity. Twenty-two healthy men (mean age 31±6) were enrolled as part of the European Space Agency HDBR studies. High fidelity (1000 Hz) 24 h Holter ECG (12-leads, Mortara Instrument) was acquired before (PRE), the last day of HDBR (HDT5), and four days after its conclusion (POST). The night period (23:00–06:30) was selected for analysis. X, Y, Z leads were derived and the vectorcardiogram computed. Selective beat averaging was used to obtain averages of P–QRS–T complexes preceded by the same RR (10 ms bin amplitude, in the range 900–1200 ms). For each averaged waveform (i.e., one for each bin), T-wave maximum amplitude (Tmax), T-wave area (Tarea), RTapex, RTend, ventricular gradient (VG) magnitude and spatial QRS-T angle were computed. Non-parametric Friedman test was applied. Compared to PRE, at HDT5 both RTapex and RTend resulted shortened (−4%), with a decrease in T-wave amplitude (−8%) and area (−13%). VG was diminished by 10%, and QRS-T angle increased by 14°. At POST, QT duration and area parameters, as well as QRS-T angle were restored while Tmax resulted larger than PRE (+5%) and VG was still decreased by 3%. Also, a marked loss in strength of the linear regression with RR was found at HDT5 in Tmax and Tarea, that could represent a new dynamic marker of increased risk for life-threatening arrhythmias. Despite the short-term HDBR, ventricular repolarization during the night period was affected. This should be taken into account in astronauts for risk assessment during space flight.     

Early renal changes in 45 degrees HDT rats

Background: Both microgravity and simulated microgravity models, such as the 45HDT (45 degrees head-down tilt), cause a redistribution of body fluids indicating a possible adaptive process to the microgravity stressor. Understanding the physiological processes that occur in microgravity is a first step to developing countermeasures to stop its harmful effects, i.e., (edema, motion sickness) during long-term space flights. Hypothesis: Because of the kidneys' functional role in the regulation of fluid volume in the body, it plays a key role in the body's adaptation to microgravity. Methods: Rats were injected intramuscularly with a radioactive tracer and then lightly anesthetized in order to facilitate their placement in the 45HDT position. They were then placed in the 45HDT position using a specially designed ramp (45HDT group) or prone position (control group) for an experimental time period of 1 h. During this period, the 99mTc-DTPA (technetium-labeled diethylenepentaacetate, MW=492 amu, physical half-life of 6.02 h) radioactive tracer clearance rate was determined by measuring gamma counts per minute. The kidneys were then fixed and sectioned for electron microscopy. A point counting method was used to quantitate intracellular spaces of the kidney proximal tubules. Results: 45HDT animals show a significantly (p=0.0001) increased area in the interstitial space of the proximal tubules. Conclusions: There are significant changes in the kidneys during a 1 h exposure to a simulated microgravity environment that consist primarily of anatomical alterations in the kidney proximal tubules. The kidneys also appear to respond differently to the initial periods of head-down tilt.     

The effect of head-down tilt on brain potentials related to visual attention

To study the possible effect of simulated weightlessness on brain function state, the brain event-related potentials (ERPs) in a simple visual selective response task were compared between HDT and HUT in 9 normal subjects. The results were: The Target(T) and non-Target(NT) flash signals both induced significant slow positive potentials which were supposed to related to the attention state; the amplitude of the positive potentials in frontal regions decreased significantly especially for NT-ERPs during HDT comprared with that during HUT. The data reported provide new evidence indicating that more attention should be paid on the brain function study during space flight.     

Human thermohomeostasis onboard "Mir" and in simulated microgravity studies.

Significant changes of thermogomeostatic parameters was obtained by thermotopometric method using the techniques simulate of microgravity effects: bed rest, pressurized isolation, suit immersion (SI). However, each of ground models made rectal temperature (T) trend downward. The autothermometric study (24 and 12 sessions, 2-13th and 6-174th flight days) was carried out onboard "Mir" by two flight engineers who had preliminary tested at SI (1-2 days). Studies of German investigators onboard "Mir" confirmed: rectal T must be higher in space flight as compared to the normal environment (n=4). Comparative studies suggest that microgravity is a key factor for the human body surface T raise and abolishment of the external/internal T-gradient. T-homeostasis was not really changing during missions and could be regarded as acute effect of microgravity. After delineation of changes in body surface T--by Carnot's thermodynamic law--rectal T raise should have been anticipated. Facts pointing to the excess entropy of human body must not be passed over.     

Autonomic regulation of circulation and cardiac contractility during a 14-month space flight

The space flight of physician cosmonaut V.V. Polyakov, the longest to date (438 days), has yielded new data about human adaptation to long-term weightlessness. Autonomic regulation of circulation and cardiac contractility were evaluated in three experiments entitled Pulstrans, Night, and Holter. In the Pulstrans experiment electrocardiographic (ECG), ballistocardiographic (BCG), seismocardiographic (SCG), and some other parameters were recorded. In the Night experiment, only the ballistocardiogram was recorded, but a special feature of this experiment is that the BCG records were obtained with a contactless method. This method has several advantages, the most important of which are the possibility of studying slow-wave variations in physiologic parameters (ultradian rhythms) on the basis of recordings made under standard conditions over a prolonged period. The Holter experiment (24-hour electrocardiographic monitoring) used a portable cardiorecorder (Spacelab, USA). The obtained electrocardiographic data were used to analyze heart rate variability. In the first 6 months of the 14-month flight, the dynamics of cardiovascular parameters in V.V. Polyakov was virtually the same as in the other cosmonauts. The data obtained after the first 6 months of Polyakov's sojourn in space are unique and mention should be made of at least three important aspects: (1) activation of a new, additional adaptive mechanism in the 8th-9th months of flight, as is evidenced by alterations in the periodicity and power of superslow wave oscillations (ultradian rhythms) reflecting the activity of the subcortical cardiovascular centers and of the higher levels of autonomic regulation; (2) growth of cardiac contractility accompanied by a decrease in heart rate during the last few months of flight; (3) a considerable increase in the daily average values of absolute power of heart rate's variability MF component, which reflects the activity of the vasomotor center. Specific mechanisms of adaptation to weightless conditions appear to be associated with activation of higher autonomic centers. The hypothesis that central levels of circulation regulation are activated in a long-term space flight was investigated by analyzing of ultradian rhythms in nighttime. The data, received during the flight of V. V. Polyakov, show, that the process of human adaptation to long influence of weightlessness consists of a number of consecutive stages, during which the activation of more and more high levels of control system of physiological functions occurs.     

Positive pressure breathing by total body negative pressure: a new simulation model for fluid balance in weightlessness?

A systems study is proposed to explore correctly the effects of the combination of HDT (Head Down Tilt) and TBNP (Total Body Negative Pressure).     

Evaluation of spontaneous baroreflex response after 28 days head down tilt bedrest

The spontaneous baroreflex response was evaluated during supine rest and head up tilt (60 degrees) before and immediately after a 28 day 6 degrees HDT bedrest in 6 healthy adult men (age 30-42 years). Sequences of 3 or more beats where RR-interval and systolic blood pressure changed in the same direction were used to evaluate baroreflex response slope (BRS). Prior to bedrest, the mean BRS and RR-interval were 18.0 +/- 3.9 ms/mm Hg and 926 +/- 61 ms at rest and 10.5 +/- 2.5 ms/mm Hg and 772 +/- 63 ms during the first 10 min of 60 degrees tilt. Following bedrest, these values changed to 15.6 +/- 2.7 ms/mm Hg and 780 +/- 53 ms at rest, and to 6.5 +/- 1.2 ms/mm Hg and 636 +/- 44 ms during tilt. Thus, (1) the spontaneous baroreflex can be evaluated in human subjects during experiments of orthostatic stress; (2) the baroreflex slope was reduced on going from supine to the head up tilt position; and (3) 28 days of bedrest reduced the spontaneous baroreflex slope.     

Central and regional hemodynamics in prolonged space flights.

This paper presents the results of measuring central and regional (head, forearm, calf) hemodynamics at rest and during provocative tests by the method of tetrapolar rheography in the course of Salyut-6-Soyuz and Salyut-7-Soyuz missions. The measurements were carried out during short-term (19 man-flights of 7 days in duration) and long-term (21 man-flights of 65-237 days in duration) manned missions. At rest, stroke volume (SV) and cardiac output (CO) as well as heart rate (HR) decreased insignificantly (in short-term flights) or remained essentially unchanged (in long-term flights). In prolonged flights CO increased significantly in response to exercise tests due to an increase in HR and the lack of changes in SV. After exercise tests SV and CO decreased as compared to the preflight level. During lower body negative pressure (LBNP) tests HR and CO were slightly higher than preflight. Changes in regional hemodynamics included a distinct decrease of pulse blood filling (PBF) of the calf, a reduction of the tone of large vessels of the calf and small vessels of the forearm. Head examination (in the region of the internal carotid artery) showed a decrease of PBF of the left hemisphere (during flight months 2-8) and a distinct decline of the tone of small vessels, mainly, in the right hemisphere. During LBNP tests the tone of pre- and postcapillary vessels of the brain returned to normal while PBF of the right and left hemisphere vessels declined. It has been shown that regional circulation variations depend on the area examined and are induced by a rearrangement of total hemodynamics of the human body in microgravity. This paper reviews the data concerning changes in central and regional circulation of men in space flights of different duration.     

Exobiological investigations on Russian spacecrafts

To investigate the possibility of prebiotic synthesis of organic molecules in open space, conditions involved irradiating nucleosides and inorganic phosphate during five Earth-orbiting Russian space missions that included Salut-7 (13- and 16-month missions), Mir, Bion-11, and Cosmos-2044. Dry films of samples were exposed from 2 weeks up to 16 months to the entire set of factors encountered in open space during Earth-orbiting missions. After each mission, products synthesized during flight and any compounds that remained undegraded were analyzed. The analyses demonstrated that increased flight duration led to the decay of both synthesized nucleotides and initial nucleosides. Corresponding laboratory experiments indicated that infrared radiation caused the greatest amount of decay to products of prebiotic reactions. Experiments revealed that 5'-mononucleotides were the main chemical products of the major derivatives synthesized of certain nucleosides. Exposure to ultraviolet (UV) C(145) was more effective than UVC(254) in producing a comparatively higher yield of mononucleotides, while the energy flux of the latter was one order of magnitude less (10(-7) as compared with 10(-6) for UVC(145)). In the course of the laboratory simulation experiments the heating of solid samples yielded the greatest production amount (6.34% for adenosine derivatives).     

Cardiovascular effects of simulated zero-gravity in humans

Head-down and head-up [correction of heat-up] tilted bedrest (5 degrees) and head out water immersion (HOWI) for 6 hr were compared. Parameters: Cardiac output (rebreathing method), blood pressure (arm cuff), forearm blood flow (venous occlusion plethysmography), total peripheral (TPR), and forearm vascular (FVR) resistances, Hct, Hb, relative plasma volume (PV) changes, and plasma catecholamines (single-isotope assay). During HOWI there was as expected a decrement in TPR, FVR, Mean arterial pressure (MAP, from 100 to 80 mmHg), Hct, and PV, and--as a new finding--catecholamines, which were 30-50% lower compared with both +5 and -5 degrees bedrest. During head down tilt, MAP was elevated (to 100-110 mmHg) and catecholamines did not fall, while TPR and EVR slowly decreased over 6 hr. HOWI is a stronger stimulus than -5 degrees bedrest, probably because HOWI elevates central venous pressure more markedly emptying the peripheral veins, while bedrest permits a distension of veins, which induces an increase in sympathetic nervous activity.     

Configuration studies for active electrostatic space radiation shielding

Developing successful and optimal solutions to mitigating the hazards of severe space radiation in deep space long duration missions is critical for the success of deep-space explorations. Space crews traveling aboard interplanetary spacecraft will be exposed to a constant flux of galactic cosmic rays (GCR), as well as intense fluxes of charged particles during solar particle events (SPEs). A recent report (Tripathi et al., Adv. Space Res. 42 (2008) 1043–1049), had explored the feasibility of using electrostatic shielding in concert with the state-of-the-art materials shielding technologies. Here we continue to extend the electrostatic shielding strategy and quantitatively examine a different configuration based on multiple toroidal rings. Our results show that SPE radiation can almost be eliminated by these electrostatic configurations. Also, penetration probabilities for novel structures such as toroidal rings are shown to be substantially reduced as compared to the simpler all-sphere geometries. More interestingly, the dimensions and aspect ratio of the toroidal rings could be altered and optimized to achieve an even higher degree of radiation protection.