Space Medicine: Scientific Foundations, Achievements, and Challenges.

This article, based on a report presented at the Scientific Session of the Russian Academy of Sciences, highlights the history of the formation of space medicine, its theoretical foundations, and the role of scientists of the Academy of Sciences in the preparation and implementation of the first manned flight into space. The achievements of domestic specialists in space physiology, biology, and medicine promoting the development of manned cosmonautics are considered. Examples are given of the implementation of the results of space research, as well as instruments and devices for medical support of space crews, into practical health care. The problems of medical support of future interplanetary flights and the ways of their solution are analyzed.

[Galactic heavy charged particles damaging effect on biological structures].

A concept of the radiation risk of the manned interplanetary flights is proposed and substantiated. Heavy charged particles that are a component of the galactic cosmic rays (GCR) have a high damaging effect on the biological structures as great amount of energy is deposited in heavy particle tracks. The high biological effectiveness of heavy ions is observed in their action on cell genetic structures and the whole organism, including the brain structures. The hippocampus is the part of the central nervous system that is the most sensitive to radiation--first of all, to heavy charged particles. Irradiation of animals with accelerated iron ions at doses corresponding to the real fluxes of GCR heavy nuclei, to which Mars mission crews can be exposed, leads to marked behavioral function disorders in the post-irradiation period. To evaluate the radiation risk for the interplanetary flight crews, the concept of successful mission accomplishment is introduced. In these conditions, the central nervous system structures can be the critical target of GCR heavy nuclei. Their damage can modify the higher integrative functions of the brain and cause disorders in the crew members' operator performances.

[The role of spinal motoneurons in the mechanisms of hypogravitational motor syndrome development].

Studies results of gravity unloading influence on spinal control system of muscle structure and functions are summarized. It was shown that demyelization of axons due to reduction of genes expression responsible for myelin proteins synthesis, decrease in one of the key enzymes of cholinergic system--cholineacetyltransferase activity, alteration of normal kinetics of quantal and non-quantal neurotransmitter secretion, impaired autoregulation of acetylcholine secretion from motor nerve endings through presynaptic cholinergic receptors, slowing of axonal transport of substances in motor neurons that innervate postural muscles played the important role in the development of hypogravitational motor symptoms. At the same time, the evidences of neuroprotective mechanisms enclosing (increase in heat shock proteins Hsp25 and Hsp70 expression), that hinder apoptosis development in motor neurons and glial cells in the spinal cord under conditions of model hypogravity, were revealed.

[The formation of the urine proteome in healthy human].

In the review it was represented the modern ideas on the processes involved in the formation of the protein composition of the urine of healthy people. In the last decade the development of highly sensitive mass spectrometric methods for the detection of proteins has given impetus to the study of the protein composition of human body fluids, including urine. Modern methods of separation of complex protein mixtures and determination of the individual components of these mixtures that are used in proteomics, can detect in urine significant number of proteins and peptides of different origin. Little-known, but very important problem for biomedical research is a physiological variation of the protein composition of urine revealed by proteomics. Under physiological conditions, there are many factors that affect the filtration of plasma proteins in the glomeruli and reabsorption in the proximal tubules of the nephron. These include hypoxia, oxidative stress, changes in acid-base balance and blood pressure, the effects of parathyroid hormone, angiotensin-II and other regulators of water and electrolyte metabolism. It is shown that the close structural and functional relationship of processes of reabsorption in the proximal tubules of the nephron causes dependence modulation of sodium reabsorption, water, chloride, phosphate, bicarbonate, and changes in the various parts of the process of re-absorption of the protein.

[Functional load tests for the investigation of the kidneys and water-electrolyte metabolism].

The paper deals with the application of functional load tests to assess the renal function and water-salt metabolism in human subjects during spaceflight simulating experiments and in cosmonauts in orbit and in the course of postflight recovery. The tests gave insight into mechanisms of the osmotic and volumetric regulation systems and enabled the development upon this knowledge of countermeasures to correct shifts in water-salt homeostasis.

[Light-isotope water as a therapeutic agent for acute radiation disease].

Eighty outbred CD-I male and female mice (initial body mass of 31-34 g) and 40 male Wistar rats (initial body mass of 280-360 g) were randomly distributed into the experimental and control groups by sex and body mass. According to the results of experiments, consumption of rectified light-isotope water over 30 days immediately after irradiation by gamma-quanta 60Co at 5 Gy and 6.5 Gy can increase survivability rate significantly, accelerate hemopoiesis recovery and prevent body mass loss in irradiated animals. Therefore, light-isotope water can be considered as an effective agent for treatment of the bone marrow syndrome.

[Changes in titin and myosin heavy chain isoform composition in skeletal muscles of Mongolian gerbil (Meriones unguiculatus) after 12-day spaceflight].

Changes of titin and myosin heavy chain isoform composition in skeletal muscles (m. soleus, m. gastrocnemius, m. tibialis anterior, m. psoas major) in Mongolian Gerbil (Meriones unguiculatus ) were investigated after 12-day spaceflight on board of Russian space vehicle "Foton-M3". In m. psoas and m. soleus in the gerbils from "Flight" group the expected increase in the content of fast myosin heavy chain isoforms (IIxd and IIa, respectively) were observed. No significant differences were found in the content of IIxd and IIa isoforms of myosin heavy chain in m. tibialis anterior in the gerbils from control group as compared to that in "Flight" group. An unexpected increase in the content of slow myosin heavy chain I isoform and a decrease in the content of fast IIx/d isoform in m. gastrocnemius of the gerbils from "Flight" group were observed. In skeletal muscles of the gerbils from "Flight" group the relative content of titin N2A-isoform was reduced (by 1,2-1,7 times), although the content of its NT-isoform, which was revealed in striated muscles of mammals in our experiments earlier, remained the same. When the content of titin N2A-isoform was decreased, no predictable abnormalities in sarcomeric structure and contractile ability of skeletal muscles in the gerbils from "Flight" group were found. An assumption on the leading role of titin NT-isoform in maintenance of structural and functional properties of striated muscles of mammals was made.

[The impact of oxygen tension in physiological regulation of human multipotent mesenchymal stromal cell functions].

The significant progress in the clarification of cellular mechanisms governing tissue homeostasis and physiological remodeling was achieved in recent decades. Undifferentiated cells such as multipotent mesenchymal stromal (stem) cells (MMSCs) play an important role in these processes. MMSCs reside in virtually all postnatal organs and tissues occupying a specific tissue niche associated with the perivascular spaces. The most important property of MMSCs is, on the one hand, their ability to provide structural integrity of tissues and on the other - to respond on paracrine stimuli and migrate into the site of injury, promoting the tissue repair. The main feature of the MMSC physiological and regenerative milieu is a low oxygen tension, which can significantly modify the properties ofstromal cells. This review is concerned with analysis of the recent data on the MMSC tissue niches in terms of integration of these cells into the comprehensive physiological and reparative tissue remodeling and the role of the partial oxygen pressure in the realization of MMSCs.

[New approaches to therapy of persistent infections: elimination of intracellular Chlamydai trachomatis by exposure to low temperature argon plasma].

AIM: Study microbicidal activity of low temperature argon plasma (LTP) that is a stream of partially ionized argon having macroscopic temperature of the environment against Chlamydia trachomatis obligate intracellular parasites. Study viability of host cells in parallel. MATERIALS AND METHODS: McCoy line cells infected with C. trachomatis (Bu-434/L2 strain) were exposed to LTP obtained by using atmospheric pressure plasma SHF generator. Intracellular localization of chlamydiae was visualized by luminescent microscopy. RESULTS: Exposure of infected McCoy line cells resulted in the destruction of chlamydia inclusions and practically complete elimination of intracellular bacteria. At the same time LTP exposure did not result in immediate death of host cells, an insignificant reduction of the number of cells was observed 24 hours after the exposure to LTP. CONCLUSION: The effect of LTP for elimination of intracellular chlamydia without significant changes in viability of eukaryotic host cells was demonstrated.

['Translational medicine as a way from fundamental biomedical science to public health services].

Increasing distance between practical public health services and collecting of theoretical information in the field of biomedical researches reflects the necessity of professional contact between clinicians and scientists in many areas associated with medicine for active carrying over ("translation") of the modern basic researches in which mechanisms of basic metabolic processes and possibilities of their correction are detected, to effective medical help to individual patient, i.e., personified medicine. Such approach was called transmitting medicine. Examples of the personified medicine in which biomedical researches together with the anamnesis morbi of individual patient that are responsible for treatment strategy including doses and regimens are discussed.

[Mechanisms of natural variability at adaptation of human physiological systems to conditions of space flight].

This article analyzes the physiological data using the principle of invariant relationships, to reveal the mechanisms of adaptive variability. It was used physical-chemical, biochemical, and hormonal blood parameters of cosmonauts who have committed short-term and long space flights. These results suggest that application of the methods of fractal geometry to quantitative estimates of homeostasis allows to allocate the processes depending on the increase/decrease of adaptive variability and fix the state of stability or instability of certain physiological regulatory subsystems, due to mobility and to reduce the level of stability which remains stable internal structure of relationships throughout the body.

[Mechanisms of human osteopenia and some peculiarities of bone metabolism in weightlessness conditions].

Systematically results and new analysis data on the investigation of human bone system in space flight, the orbital station Mir and International Space Station, are presented. The bone mineral density, bone mineral content, identified as bone mass and body composition using dual energy X-ray absorptiometry were measured. Theoretically, an expected bone mass loss in trabecular tissue of lower skeletal half may by described as a quickly developing but reversible osteopenia and considered as evidence of functional adaptation of bone tissue to the changing mechanical load. A hypothesis of main mechanisms of osteopenia in microgravity is presented. High individual variability of bone mass losses and stability of individual pattern of correlation between bone mass losses in different skeletal segments were found. It is not possible to identify the relationship between bone mass losses and duration of space missions. Therefore it is not a sufficient ground to calculate the probability of reaching the critical level of bone demineralization by prolonged space flight. The same relates to the probability of prognosis of bone quality changes. There is data about dual energy X-ray absorptiometry that is insufficient for this prognosis. The main direction of investigations is presented which might optimize the interplanetary mission from the point of view of skeletal mechanical functions preservation.

[Dynamics of heart rate changes in rats following stepwise change of treadmill running speed].

Amplitude and temporal responses of heart rate to stepwise increase or decrease of treadmill running intensity were investigated in rats. Heart rate amplitude response was shown to be connected mainly with the change of sympathetic nervous activity whereas heart rate temporal response was shown to be determined predominantly by parasympathetic cardiotrophic influences.

[Prospects for the use of low-temperature gas plasma as an antimicrobial agent].

Results of application of LTP at atmospheric pressure as an antibacterial agent during the last decade are considered with reference to physicochemical mechanisms of its bactericidal action. The principles of designing modern LTP sources are described in conjunction with the results of LTP application against pathogenic bacteria in vitro and in biofilms. The possibility to destroy biofilm matrix by LTP is estimated along with the results of its testing for the treatment of acute and chronic wound surfaces. Prospects for the development of "plasma medicine" in this country and abroad are discussed with special emphasis on its advantages, such as the absence of long-acting toxic compounds, small probability of spontaneous mutations accounting for resistance to LTP, relatively low cost of LTP sources, independence of LTP effect of the surface relief, painless application.

[From the flight of Iu. A. Gagarin to the contemporary piloted space flights and exploration missions].

The first human flight to space made by Yu. A. Gagarin on April 12, 1961 was a crucial event in the history of cosmonautics that had a tremendous effect on further progress of the human civilization. Gagarin's flight had been prefaced by long and purposeful biomedical researches with the use of diverse bio-objects flown aboard rockets and artificial satellites. Data of these researches drove to the conclusion on the possibility in principle for humans to fly to space. After a series of early flights and improvements in the medical support system space missions to the Salyut and Mir station gradually extended to record durations. The foundations of this extension were laid by systemic researches in the fields of space biomedicine and allied sciences. The current ISS system of crew medical care has been successful in maintaining health and performance of cosmonauts as well as in providing the conditions for implementation of flight duties and operations with a broad variety of payloads. The ISS abounds in opportunities of realistic trial of concepts and technologies in preparation for crewed exploration missions. At the same, ground-based simulation of a mission to Mars is a venue for realization of scientific and technological experiments in space biomedicine.

Mechanisms of gravitational sensitivity of osteogenic precursor cells.

This report is a detailed review of the current data on the mechanic and gravitational sensitivity of osteoblasts and osteogenic precursor cells in vitro. It summarizes the numerous responses of cells with an osteoblastic phenotype and osteogenic precursor cells and especially their responses to the alteration of their mechanic or gravitational surroundings. The review also discusses the osteogenic cell's pathways of signal transduction and the mechanisms of gravitational sensitivity. It was shown that the earliest multipotent stromal precursor cells of an adult organism's bone marrow can sense changes of intensity in a gravitational or mechanic field in model conditions, which may play a certain role in the development of osteopenia in microgravity.

[Molecular mechanisms of stress adaptation: immediate early genes].

Immediate early gene (IEG) expression is the important part of adaptive reactions caused by short-term high-intensity physical activities. IEG leads to activation of transcription, protein neo-synthesis and form-specific stress response. We were looking for human body physical exercise adaptation leukocytes IEG expression markers. Gene expression profiles were measured using microarray technology and validated by real time PCR. In this study, we describe several cell stress adaptation regulators groups: stress response, splicing and cell signaling.