Towards human exploration of space: the THESEUS review series on muscle and bone research priorities.

Without effective countermeasures, the musculoskeletal system is altered by the microgravity environment of long-duration spaceflight, resulting in atrophy of bone and muscle tissue, as well as in deficits in the function of cartilage, tendons, and vertebral disks. While inflight countermeasures implemented on the International Space Station have evidenced reduction of bone and muscle loss on low-Earth orbit missions of several months in length, important knowledge gaps must be addressed in order to develop effective strategies for managing human musculoskeletal health on exploration class missions well beyond Earth orbit. Analog environments, such as bed rest and/or isolation environments, may be employed in conjunction with large sample sizes to understand sex differences in countermeasure effectiveness, as well as interaction of exercise with pharmacologic, nutritional, immune system, sleep and psychological countermeasures.

Where Failure Is Not an Option -Personalized Medicine in Astronauts.

Drug safety and efficacy are highly variable among patients. Most patients will experience the desired drug effect, but some may suffer from adverse drug reactions or gain no benefit. Pharmacogenetic testing serves as a pre-treatment diagnostic option in situations where failure or adverse events should be avoided at all costs.

Salt-dependent chemotaxis of macrophages.

Besides their role in immune system host defense, there is growing evidence that macrophages may also be important regulators of salt homeostasis and blood pressure by a TonEBP-VEGF-C dependent buffering mechanism. As macrophages are known to accumulate in the skin of rats fed under high salt diet conditions and are pivotal for removal of high salt storage, the question arose how macrophages sense sites of high sodium storage. Interestingly, we observed that macrophage-like RAW264.

Long-term space flight simulation reveals infradian rhythmicity in human Na(+) balance.

The steady-state concept of Na(+) homeostasis, based on short-term investigations of responses to high salt intake, maintains that dietary Na(+) is rapidly eliminated into urine, thereby achieving constant total-body Na(+) and water content. We introduced the reverse experimental approach by fixing salt intake of men participating in space flight simulations at 12 g, 9 g, and 6 g/day for months and tested for the predicted constancy in urinary excretion and total-body Na(+) content. At constant salt intake, daily Na(+) excretion exhibited aldosterone-dependent, weekly (circaseptan) rhythms, resulting in periodic Na(+) storage.

ESSC-ESF position paper--science-driven scenario for space exploration: report from the European Space Sciences Committee (ESSC).

In 2005 the then ESA Directorate for Human Spaceflight, Microgravity and Exploration (D-HME) commissioned a study from the European Science Foundation's (ESF) European Space Sciences Committee (ESSC) to examine the science aspects of the Aurora Programme in preparation for the December 2005 Ministerial Conference of ESA Member States, held in Berlin. A first interim report was presented to ESA at the second stakeholders meeting on 30 and 31 May 2005. A second draft report was made available at the time of the final science stakeholders meeting on 16 September 2005 in order for ESA to use its recommendations to prepare the Executive proposal to the Ministerial Conference.

A research facility for habitation questions to be built at the German Aerospace Center in Cologne: future challenges of Space medicine.

For long term habitation in space and for living on Moon and Mars, many questions still need to be resolved. Such habitation questions include prevention of and rehabilitation from negative effects of weightlessness that are, in many instances, comparable to problems of aging people on Earth as well as of patients during and recovery from long term stays in bed. Therefore the DLR Institute of Aerospace Medicine has designed a concept for a research facility that will make it possible to join space research directly with terrestrial applications.

Immortalization of human melanocytes does not alter the de novo properties of nitric oxide to induce cell detachment from extracellular matrix components via cGMP.

Nitric oxide (NO) is an important mediator in many (patho)physiological processes including inflammation and skin cancer. A key transducer in NO signaling is the soluble guanylyl cyclase (sGC) that catalyzes the formation of guanosine 3',5'-cyclic monophosphate (cGMP). The basic mechanism of NO-cGMP signaling in melanocytic cells is, however, not well elucidated.

Non-linear function model of voice pitch dependency on physical and mental load.

The present work describes that under increasing physical load the voice fundamental frequency (voice pitch) remains on a given level as long as the physical load is well tolerated by the subject, whereas heart rate and blood pressure continuously increase during increasing physical load. This voice pitch level was compared to voice pitch levels under mental load. Using a word recognition system, 11 well trained, young male subjects had to solve 2 moderate mental load tasks.

Regulation of body fluid and salt homeostasis--from observations in space to new concepts on Earth.

The present manuscript summarizes recent discoveries that were made by studying salt and fluid homeostasis in weightlessness. These data indicate that 1. atrial natriuretic peptide appears not to play an important role in natriuresis in physiology, 2.

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.

Non-lesional vitiliginous melanocytes are not characterized by an increased proneness to nitric oxide-induced apoptosis.

Nitric oxide (NO) is a reactive endogenous molecule with multiple functions including inflammation and immunity. NO stimulates melanogenesis by activating soluble guanylyl cyclase (sGC) resulting in increases in intracellular guanosine 3',5'-cyclic monophosphate (cGMP). In vitro experiments showed that NO could inhibit the de novo attachment of melanocytes to extracellular matrix (ECM) suggesting that NO-induced aberrant perturbation of melanocyte-ECM interaction could be a reason for melanocyte loss in vitiliginous lesions.

L-arginine, the natural precursor of NO, is not effective for preventing bone loss in postmenopausal women.

Unlabelled: NO is an important regulator of bone turnover. L-Arginine, the natural precursor of NO, can enhance NO production. However, no effect of L-arginine hydrochloride supplementation was found on bone metabolism or on BMD, bone mass, or bone structure of healthy postmenopausal women.

Stimulation of cyclic GMP efflux in human melanocytes by hypergravity generated by centrifugal acceleration.

Gravity alteration (micro- and hypergravity) is known to influence cell functions. As guanosine 3',5'-cyclic monophosphate (cGMP) plays an important role in human melanocyte functions and different guanylyl cyclase isoforms are responsible for cGMP synthesis in human non-metastatic and metastatic melanoma cells, we investigated the effects of hypergravity on the regulation of cGMP levels in cultured human melanocytes and in melanoma cell lines with different metastatic potentials. Hypergravity was produced by horizontal centrifugal acceleration.

Gravity and cyclic GMP levels in melanocytic cells.

Guanosine 3',5'-cyclic monophosphate (cyclic GMP) is a major second messenger molecule, that is believed to play a role in various physiological and pathophysiological processes. Here we report that hypergravity induces differential effects on cyclic GMP turnover in melanocytic cells. Nonmetastatic melanoma cells responded to long-time exposure (24 h) of hypergravity (up to 5 x g) with decrease in intracellular cyclic GMP accumulation in the presence of an universal inhibitor of phosphodiesterases (IBMX), whereas the extracellular cyclic GMP increase.

Effects of L-arginine supplementation on bone metabolism.

Recent experimental studies indicate that nitric oxide (NO) is an important regulator of bone turnover in humans by exerting an anabolic effect on bone cell activity. NO is synthesised from the nonessential amino acid L-arginine. Therefore, a supplementation with oral L-arginine might be highly potent to affect bone cell activity via NO synthesis from L-arginine.

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).

HUMEX, a study on the survivability and adaptation of humans to long-duration exploratory missions, part I: lunar missions.

The European Space Agency has recently initiated a study of the human responses, limits and needs with regard to the stress environments of interplanetary and planetary missions. Emphasis has been laid on human health and performance care as well as advanced life support developments including bioregenerative life support systems and environmental monitoring. The overall study goals were as follows: (i) to define reference scenarios for a European participation in human exploration and to estimate their influence on the life sciences and life support requirements; (ii) for selected mission scenarios, to critically assess the limiting factors for human health, wellbeing, and performance and to recommend relevant countermeasures; (iii) for selected mission scenarios, to critically assess the potential of advanced life support developments and to propose a European strategy including terrestrial applications; (iv) to critically assess the feasibility of existing facilities and technologies on ground and in space as testbeds in preparation for human exploratory missions and to develop a test plan for ground and space campaigns; (v) to develop a roadmap for a future European strategy towards human exploratory missions, including preparatory activities and terrestrial applications and benefits.

Bone resorption is induced on the second day of bed rest: results of a controlled crossover trial.

The aim of the study was to analyze the kinetics of short-term changes in bone turnover. We studied in a randomized crossover design the effects of 6 days of bed rest on eight healthy male subjects (mean body wt: 70.1 +/- 5.

Critical issues in connection with human missions to Mars: protection of and from the Martian environment.

Human missions to Mars are planned to happen within this century. Activities associated therewith will interact with the environment of Mars in two reciprocal ways: (i) the mission needs to be protected from the natural environmental elements that can be harmful to human health, the equipment or to their operations; (ii) the specific natural environment of Mars should be protected so that it retains its value for scientific and other purposes. The following environmental elements need to be considered in order to protect humans and the equipment on the planetary surface: (i) cosmic ionizing radiation, (ii) solar particle events; (iii) solar ultraviolet radiation; (iv) reduced gravity; (v) thin atmosphere; (vi) extremes in temperatures and their fluctuations; and (vii) surface dust.

Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial.

Introduction: The melatonin agonist LY 156735 (LY) is a new investigational drug under development to treat circadian rhythm disorders. The present study assessed the efficacy of LY to alleviate the symptoms of shift lag and to enhance readaptation of desynchronized circadian rhythms to a new time zone.

Subjects And Methods: Eight healthy male volunteers of age 25-35 yr participated in three identical trials of 13d duration in a temporal isolation unit separated by washout intervals.

Influence of microgravity on plasma levels of gastroenteropancreatic peptides: a case study.

Background: No data are available about the short- or long-term influences of microgravity in space on the release of gastroenteropancreatic peptides, although these peptides are involved in the regulation of gastrointestinal functions.

Methods: Fasting plasma samples were gained during the EUROMIR-94 mission from a European Space Agency (ESA) astronaut who experienced no signs of space motion sickness in orbit. Plasma concentrations of nine gastroenteropancreatic peptides were measured with sensitive and specific radioimmunoassays.

NO-independent regulatory site of direct sGC stimulators like YC-1 and BAY 41-2272.

Background: The most important receptor for nitric oxide is the soluble guanylate cyclase (sGC), a heme containing heterodimer. Recently, a pyrazolopyridine derivative BAY 41-2272, structurally related to YC-1, was identified stimulating soluble guanylate cyclase in an NO-independent manner, which results in vasodilatation and antiplatelet activity. The study described here addresses the identification of the NO-independent site on soluble guanylate cyclase.

Hypoxia modulates rapid effects of aldosterone on oxidative metabolism in human calf muscle.

Non-genomic effects of aldosterone on oxidative metabolism of skeletal muscle have been shown, recently. To further characterize these rapid effects on the increase of phosphocreatine (PCr) in the recovery period after isometric exercise, a randomized cross-over placebo-controlled study was conducted on 9 healthy volunteers. Hypoxia was chosen to test the dependence of the effect on oxygen supply and thus its relation to oxidative vs non-oxidative metabolism.