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International audience; Background Immobilization and related oxidative stress are associated with bone loss. Antioxidants like polyphenols, omega-3 fatty acids, vitamins, and micronutrients may mitigate these negative effects on bone metabolism through scavenging of free radicals. Objectives We hypothesized that antioxidant supplementation during 60 days of 6° head-down tilt bed rest (HDBR) would reduce bone resorption and increase bone formation compared to nonsupplemented controls. Methods This exploratory randomized, controlled, single-blind intervention study conducted in a parallel design included 20 healthy male volunteers (age, 34 ± 8 years; weight, 74 ± 6 kg). The study consisted of a 14-day adaptation phase [baseline data collection (BDC)], followed by 60 days of HDBR and a 14-day recovery period (R). In the antioxidant group, volunteers received an antioxidant cocktail (741 mg/d polyphenols, 2.1 g/d omega-3 fatty acids, 168 mg/d vitamin E, and 80 μg/d selenium) with their daily meals. In the control group, volunteers received no supplement. Based on their body weight, all volunteers received an individually tailored and strictly controlled diet, consistent with DRIs. We analyzed biomarkers of calcium homeostasis, bone formation, and bone resorption during BDC, HDBR, and R, as well as for 30 days after the end of HDBR. Data were analyzed by linear mixed models. Results The antioxidant supplement did not affect serum calcium, parathyroid hormone, urinary C-telopeptide of type I collagen (CTX), urinary N-telopeptide of type I collagen, serum β–C-telopeptide of type I collagen (β-CTX), bone alkaline phosphatase, aminoterminal propeptide of type I collagen, osteocalcin, or urinary calcium excretion. In both groups, typical bed rest–related changes were observed. Conclusions Supplementation of an antioxidant cocktail to a diet matching the DRIs did not affect bone resorption or formation during 60 days of HDBR in healthy young men. This trial was registered at clinicaltrials.gov as NCT03594799.

ObjectivesBone loss remains a primary health concern for astronauts, despite in-flight exercise. We examined changes in bone microarchitecture, density and strength before and after long-duration spaceflight in relation to biochemical markers of bone turnover and exercise.MethodsSeventeen astronauts had their distal tibiae and radii imaged before and after space missions to the International Space Station using high-resolution peripheral quantitative CT. We estimated bone strength using finite element analysis and acquired blood and urine biochemical markers of bone turnover before, during and after spaceflight. Pre-flight exercise history and in-flight exercise logs were obtained. Mixed effects models examined changes in bone and biochemical variables and their relationship with mission duration and exercise.ResultsAt the distal tibia, median cumulative losses after spaceflight were −2.9% to −4.3% for bone strength and total volumetric bone mineral density (vBMD) and −0.8% to −2.6% for trabecular vBMD, bone volume fraction, thickness and cortical vBMD. Mission duration (range 3.5–7 months) significantly predicted bone loss and crewmembers with higher concentrations of biomarkers of bone turnover before spaceflight experienced greater losses in tibia bone strength and density. Lower body resistance training volume (repetitions per week) increased 3–6 times in-flight compared with pre-spaceflight. Increases in training volume predicted preservation of tibia bone strength and trabecular vBMD and thickness.ConclusionsFindings highlight the fundamental relationship between mission duration and bone loss. Pre-flight markers of bone turnover and exercise history may identify crewmembers at greatest risk of bone loss due to unloading and may focus preventative measures.

Background and Aims In daily clinical practice, individual-level sodium (Na) intake is often estimated by measuring Na excretion in a single 24h urine collection, but long-term Na balance studies indicate that 7 consecutive 24h urine collections are needed. However, this approach is not feasible in clinical settings. In this study, we investigate whether the use of repeated spot urine sampling is an appropriate alternative for repeated 24h urine collections. Method We performed a post-hoc analysis of a metabolic ward study in 8 healthy male adults who consumed a 7-day diet with a fixed amount of Na (200 mmol/d). Urine was collected in four daily intervals: 7-13h, 13-19h, 19-23h and 23-7h. After reaching steady state, we estimated Na intake with 1 and 3 consecutive 24h urine collections and 3-day spot urine sampling, using the Kawasaki formula with measured 24h urine creatinine excretion. Results: On day 5, mean 24h Na excretion matched intake, indicating that steady state was achieved (Fig A). Mean and standard deviation of absolute differences between estimated and measured Na intake (ΔNa) for each method were: 18.8 ±14.6 mmol (3 x spot urine 7-13h), 32.3 ±18.7 mmol (3 x spot urine 13-19h), 74.6 ±30.0 mmol (3 x spot urine 19-23h), 28.2 ±19.8 mmol (3 x spot urine 23-7h), 29.8 ±23.9 mmol (1 x 24h urine) and 22.9 ±11.3 mmol (3 x 24h urine) (Fig B). With the exception of the 19-23h spot urine collection period, the accuracy of 3-day spot urine sampling did not significantly differ from accuracy of 1 and 3 consecutive 24h urine collections. When combining the pre-night and morning spot urine collections (19-7h), the accuracy of the estimation did not improve (ΔNa 28.7 ±19.6 mmol). Conclusion 3-day spot urine sampling did not perform significantly different than 1 and 3 24h urine collections for estimation of individual-level Na intake. Adequately powered studies need to confirm whether repeated spot urine sampling is an accurate and low burden alternative to repeated 24h urine collections.

When astronauts enter weightlessness, cephalad fluid shifts increase left ventricular dimensions, whereas central venous pressure is surprisingly reduced. More chronically, counterregulatory adjustments attenuate total blood volume; however, the internal jugular vein remains grossly dilated.1 This finding would raise suspicion for central volume overload in terrestrial medicine. Moreover, a single astronaut retained substantial amounts of sodium in space without body mass gain. It is possible that weightlessness alters osmotically inactive sodium storage, a recently recognized mechanism for human volume regulation.2,3 Prolonged −6° head-down bed rest, which produces cephalad volume shifts similar to those in weightlessness, elicited sustained increases in circulating atrial natriuretic peptide concentrations.4 Conversely, individual astronauts have shown reduced natriuretic peptide signalling in space.5 Cardiac natriuretic peptide deficiency could exacerbate central hypervolemia. We assessed natriuretic peptides in astronauts in the first study comparing lower-sodium and higher-sodium diets in space and on Earth. The SOLO study (Sodium Load in Microgravity) was approved by the Johnson Space Center institutional review board and the European Space Agency medical board. After giving informed consent, we tested 8 male astronauts (50±2.8 years old; weight, 85.61±8.89 kg) on both lower-sodium (2 g/d) and higher-sodium (5.5 g/d) diets for 5 consecutive days in space and 6 to 12 months after landing on Earth. In space, diets were applied in random order no earlier than 4 weeks into the mission. Dietary nutrient and water intakes were kept constant. Blood samples were obtained on day 5 of each intervention and analyzed for sodium, creatinine, midregional proatrial natriuretic peptide (MRproANP), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and aldosterone. On Earth, samples were obtained while subjects were seated in the morning after they had traveled from the hotel to the study center. The same day, urinary sodium, creatinine, and body mass were measured. Body mass on the International Space Station was measured with the National Aeronautics and Space Administration’s Space Linear Acceleration Mass Measurement Device; on Earth, we used a standard scale. To gauge changes in central blood volume, we assessed thoracic bioimpedance in 16 cosmonauts (45.56±5.59 years old; weight, 79.88±6.94 kg) before launch, monthly onboard the International Space Station, and after return to Earth. The study in cosmonauts was approved by the Biomedicine Ethics Committee of the State Research Center of the Russian Federation, the Institute of Biomedical Problems, the Russian Academy of Science, and the subjects gave informed consent. On the lower-sodium diet, astronauts excreted 74.3±7.0 mmol of sodium per day (mean+SEM) in space and 82.6±10.3 mmol/d on Earth (P=0.172). On the higher-sodium diet, astronauts excreted 175±12 mmol/d in space and 196±13 mmol/d on Earth (P=0.249). Glomerular filtration rate was unchanged, whereas fractional sodium excretion increased similarly on the higher-sodium diet (P

Biomarkers of cartilage metabolism are sensitive to changes in the biological and mechanical environment and can indicate early changes in cartilage homeostasis. The purpose of this study was to determine if a daily locomotion replacement program can serve as a countermeasure for changes in cartilage biomarker serum concentration caused by immobilization. Ten healthy male subjects (mean ± 1 standard deviation; age: 29.4 ± 5.9 years; body mass: 77.7 ± 4.1 kg) participated in the crossover 5-day bed rest study with three interventions: control (CON), standing (STA), and locomotion replacement training (LRT). Serum samples were taken before, during, and after bed rest. Biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. Cartilage oligomeric matrix protein (COMP) levels after 24 hours of bed rest decreased independently of the intervention (-16.8% to -9.8%) and continued to decrease until 72 hours of bed rest (minimum, -23.2% to -20.6%). LRT and STA did not affect COMP during bed rests (P = .056) but there was a strong tendency for a slower decrease with LRT (-9.4%) and STA (-11.7%) compared with CON (-16.8%). MMP-3 levels decreased within the first 24 hours of bed rest (CON: -22.3%; STA: -14.7%; LRT: -17%) without intervention effect. Both COMP and MMP-3 levels recovered to baseline levels during the 6-day recovery period. MMP-1, MMP-9, and TNF-α levels were not affected by immobilization or intervention. COMP and MMP-3 are mechano-sensitive cartilage biomarkers affected by immobilization, and simple interventions such as standing upright or LRT during bed rest cannot prevent these changes. Clinical significance: simple locomotion interventions cannot prevent cartilage biomarker change during bed rest.

International audience; The intention to send a crewed mission to Mars involves a huge amount of planning to ensure a safe and successful mission. Providing adequate amounts of food for the crew is a major task, but 20 years of feeding astronauts on the International Space Station (ISS) have resulted in a good knowledge base. A crucial observation from the ISS is that astronauts typically consume only 80% of their daily calorie requirements when in space. This is despite daily exercise regimes that keep energy usage at very similar levels to those found on Earth. This calorie deficit seems to have little effect on astronauts who spend up to 12 months on the ISS, but given that a mission to Mars would take 30 to 36 months to complete, there is concern that a calorie deficit over this period may lead to adverse effects in crew members. The key question is why astronauts undereat when they have a supply of food designed to fully deliver their nutritional needs. This review focuses on evidence from astronauts that foods taste different in space, compared to on Earth. The underlying hypothesis is that conditions in space may change the perceived flavor of the food, and this flavor change may, in turn, lead to underconsumption by astronauts. The key areas investigated in this review for their potential impact on food intake are the effects of food shelf life, physiological changes, noise, air and water quality on the perception of food flavor, as well as the link between food flavor and food intake.

Background Bed rest studies document that a lower dietary acid load is associated with lower bone resorption. Objective We tested the effect of dietary acid load on bone metabolism during spaceflight. Design Controlled 4-d diets with a high or low animal protein–to-potassium (APro:K) ratio (High and Low diets, respectively) were given to 17 astronauts before and during spaceflight. Each astronaut had 1 High and 1 Low diet session before flight and 2 High and 2 Low sessions during flight, in addition to a 4-d session around flight day 30 (FD30), when crew members were to consume their typical in-flight intake. At the end of each session, blood and urine samples were collected. Calcium, total protein, energy, and sodium were maintained in each crew member's preflight and in-flight controlled diets. Results Relative to preflight values, N-telopeptide (NTX) and urinary calcium were higher during flight, and bone-specific alkaline phosphatase (BSAP) was higher toward the end of flight. The High and Low diets did not affect NTX, BSAP, or urinary calcium. Dietary sulfur and age were significantly associated with changes in NTX. Dietary sodium and flight day were significantly associated with urinary calcium during flight. The net endogenous acid production (NEAP) estimated from the typical dietary intake at FD30 was associated with loss of bone mineral content in the lumbar spine after the mission. The results were compared with data from a 70-d bed rest study, in which control (but not exercising) subjects’ APro:K was associated with higher NTX during bed rest. Conclusions Long-term lowering of NEAP by increasing vegetable and fruit intake may protect against changes in loss of bone mineral content during spaceflight when adequate calcium is consumed, particularly if resistive exercise is not being performed. This trial was registered at clinicaltrials.gov as NCT01713634.

The objective of the study was to test the hypothesis that serum levels of cartilage oligomeric matrix protein (COMP) would decrease and serum levels of tumor-necrosis factor alpha (TNF-α) and selected matrix metalloproteinases (MMPs) would increase in response to bed rest (BR) and that these changes are unaffected by the intake of potassium bicarbonate or whey protein. Seven and nine healthy male subjects participated in two 21-day 6° head down tilt crossover BR-studies with nutrition interventions. Serum samples were taken before, during, and after BR and biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. MMP-3 during BR was significantly lower than at baseline (reduction greater 20%; p

BACKGROUND & AIMS: Physical inactivity is associated with lean body mass wasting, oxidative stress and pro-inflammatory changes of cell membrane lipids. Alkalinization may potentially counteract these alterations. We evaluated the effects of potassium bicarbonate supplementation on protein kinetics, glutathione status and pro- and anti-inflammatory polyunsaturated fatty acids (PUFA) in erythrocyte membranes in humans, during experimental bed rest. METHODS: Healthy, young, male volunteers were investigated at the end of two 21-day bed rest periods, one with, and the other without, daily potassium bicarbonate supplementation (90 mmol × d-1), according to a cross-over design. Oxidative stress in erythrocytes was evaluated by determining the ratio between reduced (GSH) and oxidized glutathione (GSSG). Glutathione turnover and phenylalanine kinetics, a marker of whole body protein metabolism, were determined by stable isotope infusions. Erythrocyte membranes PUFA composition was analyzed by gas-chromatography. RESULTS: At the end of the two study periods, urinary pH was 10 ± 3% greater in subjects receiving potassium bicarbonate supplementation (7.23 ± 0.15 vs. 6.68 ± 0.11, p < 0.001). Alkalinization increased total glutathione concentrations by 5 ± 2% (p < 0.05) and decreased its rate of clearance by 38 ± 13% (p < 0.05), without significantly changing GSH-to-GSSG ratio. After alkalinization, net protein balance in the postabsorptive state improved significantly by 17 ± 5% (p < 0.05) as well as the sum of n-3 PUFA and the n-3-to-n-6 PUFA ratio in erythrocyte membranes (p < 0.05). CONCLUSIONS: Alkalinization during long-term inactivity is associated with improved glutathione status, anti-inflammatory lipid pattern in cell membranes and reduction in protein catabolism at whole body level. This study suggests that, in clinical conditions characterized by inactivity, oxidative stress and inflammation, alkalinization could be a useful adjuvant therapeutic strategy.

Bone loss and renal stone risk are longstanding concerns for astronauts. Bone resorption brought on by spaceflight elevates urinary calcium and the risk of renal stone formation. Loss of bone calcium leads to concerns about fracture risk and increased long-term risk of osteoporosis. Bone metabolism involves many factors and is interconnected with muscle metabolism and diet. We report here bone biochemistry and renal stone risk data from astronauts on 4- to 6-month International Space Station missions. All had access to a type of resistive exercise countermeasure hardware, either the Advanced Resistance Exercise Device (ARED) or the Interim Resistance Exercise Device (iRED). A subset of the ARED group also tested the bisphosphonate alendronate as a potential anti-resorptive countermeasure (Bis+ARED). While some of the basic bone marker data have been published, we provide here a more comprehensive evaluation of bone biochemistry with a larger group of astronauts. Regardless of exercise, the risk of renal stone formation increased during spaceflight. A key factor in this increase was urine volume, which was lower during flight in all groups at all time points. Thus, the easiest way to mitigate renal stone risk is to increase fluid consumption. ARED use increased bone formation without changing bone resorption, and mitigated a drop in parathyroid hormone in iRED astronauts. Sclerostin, an osteocyte-derived negative regulator of bone formation, increased 10-15% in both groups of astronauts who used the ARED (p

Human studies in space provide unique and often unexpected findings regarding the role of terrestrial gravity for human cardiovascular and renal regulation. While vascular volume is shifted towards the head, which would be expected to increase natriuretic peptide (NP) release, preliminary observations suggested the opposite. Therefore, we assessed natriuretic peptide regulation on different controlled sodium diets in space and on Earth. Eight male astronauts (50±2.8 yrs.) ingested higher (5.5 g/day) and low sodium (2g/day) diets for five days each on Earth and on the International Space Station (ISS) in alternating order. Dietary nutrient intake was individually tailored and kept constant. At day five of each intervention, midregional-pro atrial NP (MRproANP), N-terminal pro B-type NP (NTproBNP), and aldosterone in blood, urinary sodium excretion, and body mass were measured. On Earth, MRproANP was 71.86±4.39 pmol/L on moderately high and 65.13±6.71 pmol/L on low sodium intake. In space, MRproANP was 44.61±4.26 pmol/L on high and 31.37±4.02 pmol/L on low sodium intake (p

Potassium bicarbonate was administrated to an already alkaline diet in seven male subjects during a 21-day bed rest study and was able to decrease bed rest induced increased calcium excretion but failed to prevent bed rest-induced bone resorption. Supplementation with alkali salts appears to positively influence calcium and bone metabolism and, thus, could be a countermeasure for population groups with an increased risk for bone loss. However, the extent to which alkalization counteracts acid-induced bone resorption or whether it merely has a calcium and bone maintenance effect is still not completely understood. In the present study, we hypothesized that additional alkalization to an already alkaline diet can further counteract bed rest-induced bone loss. Seven healthy male subjects completed two parts of a crossover designed 21-day bed rest study: bed rest only (control) and bed rest supplemented with 90 mmol potassium bicarbonate (KHCO3) daily. KHCO3supplementation during bed rest resulted in a more alkaline status compared to the control intervention, demonstrated by the increase in pH and buffer capacity level (pH p = 0.023, HCO3p = 0.02, ABE p = 0.03). Urinary calcium excretion was decreased during KHCO3 supplementation (control 6.05 ± 2.74 mmol/24 h; KHCO3 4.87 ± 2.21 mmol/24 h, p = 0.03); whereas, bone formation was not affected by additional alkalization (bAP p = 0.58; PINP p = 0.60). Bone resorption marker UCTX tended to be lower during alkaline supplementation (UCTX p = 0.16). The more alkaline acid-base status, achieved by KHCO3 supplementation, reduced renal calcium excretion during bed rest, but was not able to prevent immobilization-induced bone resorption. However, advantages of alkaline salts on bone metabolism may occur under acidic metabolic conditions or with respect to the positive effect of reduced calcium excretion within a longer time frame. Trial number: NCT01509456

Inhibition of sodium glucose cotransporter 2 with empagliflozin results in caloric loss by increasing urinary glucose excretion and has a mild diuretic effect. Diuretic effects are usually associated with reflex-mediated increases in sympathetic tone, whereas caloric loss is associated with decreased sympathetic tone. In an open-label trial, muscle sympathetic nerve activity (MSNA) (burst frequency, burst incidence, and total MSNA) was assessed using microneurography performed off-treatment and on day 4 of treatment with empagliflozin 25 mg once daily in 22 metformin-treated patients with type II diabetes (mean [range] age 54 [40–65] years). Systolic and diastolic blood pressure (BP), heart rate, urine volume, and body weight were assessed before and on day 4 (BP, heart rate), day 5 (urine volume), or day 6 (body weight) of treatment with empagliflozin. After 4 days of treatment with empagliflozin, no significant changes in MSNA were apparent despite a numerical increase in urine volume, numerical reductions in BP, and significant weight loss. There were no clinically relevant changes in heart rate. Empagliflozin is not associated with clinically relevant reflex-mediated sympathetic activation in contrast to increases observed with diuretics in other studies. Our study suggests a novel mechanism through which sodium glucose cotransporter 2 inhibition affects human autonomic cardiovascular regulation.

Bed rest (BR) causes bone loss, even in otherwise healthy subjects. Several studies suggest that ambulatory subjects may benefit from high-protein intake to stimulate protein synthesis and to maintain muscle mass. However, increasing protein intake above the recommended daily intake without adequate calcium and potassium intake may increase bone resorption. We hypothesized that a regimen of high-protein intake (HiPROT), applied in an isocaloric manner during BR, with calcium and potassium intake meeting recommended values, would prevent any effect of BR on bone turnover. After a 20-day ambulatory adaptation to a controlled environment, 16 women participated in a 60-day, 6° head-down-tilt (HDT) BR and were assigned randomly to 1 of 2 groups. Control (CON) subjects (n = 8) received 1 g/(kg body mass·day)−1 dietary protein. HiPROT subjects (n = 8) received 1.45 g protein/(kg body mass·day)−1 plus an additional 0.72 g branched-chain amino acids per day during BR. All subjects received an individually tailored diet (before HDTBR: 1888 ± 98 kcal/day; during HDTBR: 1604 ± 125 kcal/day; after HDTBR: 1900 ± 262 kcal/day), with the CON group’s diet being higher in fat and carbohydrate intake. High-protein intake exacerbated the BR-induced increase in bone resorption marker C-telopeptide (>30%) (p < 0.001) by the end of BR. Bone formation markers were unaffected by BR and high-protein intake. We conclude that high-protein intake in BR might increase bone loss. Further long-duration studies are mandatory to show how the positive effect of protein on muscle mass can be maintained without the risk of reducing bone mineral density.

Bone loss, a key concern for long-duration space travelers, is typically considered a female issue. The number of women who have flown long-duration space missions is now great enough to allow a quantitative comparison of changes in bone and renal stone risk by sex. Participants were 42 astronauts (33 men and 9 women) on long-duration missions to the International Space Station. Bone mineral density (by dual-energy X-ray absorptiometry) and biochemical markers of bone metabolism (from blood and urine samples) were evaluated before and after flight. Data were analyzed in two groups, based on available resistance exercise equipment. Missions were 49 to 215 days in duration, flown between 2000 and 2012. The bone density response to spaceflight was the same for men and women in both exercise groups. The bone mineral density response to flight was the same for men and women, and the typical decrease in bone mineral density (whole body and/or regional) after flight was not observed for either sex for those using an advanced resistive exercise device. Biochemical markers of bone formation and resorption responded similarly in male and female astronauts. The response of urinary supersaturation risk to spaceflight was not significantly different between men and women, although risks were typically increased after flight in both groups, and risks were greater in men than in women before and after flight. The responses of men and women to spaceflight with respect to these measures of bone health were not different.

We assessed the potential for countermeasures to lessen the loss of bone calcium during bed rest. Subjects ingested less calcium during bed rest, and with artificial gravity, they also absorbed less calcium. With exercise, they excreted less calcium. To retain bone during bed rest, calcium intake needs to be maintained.This study aims to assess the potential for artificial gravity (AG) and exercise (EX) to mitigate loss of bone calcium during space flight.We performed two studies: (1) a 21-day bed rest (BR) study with subjects receiving 1 h/day AG (n = 8) or no AG (n = 7) and (2) a 28-day BR study with 1 h/day resistance EX (n = 10) or no EX (n = 3). In both studies, stable isotopes of Ca were administered orally and intravenously, at baseline and after 10 days of BR, and blood, urine, and feces were sampled for up to 14 days post dosing. Tracers were measured using thermal ionization mass spectrometry. Data were analyzed by compartmental modeling.Less Ca was absorbed during BR, resulting in lower Ca balance in BR+AG (-6.04 ± 3.38 mmol/day, P = 0.023). However, Ca balance did not change with BR+EX, even though absorbed Ca decreased and urinary Ca excretion increased, because endogenous excretion decreased, and there was a trend for increased bone deposition (P = 0.06). Urinary N-telopeptide excretion increased in controls during BR, but not in the EX group. Markers of bone formation were not different between treatment groups for either study. Ca intake decreased during BR (by 5.4 mmol/day in the AG study and 2.8 mmol/day in the EX study), resulting in lower absorbed Ca.During BR (or space flight), Ca intake needs to be maintained or even increased with countermeasures such as exercise, to enable maintenance of bone Ca.

The space flight environment is known to induce bone loss and, subsequently, calcium loss. The longer the mission, generally the more bone and calcium are lost. This review provides a history of bone and calcium studies related to space flight and highlights issues related to calcium excretion that the space program must consider so that urine can be recycled. It also discusses a novel technique using natural stable isotopes of calcium that will be helpful in the future to determine calcium and bone balance during space flight.

Our aim was to investigate the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on urinary and serum glucose and electrolytes, urinary volume, osmolality, and the renin-angiotensin system in patients with type 2 diabetes.In an open-label study, 22 patients receiving metformin (median age 56 years; range 40-65 years) received empagliflozin 25 mg once daily for 5 days. Food, fluid, and sodium intake were standardized for 3 days before and during treatment.Twenty patients completed treatment. After single and multiple doses of empagliflozin, mean (SE) changes from baseline in 24-hour urinary glucose excretion were 463.3 (57.3) mmol/d and 599.5 (60.0) mmol/d, respectively (83.5 [10.3] g/d and 108.0 [10.8] g/d, respectively) (both P0.001), and in fasting serum glucose concentration were -1.8 (0.4) mmol/L and -1.1 (0.3) mmol/L, respectively (both P0.001). After a single dose, mean (SE) change from baseline in urine sodium excretion was 45.3 (9.6) mmol/d (P0.001), and in urine volume was 341.0 (140.5) g/d (P = 0.025), but there were no changes compared with baseline in either parameter after multiple doses. There were no changes in plasma renin or serum aldosterone with single or multiple doses of empagliflozin. There was a nonsignificant reduction in weight after a single dose of empagliflozin and a mean (SE) change of -1.4 (0.5) kg after multiple doses (P = 0.020).Empagliflozin 25 mg increased urinary glucose excretion and decreased serum glucose and weight with transient natriuresis and increases in urine volume, without significant changes in the renin-angiotensin system. Clinicaltrials.gov Identifier: NCT01276288.

Purpose The goal of this study was to investigate the pharmacodynamic effects of co-administration of empagliflozin, a sodium glucose cotransporter 2 inhibitor, with diuretic agents. Methods In a randomized, open-label cross-over study, 22 patients with type 2 diabetes mellitus received empagliflozin 25 mg for 5 days and either hydrochlorothiazide 25 mg for 4 days followed by hydrochlorothiazide 25 mg plus empagliflozin 25 mg for 5 days, or torasemide 5 mg for 4 days followed by torasemide 5 mg plus empagliflozin 25 mg for 5 days; 20 completed treatment. Food, fluid, and sodium intake were standardized for 3 days before and during treatment. Findings At baseline, the median age of the treated patients was 56 years (range, 40–65 years), body mass index was 26.8 kg/m 2 (range, 20.1–34.4 kg/m 2 ), fasting plasma glucose was 8.6 mmol/L (range, 6.0–12.9 mmol/L), and glycosylated hemoglobin level was 7.6% (range, 7%–10%). Empagliflozin significantly increased 24-hour urinary glucose excretion and reduced fasting serum glucose levels. These effects were maintained after co-administration with either diuretic. Urinary sodium excretion did not significantly change with empagliflozin or diuretic administration alone, but seemed to increase compared with either diuretic alone when empagliflozin was co-administered with either diuretic. Plasma renin and serum aldosterone levels were unaltered with empagliflozin or torasemide alone, but tended to increase with hydrochlorothiazide alone, and tended to increase when empagliflozin was co-administered with a diuretic compared with either diuretic alone. Urinary volume did not increase with empagliflozin or diuretics alone, but increased when empagliflozin was co-administered with either diuretic. Implications Empagliflozin alone for 5 days increased urinary glucose excretion but did not seem to have a relevant impact on urine volume or electrolytes. When empagliflozin was co-administered with a diuretic agent, urinary glucose excretion remained increased, and the renin-angiotensin system was activated. Clinicaltrials.gov identifier: NCT01276288.

The impact of effective exercise against bone loss during experimental bed rest appears to be associated with increases in bone formation rather than reductions of bone resorption. Sclerostin and dickkopf-1 are important inhibitors of osteoblast activity. We hypothesized that exercise in bed rest would prevent increases in sclerostin and dickkopf-1. Twenty-four male subjects performed resistive vibration exercise (RVE; n = 7), resistive exercise only (RE; n = 8), or no exercise (control n = 9) during 60 days of bed rest (2nd Berlin BedRest Study). We measured serum levels of BAP, CTX-I, iPTH, calcium, sclerostin, and dickkopf-1 at 16 time-points during and up to 1 year after bed rest. In inactive control, after an initial increase in both BAP and CTX-I, sclerostin increased. BAP then returned to baseline levels, and CTX-I continued to increase. In RVE and RE, BAP increased more than control in bed rest (p ≤ 0.029). Increases of CTX-I in RE and RVE did not differ significantly to inactive control. RE may have attenuated increases in sclerostin and dickkopf-1, but this was not statistically significant. In RVE there was no evidence for any impact on sclerostin and dickkopf-1 changes. Long-term recovery of bone was also measured and 6–24 months after bed rest, and proximal femur bone mineral content was still greater in RVE than control (p = 0.01). The results, while showing that exercise against bone loss in experimental bed rest results in greater bone formation, could not provide evidence that exercise impeded the rise in serum sclerostin and dickkopf-1 levels.

Approximately 20% (7 of 38) of astronauts on International Space Station (ISS) missions have developed measurable ophthalmic changes after flight. This study was conducted to determine if the folate- and vitamin B-12-dependent 1-carbon metabolic pathway is altered in these individuals. Since 2006, we have conducted experiments on the ISS to evaluate nutritional status and related biochemical indices of astronauts before, during, and after flight. Data were modeled to evaluate differences between individuals with ophthalmic changes (n = 5) and those without them (n = 15), all of whom were on ISS missions of 48-215 d. We also determined whether mean preflight serum concentrations of the 1-carbon metabolites and changes in measured cycloplegic refraction after flight were associated. Serum homocysteine (Hcy), cystathionine, 2-methylcitric acid (2MCA), and methylmalonic acid concentrations were 25-45% higher (P < 0.001) in astronauts with ophthalmic changes than in those without them. These differences existed before, during, and after flight. Preflight serum concentrations of Hcy and cystathionine, and mean in-flight serum folate, were correlated with change (postflight relative to preflight) values in refraction (P < 0.05), and preflight serum concentrations of 2MCA tended to be associated (P = 0.06) with ophthalmic changes. The biochemical differences observed in crewmembers with vision issues strongly suggest that their folate- and vitamin B-12-dependent 1-carbon transfer metabolism was affected before and during flight. The consistent differences in markers of 1-carbon metabolism between those who did and those who did not develop changes in vision suggest that polymorphisms in enzymes of this pathway may interact with microgravity to cause these pathophysiologic changes.

Limited data suggest that testosterone is decreased during space flight, which could contribute to bone and muscle loss.The main objective was to assess testosterone and hormone status in long- and short-duration space flight and bed rest environments and to determine relationships with other physiological systems, including bone and muscle.Blood and urine samples were collected before, during, and after long-duration space flight. Samples were also collected before and after 12- to 14-d missions and from participants in 30- to 90-d bed rest studies.Space flight studies were conducted on the International Space Station and before and after Space Shuttle missions. Bed rest studies were conducted in a clinical research center setting. Data from Skylab missions are also presented.All of the participants were male, and they included 15 long-duration and nine short-duration mission crew members and 30 bed rest subjects.Serum total, free, and bioavailable testosterone were measured along with serum and urinary cortisol, serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and SHBG.Total, free, and bioavailable testosterone was not changed during long-duration space flight but were decreased (P0.01) on landing day after these flights and after short-duration space flight. There were no changes in other hormones measured. Testosterone concentrations dropped before and soon after bed rest, but bed rest itself had no effect on testosterone.There was no evidence for decrements in testosterone during long-duration space flight or bed rest.

As part of the nutrition-countermeasures (NUC) study in Cologne, Germany in 2010, seven healthy male subjects underwent 21 days of head-down tilt bed rest and returned 153 days later to undergo a second bout of 21-day bed rest. As part of this model, we aimed to examine the recovery of the lumbar intervertebral discs and muscle cross-sectional area (CSA) after bed rest using magnetic resonance imaging and conduct a pilot study on the effects of bed rest in lumbar muscle activation, as measured by signal intensity changes in T2-weighted images after a standardized isometric spinal extension loading task. The changes in intervertebral disc volume, anterior and posterior disc height, and intervertebral length seen after bed rest did not return to prebed-rest values 153 days later. While recovery of muscle CSA occurred after bed rest, increases ( P ≤ 0.016) in multifidus, psoas, and quadratus lumborum muscle CSA were seen 153 days after bed rest. A trend was seen for greater activation of the erector spinae and multifidus muscles in the standardized loading task after bed rest. Greater reductions of multifidus and psoas CSA muscle and greater increases in multifidus signal intensity with loading were associated with incidence of low back pain in the first 28 days after bed rest ( P ≤ 0.044). The current study contributes to our understanding of the recovery of the lumbar spine after 21-day bed rest, and the main finding was that a decrease in spinal extensor muscle CSA recovers within 5 mo after bed rest but that changes in the intervertebral discs persist.

The absence of mechanical loading leads to a prompt increase in bone resorption measured by bone resorption markers. There is high potential that vibration training can positively influence bone metabolism in immobilized subjects, reduce the increase in osteoclastic activity and increase bone formation processes. We investigated whether vibration training at 20 Hz with an amplitude of 2-4 mm influences bone metabolism during immobilization. Eight male subjects (26.4 ± 4.9 years; 78.1 ± 9.5 kg) performed a 14 day bed rest in 6°-head down tilt (HDT). Subjects received vibration training for 2 × 5 min/day or a control intervention without vibration (crossover design). Calcium excretion and bone resorption markers C-telopeptide (CTX) and N-telopeptide (NTX) were analyzed from 24 h urine samples. Bone formation markers, bone alkaline phosphatase (bAP) and procollagen-N propeptide (PINP) were analyzed from fasting blood samples. Our results show an increase in bone resorption very early during HDT bed rest in both interventions (CTX: p < 0.01; NTX: p < 0.001). Vibration training did not have any different effect on bone resorption markers (CTX: p = 0.10; NTX: p = 0.58), bone formation markers (PINP: p = 0.21; bAP: p = 0.12) and calcium excretion (p < 0.64) compared to the control condition. Mere vibration training with 20 Hz for 2 × 5 min/day does not prevent increase in bone resorption as measured with the described methods in our short-term HDT bed rest.

Previously published data (J Bone Miner Res (2005); 20: 471) did not give evidence that the administration of the nitric oxide precursor L-arginine increases bone formation and decreases bone resorption in postmenopausal women. Data of this trial were reanalysed for putative effects of L-arginine on muscle mass and muscular function. Therefore, 11 females of the former study group (n=15; age 54.5+/-4.1 years; daily oral administration of 18 g L-arginine hydrochloride (equivalent of 14.2 g L-arginine) over 6 months) and 12 females of the control group (n=15; age 55.3+/-4.4 years; daily administration of 18 g dextrose over 6 months) were analysed for biomechanical parameters (MIGF, maximal isometric grip force; PJF, peak jump force; PJP, peak jump power) and for the cross-sectional muscle area (MA) and fat area (FA) at forearm and leg (calf) measured by peripheral quantitative computed tomography. The study was performed in a double-blind design. The assessment of muscular and biomechanical parameters was undertaken before and after 6 months of L-arginine versus placebo administration. L-arginine-supplemented females had a significant increase of PJF/kg in comparison with the control group. PJP/kg, MIGF, MA and FA were not significantly influenced by the administration of L-arginine. In conclusion, the administration of L-arginine increased maximal force in mechanographic analyses and may prevent a decline of muscle force in postmenopausal women.

Bone loss associated with disuse during bed rest (BR), an analog of space flight, can be attenuated by exercise. In previous studies, the efficacy of either aerobic or resistive exercise countermeasures has been examined separately. We hypothesized that a regimen of combined resistive and aerobic exercise during BR would prevent bone resorption and promote bone formation. After a 20-day ambulatory adaptation to controlled confinement and diet, 16 women participated in a 60-day, 6° head-down-tilt BR and were assigned randomly to one of the two groups. Control subjects (CON, n=8) performed no countermeasure. Exercise subjects (EX, n=8) participated in an exercise program during BR, alternating between supine treadmill exercise within lower body negative pressure (3– 4dw k �1 ) and flywheel resistive exercise (2– 3dw k �1 ). By the last week of BR, excretion of helical peptide (CON, 79%±44 increase; EX, 64%±50, mean±SD) and N-terminal cross-linking telopeptide (CON, 51%±34; EX, 43%±56), markers of bone resorption, were greater than they were before BR in both groups (Pb0.05). However, serum concentrations of the bone formation marker procollagen type I N propeptide were greater in EX than CON throughout and after bed rest (Pb0.05), while concentrations of the bone formation marker bone alkaline phosphatase tended to be greater in EX than CON. Dual-energy X-ray absorptiometry results indicated that the exercise treatment significantly (Pb0.05) attenuated loss of hip and leg bone mineral density in EX compared to CON. The combination of resistive and aerobic exercise did not prevent bone resorption but did promote bone formation, and helped mitigate the net bone loss associated with simulated microgravity. © 2007 Published by Elsevier Inc.

The vitamin B-complex group and vitamin C are the so-called water-soluble vitamins, which dissolve in water and are not stored by the body (IOM (Institute of Medicine) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes 1998). As they are eliminated in urine, a continuous daily supply in the diet is required. Eight of the water-soluble vitamins are known as the vitamin B-complex group: folate (folic acid), thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), vitamin B6 (pyridoxine), vitamin B12, biotin, and pantothenic acid. B vitamins fall into two categories. They are involved in the reactions of intermediary metabolism related to energy production and redox status, or they are involved in the transfer of single-carbon units (IOM (Institute of Medicine) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes 1998). Moreover, vitamin C is a water-soluble vitamin and it is essential for humans, as we do not have the ability to biosynthesize the compound from glucose due to the lack of gulonolactone oxidase. Vitamin C functions physiologically as a water-soluble antioxidant. It is a matter of concern that water-soluble vitamins are easily destroyed or washed out during food storage and preparation. Despite the presence of fruits and vegetables in the daily diet, nutrient loss is possible during the storage and processing of food. This is also of concern for spaceflight and especially for long-term spaceflight. The space radiation environment is another critical factor that must be controlled for an adequate intake of water-soluble vitamins (Smith and Zwart 2008). Not all water-soluble vitamins are critical or of concern for crewmembers. In the following discussions, only the spaceflight-relevant water-soluble vitamins are pointed out.

The effect of weightlessness on the human skeletal system is one of the greatest concerns in safely extending space missions. The ability to understand and counteract weightlessness-induced bone mineral loss will be vital to crew health and safety during and after extended-duration space station and exploration missions. Research on bone mineral loss during space flight has gone on for more than half a century, and recent studies have shown significant progress in developing countermeasures that have proved to be effective, including good nutrition and exercise. We review the history of this research here and provide a summary of recent and ongoing studies, including efforts to counteract bone and calcium loss resulting from weightlessness.

Astronauts are often on a voluntarily reduced energy intake during space missions, possibly caused by a metabolic or emotional stress response with involvement of the central serotonergic system (SES). We investigated 24 h urinary excretion (24 h-E) of serotonin (5-HT) and 5-hydroxyindol acidic acid as indicators of the SES in healthy males under two different normocaloric conditions: normal physical activity (NPA) and - 6 ∘ head-down-tilt (HDT). HDT or NPA were randomly arranged with a recovery period of 6 months in between. 24 h-E of hormones varied widely among individuals. Values were higher in HDT compared to NPA. Assuming that the 24 h-E values are, beside being indicators for alterations in the number and metabolism of platelets, Also indicators of central SES, HDT condition seems to activate central SES in a higher degree compared to NPA. Therefore, changes in central SES might be involved in the mechanisms associated with space flight or microgravity, including possible maladaptations such as voluntary undernutrition.

The United States has had human space flight programs for >50 y and has had a continued presence in space since 2000. Providing nutritious and safe food is imperative for astronauts because space travelers are totally dependent on launched food. Space flight research topics have included energy, protein, nutritional aspects of bone and muscle health, and vision issues related to 1-carbon metabolism. Research has shown that energy needs during flight are similar to energy needs on Earth. Low energy intakes affect protein turnover. The type of dietary protein is also important for bone health, plant-based protein being more efficacious than animal protein. Bone loss is greatly ameliorated with adequate intakes of energy and vitamin D, along with routine resistive exercise. Astronauts with lower plasma folate concentrations may be more susceptible to vision changes. Foods for space flight were developed initially by the U.S. Air Force School of Aerospace Medicine in conjunction with the U.S. Army Natick Laboratories and NASA. Hazard Analysis Critical Control Point safety standards were specifically developed for space feeding. Prepackaged foods for the International Space Station were originally high in sodium (5300 mg/d), but NASA has recently reformulated >90 foods to reduce sodium intake to 3000 mg/d. Food development has improved nutritional quality as well as safety and acceptability.

Nutrients affect hunger and satiety. However, food structure, in particular that of emulsions, may also affect the body's satiety mechanisms. Olibra™ is a fat emulsion, a mixture of fractionated palm oil and fractionated oat oil manufactured by Lipid Technologies Provider AB, Sweden, which affects hunger sensation. However, up to now, no data have shown convincingly that reduced appetite or hunger sensations induced by Olibra lead, in the long run, to a significant and clinically relevant reduction in body mass. To clearly demonstrate a cause-and-effect relationship of Olibra to weight loss, it seems that longer studies with strict control of energy intake and nutrient composition, as well as control of energy expenditure by exercise, are needed.

Weightlessness induces bone loss. Understanding the nature of this loss and developing means to counteract it are significant challenges to potential human exploration missions. This article reviews the existing information from studies of bone and calcium metabolism conducted during space flight. It also highlights areas where nutrition may play a specific role in this bone loss, and where countermeasures may be developed to mitigate that loss.

The purpose of this study was to directly assess sex differences in bone loss, bone biochemistry, and renal stone risk in bed rest. Bed rest simulates some spaceflight effects on human physiology and can be used to address the potential existence of sex‐specific effects on bone metabolism and renal stone risk in space. We combined data from the control subjects in five head‐down‐tilt bed rest studies (combined n = 50 men, 24 women) of differing durations (14–90 days). All subjects were healthy volunteers. Mean age was 35 ± 9 years for women and 33 ± 8 years for men. The main outcome measures were bone density and biochemistry, and renal stone risk chemistry. Before bed rest began, men had higher bone mineral density and content (P < 0.001), and excreted more biomarkers of bone resorption and calcium per day than did women (P < 0.05). These differences remained during bed rest. A number of urine chemistry analytes increased (e.g., calcium) or decreased (e.g., sodium, citrate, and urine volume) significantly for men and women during bed rest. These changes may predispose men to higher stone risk. Men and women do not have substantially different responses to the skeletal unloading of bed rest., We report here that bed rest‐induced bone loss, bone biochemistry, and renal stone risk in humans does not depend on sex. These data are a compilation and analysis of original data from our multiple (published) studies; none of those were adequately powered to assess sex differences. Thus, the resulting findings provide an important new look at the data.

Bone loss on Earth is more prevalent in women than men, leading to the assumption that women may be at greater risk from bone loss during flight. Until recently, the number of women having flown long-duration missions was too small to allow any type of statistical analysis. We report here data from 42 astronauts on long-duration missions to the International Space Station, 33 men and 9 women. Bone mineral density (dual-energy X-ray absorptiometry), bone biochemistry (from blood and urine samples), and renal stone risk factors were evaluated before and after flight. Data were analyzed in two groups, based on available resistance exercise equipment. The response of bone mineral density to flight was the same for men and women, and the typical decrease in bone mineral density (whole body and/or regional) after flight was not observed for either sex for those using an Advanced Resistive Exercise Device. Bone biochemistry, specifically markers of formation and resorption, generally responded similarly in male and female astronauts. The response of urinary supersaturation risk to space flight was not significantly different between men and women, although risks were typically increased after flight in both groups and risks were generally greater in men than in women before and after flight. Overall, the bone and renal stone responses of men and women to space flight were not different.

Aim. We hypothesized that 4 days of normal daily activity after 21 days of experimental bed rest (BR) will not reverse BR induced impaired glucose tolerance.Design. Glucose tolerance of seven male, healthy, untrained test subjects (age: 27.6 (3.3) years (mean (SD)); body mass: 78.6 (6.4) kg; height: 1.81 (0.04) m; VO2max: 39.5 (5.4) ml/kg body mass/min) was studied. They stayed twice in the metabolic ward (crossover design), 21 days in bed and 7 days before and after BR each. Oral glucose tolerance tests were applied before, on day 21 of BR, and 5 and 14 days after BR.Results. On day 21 of BR, AUC120 minof glucose concentration was increased by 28.8 (5.2)% and AUC120 minof insulin by 35.9 (10.2)% (glucose:P<0.001; insulin:P=0.02). Fourteen days after BR, AUC120 minof serum insulin concentrations returned to pre-bed-rest concentrations (P=0.352) and AUC120 minof glucose was still higher (P=0.038). Insulin resistance did not change, but sensitivity index was reduced during BR (P=0.005).Conclusion. Four days of light physical workload does not compensate inactivity induced impaired glucose tolerance. An individually tailored and intensified training regime is mandatory in patients being in bed rest to get back to normal glucose metabolism in a reasonable time frame.

Inactivity, as it appears during space flight and in bed rest, induces reduction of lean body and bone mass, glucose intolerance, and weakening of the cardiovascular system. Increased protein intake, whey protein in particular, has been proposed to counteract some of these effects, but has also been associated with negative effects on bone, likely caused by a correspondingly high ratio of acid to alkali precursors in the diet. The main hypothesis of the presented cross-over study (MEP study) was that supplementing high protein intake (1.2 g/kg body weight/d plus 0.6 g/kg body weight/d whey protein) with alkaline salts (90 mmol potassium bicarbonate/d) will maintain lean body mass during bed rest without increasing bone resorption. A 21-day head-down-tilt bed rest study was performed to examine several physiological systems in a multidisciplinary approach. Ten healthy men (age: 31±6 years; body weight: 76.5±5.6 kg) were randomly assigned to the dietary countermeasure or isocaloric control first, one test subject randomized to the dietary countermeasure first dropped out after the first campaign.

Many studies have used water immersion and head-down bed rest as experimental models to simulate responses to microgravity. However, some data collected during space missions are at variance or in contrast with observations collected from experimental models. These discrepancies could reflect incomplete knowledge of the characteristics inherent to each model. During water immersion, the hydrostatic pressure lowers the peripheral vascular capacity and causes increased thoracic blood volume and high vascular perfusion. In turn, these changes lead to high urinary flow, low vasomotor tone, and a high rate of water exchange between interstitium and plasma. In contrast, the increase in thoracic blood volume during a space mission is combined with stimulated orthosympathetic tone and lowered urine flow. During bed rest, body tissues are compressed by pressure from gravity, whereas microgravity causes a negative pressure around the body. The differences in renal function between space and experimental models appear to be explained by the physical forces affecting tissues and hemodynamics as well as by the changes secondary to these forces. These differences may help in selecting experimental models to study possible effects of microgravity.

An inadequate nutrient intake during space flight may compromise the crewmembers' health status. In fact, during recent European missions (D-2, EuroMIR 94 and EuroMIR 95), monitoring of the astronauts' food intake revealed that they had a deficient energy, fluid, and calcium intake and an excessive sodium consumption compared to the dietary reference intakes for earthbound conditions. Inappropriate amounts of these nutrients have a considerable impact on body fluid regulation, the cardiovascular system and on calcium and bone metabolism, especially bone mineral density, which are all stressed by the microgravity environment. Provision of adequate nutrition especially when facing long-term space flights is therefore one of the foremost challenges. Therefore, for the German MIR 97 mission, we considered the data obtained from previous European missions to devise a constant and controlled nutrient intake that matched the earthbound dietary reference intake values in our experiments. Specific markers indicated that bone formation continually declined and bone resorption increased in the MIR 97 astronaut. This suggests that the nutritional criteria chosen for the subjects remaining on Earth may be inadequate for extended space missions. Therefore, more emphasis has to be placed on investigating the effects of a deficient nutrient intake on astronauts during exposure to microgravity, to manage their nutritional care appropriately during long-term missions.

We tested the hypothesis that sympathoadrenal activity in humans is low during spaceflight and that this effect can be simulated by head-down bed rest (HDBR). Platelet norepinephrine and epinephrine were measured as indexes of long-term changes in sympathoadrenal activity. Ten normal healthy subjects were studied before and during HDBR of 2-wk duration, as well as during an ambulatory study period of a similar length. Platelet norepinephrine concentrations (half-life = 2 days) were studied in five cosmonauts, 2 wk before launch, within 12 h after landing after 11–12 days of flight, and at least 2 wk after return to Earth. Because of the long half-life of platelet norepinephrine, data obtained early after landing would still reflect the microgravity state. Platelet norepinephrine decreased markedly during HDBR ( P < 0.001), whereas there were no significant changes when subjects were ambulatory. Platelet epinephrine did not change during HDBR. During microgravity, platelet norepinephrine and epinephrine increased in four of the five cosmonauts. Platelet norepinephrine concentrations expressed in percentage of preflight and pre-HDBR values, respectively, were significantly different during microgravity compared with HDBR [153 ± 28% (mean ± SE) vs. 60 ± 6%, P < 0.004]. Corresponding values for platelet epinephrine were also significant (293 ± 85 vs. 90 ± 12%, P < 0.01). The mechanism of the platelet norepinephrine and epinephrine response during spaceflight flight is most likely related to the concomitant decrease in plasma volume. HDBR cannot be applied to simulate changes in sympathoadrenal activity during microgravity.

We tested whether physical inactivity (PI) is an independent predictor of plasma visfatin, a newly discovered adipokine likely involved in the relationship between obesity-associated low-grade inflammation and insulin resistance. PI was induced in healthy men (Body Mass Index = 23.4 ± 0.6 kg·m−2) by 10 days of confinement (n = 8), 1 month of detraining (n = 10), and 3 months of bed rest with (n = 7) and without exercise (n = 8). Visfatin was negatively associated with activity energy expenditure (p = 0.03). No relationship was observed with insulin sensitivity. This suggested that PI itself increases visfatin concentrations.

It is apparent that composition and quantity of dietary intake has a profound effect on human health. Therefore, provision of adequate food and nutrition is one of the foremost challenges facing long-termspaceflight. This includes recognition of the manner in which weight-lessness alters human metabolism and provision for adequate life support. Since the beginning of manned spaceflight, there has been a steady improvement in the understanding of nutritional needs as missions have increased from days to weeks to one year in duration. But our knowledge of changes in nutritional requirements due to microgravity is far from complete. To date, measures used have been almost entirely empiric and focused on providing a near Earth-like environment and palatable diet. Interplanetary travel will be impos- sible without recycling wastes, generating drinkable water, and growing a limited number of food stuffs. Now emphasis must shift to a more thorough understanding of the fundamental processes involved with long-term stays in space and appropriate application of proce- dures leading to amelioration of induced changes. The following chapter will discuss those changes in macro- and micro-nutrients which are known to occur with weightlessness and present relevant considerations for maintaining appropriate nutrition during prolonged space missions. Special attention will be focused on two minerals, sodium and calcium, which are known to show important changes in the human body during spaceflight.

Bed rest studies provide an important tool for modeling physiological changes that occur during spaceflight. Markers of bone metabolism and nutritional status were evaluated in 12 subjects (8 men, 4 women; ages 25–49 yr) who participated in a 30-day −6° head-down-tilt diet-controlled bed rest study. Blood and urine samples were collected twice before, once a week during, and twice after bed rest. Data were analyzed using a mixed-effects linear regression with a priori contrasts comparing all days to the second week of the pre-bed rest acclimation period. During bed rest, all urinary markers of bone resorption increased ∼20% ( P < 0.001), and serum parathyroid hormone decreased ∼25% ( P < 0.001). Unlike longer (>60 days) bed rest studies, neither markers of oxidative damage nor iron status indexes changed over the 30 days of bed rest. Urinary oxalate excretion decreased ∼20% during bed rest ( P < 0.001) and correlated inversely with urinary calcium ( R = −0.18, P < 0.02). These data provide a broad overview of the biochemistry associated with short-duration bed rest studies and provide an impetus for using shorter studies to save time and costs wherever possible. For some effects related to bone biochemistry, short-duration bed rest will fulfill the scientific requirements to simulate spaceflight, but other effects (antioxidants/oxidative damage, iron status) do not manifest until subjects are in bed longer, in which case longer studies or other analogs may be needed. Regardless, maximizing research funding and opportunities will be critical to enable the next steps in space exploration.

About 20% of astronauts on International Space Station missions have developed measurable ophthalmic changes after flight. This study was conducted to determine whether the folate-dependent 1-carbon pathway is altered in these individuals. Data were modeled to evaluate differences between individuals with ophthalmic changes (n=5) and those without them (n=15). We also correlated mean preflight serum concentrations of the 1-carbon metabolites with changes in measured refraction after flight. Serum homocysteine (HCy), cystathionine, 2-methylcitric acid, and methylmalonic acid concentrations were 25%-45% higher (P

We have tested the effects of weightlessness on renal function in one subject who flew the recent week-long Russian-German MIR'92 space mission. Urine flow, renal sodium excretion, and the excretion of urodilatin were measured during the first and last days of the flight. Our results demonstrated, in contrast to expectations, that urine flow and sodium excretion during weightlessness were actually lower than the values obtained during preflight measurements. These results therefore are inconsistent with the commonly held hypothesis that weightlessness induces a diuresis and natriuresis in human subjects. It would seem that further studies are necessary to resolve this issue and to determine whether currently used ground-based models of weightlessness correctly predict physiological adaptations that occur during space flight.