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1.  Effect of Physical Inactivity on the Oxidation of Saturated and Monounsaturated Dietary Fatty Acids: Results of a Randomized Trial  
PLoS Clinical Trials  2006;1(5):e27.
Changes in the way dietary fat is metabolized can be considered causative in obesity. The role of sedentary behavior in this defect has not been determined. We hypothesized that physical inactivity partitions dietary fats toward storage and that a resistance exercise training program mitigates storage.
We used bed rest, with randomization to resistance training, as a model of physical inactivity.
The trial took place at the Space Clinic (Toulouse, France).
A total of 18 healthy male volunteers, of mean age ± standard deviation 32.6 ± 4.0 y and body mass index 23.6 ± 0.7 kg/m2, were enrolled.
An initial 15 d of baseline data collection were followed by 3 mo of strict bed-rest alone (control group, n = 9) or with the addition of supine resistance exercise training every 3 d (exercise group, n = 9).
Outcome measures:
Oxidation of labeled [d31]palmitate (the main saturated fatty acid of human diet) and [1-13C]oleate (the main monounsaturated fatty acid), body composition, net substrate use, and plasma hormones and metabolites were measured.
Between-group comparisons showed that exercise training did not affect oxidation of both oleate (mean difference 5.6%; 95% confidence interval [95% CI], −3.3% to 14.5%; p = 0.20) and palmitate (mean difference −0.2%; 95% CI, −4.1% to 3.6%; p = 0.89). Within-group comparisons, however, showed that inactivity changed oxidation of palmitate in the control group by −11.0% (95% CI, −19.0% to −2.9%; p = 0.01) and in the exercise group by −11.3% (95% CI, −18.4% to −4.2%; p = 0.008). In contrast, bed rest did not significantly affect oleate oxidation within groups. In the control group, the mean difference in oleate oxidation was 3.2% (95% CI, −4.2% to 10.5%; p = 0.34) and 6.8% (95% CI, −1.2% to 14.7%; p = 0.08) in the exercise group.
Independent of changes in energy balance (intake and/or output), physical inactivity decreased the oxidation of saturated but not monounsaturated dietary fat. The effect is apparently not compensated by resistance exercise training. These results suggest that Mediterranean diets should be recommended in sedentary subjects and recumbent patients.
Editorial Commentary
Background: Obesity is an important contributor to the burden of chronic diseases, particularly type II diabetes, cardiovascular disease, hypertension, and stroke. Being inactive is a risk factor for all of these conditions. However, the physiological effects of inactivity are not well understood. In this trial, supported by the European Space Agency, a group of researchers aimed to further understand the effects of physical inactivity on the way that fat from the diet is metabolized (i.e., broken down to generate energy). 18 healthy male volunteers were randomized into two groups, both of whom underwent 90 days of bed rest, aiming to mimic sedentary behavior. One group also received an exercise training program during the 90 days' bed rest. The researchers examined to what extent two different types of fatty acids common in the diet were metabolized over the duration of the trial: oleate (monounsaturated fat) and palmitate (saturated fat). As secondary objectives of the study, body weight, water, fat, and energy expenditure were also examined in the participants.
What this trial shows: The researchers did not see any statistically significant changes between the groups—that is, participants receiving bed rest, and those receiving bed rest plus exercise training—for any of the primary or secondary outcomes, except for resting metabolic rate, which was higher in the exercise group. However, they did see physiologically relevant changes in fat metabolism of one of the fatty acids, palmitate, over the course of the trial within both groups studied. Although metabolism of oleate (monounsaturated fat) did not show significant changes over the course of the trial, metabolism of palmitate (saturated fat) dropped by nearly 10% in both groups (bed rest, and bed rest plus exercise).
Strengths and limitations: The study design was appropriate to the questions being posed, and the techniques for examining fat metabolism were relevant. Although the number of participants was very small, this problem is true of many such studies due to the cost and complexity of the interventions. The model for inactivity used in this trial—90 days' bed rest—is very extreme. Very few studies of this type have been performed, with most of the evidence relating to activity and fat handling coming from training studies in otherwise sedentary people.
Contribution to the evidence: It is already known that physical activity has numerous health benefits, including the prevention of obesity. This trial provides data showing that inactivity lowers the ability to metabolize fat, specifically saturated fat, from the diet, which would therefore be more likely to be stored in the body.
PMCID: PMC1584255  PMID: 17016547
2.  The effects of rehabilitation on the muscles of the trunk following prolonged bed rest 
European Spine Journal  2010;20(5):808-818.
Microgravity and inactivity due to prolonged bed rest have been shown to result in atrophy of spinal extensor muscles such as the multifidus, and either no atrophy or hypertrophy of flexor muscles such as the abdominal group and psoas muscle. These effects are long-lasting after bed rest and the potential effects of rehabilitation are unknown. This two-group intervention study aimed to investigate the effects of two rehabilitation programs on the recovery of lumbo-pelvic musculature following prolonged bed rest. 24 subjects underwent 60 days of head down tilt bed rest as part of the 2nd Berlin BedRest Study (BBR2-2). After bed rest, they underwent one of two exercise programs, trunk flexor and general strength (TFS) training or specific motor control (SMC) training. Magnetic resonance imaging of the lumbo-pelvic region was conducted at the start and end of bed rest and during the recovery period (14 and 90 days after re-ambulation). Cross-sectional areas (CSAs) of the multifidus, psoas, lumbar erector spinae and quadratus lumborum muscles were measured from L1 to L5. Morphological changes including disc volume, spinal length, lordosis angle and disc height were also measured. Both exercise programs restored the multifidus muscle to pre-bed-rest size, but further increases in psoas muscle size were seen in the TFS group up to 14 days after bed rest. There was no significant difference in the number of low back pain reports for the two rehabilitation groups (p = .59). The TFS program resulted in greater decreases in disc volume and anterior disc height. The SMC training program may be preferable to TFS training after bed rest as it restored the CSA of the multifidus muscle without generating potentially harmful compressive forces through the spine.
PMCID: PMC3082685  PMID: 20593204
Bed rest; Magnetic resonance imaging; Gravity; Multifidus muscle; Psoas muscle; Rehabilitation
3.  Effects of long-term head-down-tilt bed rest and different training regimes on the coagulation system of healthy men 
Physiological Reports  2013;1(6):e00135.
Immobility plus preexisting chronic disease or acute trauma can activate the coagulation system, thus increasing the risk for thromboembolic events. The effects of long-term bed-rest immobility and microgravity on the coagulation system of healthy persons (e.g., during crewed Mars missions) have not yet been studied. The main objective of the second Berlin BedRest Study (BBR2-2) “Coagulation Part” was to investigate adaptations of the hemostatic system during long-term bed rest (60 days) under simulated microgravity (6° head-down-tilt [6°HDT]) and after mobilization in three different volunteer groups (randomly assigned to CTR= inactive control group; RE= resistive exercise only group; and RVE= resistive exercise with whole-body vibration group). In 24 males (aged 21–45 years), before, during, and after long-term bed rest, key parameters of coagulation were measured from venous blood samples: D-dimer (DD), thrombin–antithrombin III complex (TAT), and prothrombin fragment F1 + 2 (PT-F1 + 2). Additionally, modified rotational thrombelastometry (ROTEM®) analysis was performed. Times of exploratory analyses were as follows: baseline data collection 2 days before bed rest (BDC-2); eight different days of 6°HDT bed rest (HDT1–HDT60), and two different days after reambulation (R + 3 and R + 6). We found significant changes in DD, TAT, and PT-F1 + 2 over the total time course, but no consistent effect of physical interventions (RE, RVE) on these parameters. Notably, no parameter reached levels indicative of intravascular thrombin formation. All ROTEM® parameters remained within the normal range and no pathological traces were found. Sixty days of 6°HDT bed rest are not associated with pronounced activation of the coagulation system indicative of intravascular thrombus formation in healthy volunteers independent of the training type during the bed rest.
PMCID: PMC3871450  PMID: 24400137
Hemostasis; head-down tilt; immobilization; resistance training; thromboelastography
4.  Physical Inactivity Rapidly Induces Insulin Resistance and Microvascular Dysfunction in Healthy Volunteers 
Sedentary lifestyle increases the risk of cardiovascular disease and diabetes. Vascular dysfunction contributes to atherogenesis and has been linked to insulin resistance.
Methods and Results
We measured insulin sensitivity by glucose tolerance test and vascular function by ultrasound and venous occlusion plethysmography in 20 healthy subjects (14 men, 6 women) at baseline and during 5 days of bed rest. Bed rest led to a 67% increase in the insulin response to glucose loading (P<0.001) suggesting increased insulin resistance and produced increases in total cholesterol and triglycerides. Bed rest led to decreased reactive hyperemia in the forearm (1317±404 to 1112±260 mL/min, P=0.01) and the calf (28.5±7.0 to 22.2±8.7 mL/min/dL, P=0.003) indicating impaired microvascular function. Bed rest decreased brachial artery diameter and increased systolic blood pressure suggesting increased basal arterial tone. There were no changes in circulating inflammatory markers arguing against systemic inflammation as a mechanism for vascular dysfunction in this setting.
Physical inactivity was associated with the development of insulin resistance, dyslipidemia, increased blood pressure, and impaired microvascular function in healthy volunteers. Our findings may provide insight into the pathogenesis of vascular disease in sedentary individuals and emphasize that even short-term physical inactivity may have adverse metabolic and vascular consequences.
PMCID: PMC2596308  PMID: 17932315
insulin resistance; sedentary lifestyle; obesity; endothelium; blood pressure; reactive hyperemia
5.  Lower body negative pressure treadmill exercise as a countermeasure for bed rest-induced bone loss in female identical twins 
Bone  2006;40(2):529-537.
Supine weight-bearing exercise within lower body negative pressure (LBNP) alleviates some of the skeletal deconditioning induced by simulated weightlessness in men. We examined the potential beneficial effect in women. Because dietary acid load affected the degree of bone resorption in men during bed rest, we also investigated this variable in women. Subjects were 7 pairs of female identical twins assigned at random to 2 groups, sedentary bed rest (control) or bed rest with supine treadmill exercise within LBNP. Dietary intake was controlled and monitored. Urinary calcium and markers of bone resorption were measured before bed rest (BR) and on BR days 5/6, 12/13, 19/20, and 26/27. Bone mineral content was assessed by dual-energy X-ray absorptiometry before and after bed rest. Data were analyzed by repeated measures two-way analysis of variance. Pearson correlation coefficients were used to define the relationships between diet and markers of bone metabolism, and to estimate heritability of markers. During bed rest, all markers of bone resorption and urinary calcium and phosphorus increased (P < 0.001); parathyroid hormone (P = 0.06), bone-specific alkaline phosphatase (P = 0.06), and 1,25-dihydroxyvitamin D (P = 0.09) tended to decrease. LBNP exercise tended to mitigate bone density loss. The ratio of dietary animal protein to potassium was positively correlated with urinary calcium excretion for all weeks of bed rest in the control group, but only during weeks 1 and 3 for the exercise group. Pre-bed rest data suggested that many markers of bone metabolism have strong genetic determinants. Treadmill exercise within LBNP had less of a protective effect on bone resorption during bed rest in women than previously-published results had shown for its effect in men, but the same trends were observed for both sexes. Dietary acid load of these female subjects was significantly correlated with calcium excretion but not with other bone resorption markers.
PMCID: PMC1876821  PMID: 17070743
Exercise; Nutrition; Osteoporosis; Bone turnover markers; Weightlessness
6.  Effects of 60-day bed rest with and without exercise on cellular and humoral immunological parameters 
Cellular and Molecular Immunology  2014;12(4):483-492.
Exercise at regular intervals is assumed to have a positive effect on immune functions. Conversely, after spaceflight and under simulated weightlessness (e.g., bed rest), immune functions can be suppressed. We aimed to assess the effects of simulated weightlessness (Second Berlin BedRest Study; BBR2-2) on immunological parameters and to investigate the effect of exercise (resistive exercise with and without vibration) on these changes. Twenty-four physically and mentally healthy male volunteers (20–45 years) performed resistive vibration exercise (n=7), resistance exercise without vibration (n=8) or no exercise (n=9) within 60 days of bed rest. Blood samples were taken 2 days before bed rest, on days 19 and 60 of bed rest. Composition of immune cells was analyzed by flow cytometry. Cytokines and neuroendocrine parameters were analyzed by Luminex technology and ELISA/RIA in plasma. General changes over time were identified by paired t-test, and exercise-dependent effects by pairwise repeated measurements (analysis of variance (ANOVA)). With all subjects pooled, the number of granulocytes, natural killer T cells, hematopoietic stem cells and CD45RA and CD25 co-expressing T cells increased and the number of monocytes decreased significantly during the study; the concentration of eotaxin decreased significantly. Different impacts of exercise were seen for lymphocytes, B cells, especially the IgD+ subpopulation of B cells and the concentrations of IP-10, RANTES and DHEA-S. We conclude that prolonged bed rest significantly impacts immune cell populations and cytokine concentrations. Exercise was able to specifically influence different immunological parameters. In summary, our data fit the hypothesis of immunoprotection by exercise and may point toward even superior effects by resistive vibration exercise.
PMCID: PMC4496533  PMID: 25382740
immune function; monitoring of immunological parameters; physical inactivity; spaceflight
7.  Effectiveness of bed rest after mild traumatic brain injury: a randomised trial of no versus six days of bed rest 
Background: Outcome after mild traumatic brain injury (MTBI) is determined largely by the appearance of post-traumatic complaints (PTC). The prevalence of PTC after six months is estimated to be between 20 and 80%. Bed rest has been advocated to prevent PTC but its effectiveness has never been established.
Objective: To evaluate the effect of bed rest on the severity of PTC after MTBI.
Methods: Patients presenting with MTBI to the emergency room were randomly assigned to two intervention strategies. One group was advised not to take bed rest (NO) and the other to take full bed rest (FULL) for six days after the trauma. The primary outcome measures were severity of PTC on a visual analogue scale and physical and mental health on the medical outcomes study 36 item short form health survey (SF-36) at two weeks and three and six months after the trauma.
Results: Between October 1996 and July 1999, 107 (54 NO, 53 FULL) patients were enrolled. Outcome variables in both groups clearly improved between two weeks and six months. After adjustment for differences in baseline variables, most PTC tended to be somewhat more severe in the FULL group six months after the trauma, but no significant differences were found. Neither were there any significant differences in the outcome parameters between the two groups after three months. Two weeks after the trauma, most PTC in the FULL group were slightly less severe than those in the NO group, and physical subscores of the SF-36 in the FULL group were slightly better. These differences were not significant. Patients in the FULL group reported significantly less dizziness during the intervention period.
Conclusions: As a means of speeding up recovery of patients with PTC after MTBI, bed rest is no more effective than no bed rest at all. Bed rest probably has some palliative effect within the first two weeks after the trauma.
PMCID: PMC1737969  PMID: 12122176
8.  Effects of Bed-Rest on Urea and Creatinine: Correlation with Changes in Fat-Free Mass 
PLoS ONE  2014;9(9):e108805.
Bed-rest experiments are designed for investigation on catabolic effects of hypokinetic conditions and/or for microgravity simulation in on-ground aerospace research. Bed-rest effects include a reduction in fat-free mass and muscle mass. Urea and creatinine are catabolites of endogenous protein and of muscular energetic metabolism which are excreted mainly by the kidney. The study investigated on urea, creatinine, and kidney function during bed-rest.
Twenty healthy young men underwent a 7-day adaptation period (day-6 to day-0) and a 35-day bed-rest experiment (day1 to day35) during normocaloric diet. Urine were collected from day-3 to day0 (baseline) and from day1 to day35. Blood samples and anthropometrical data were collected at day0 (baseline) and bed-rest days 7, 14, 21, 28, and 35.
Bed-rest reduced plasma volume, weight, fat-free mass, and muscle mass (P<0.001). During bed-rest there was a transient increase in plasma and urinary urea, a decrease in plasma creatinine, and no change in urinary creatinine. The overall integral of changes from day0 to day35 was on average +101.7 mg/dL for plasma urea (95%CI = +43.4/+159.9), +82.2 g/24 h for urinary urea (95%CI = +55.8/+108.7), −2.5 mg/dL for plasma creatinine (95%CI = −3.1/−1.9). Bed-rest reduced plasma cistatyn C also, which was used as mass-independent marker of glomerular filtration rate (−13.1%, P<0.05). Correlations with final reduction in fat-free mass and muscle mass were significant for the overall integral of changes in urinary urea from day0 to day35 (R = 0.706, P<0.001) and for early changes in urinary urea and plasma urea from day0 to day7 (R = 0.566, P = 0.009 and R = 0.715, P<0.001, respectively).
Study results shows that urea is a marker of catabolic conditions secondary to hypokinetic conditions.
PMCID: PMC4181864  PMID: 25265226
9.  Characteristics of fast voluntary and electrically evoked isometric knee extensions during 56 days of bed rest with and without exercise countermeasure 
The contractile characteristics of fast voluntary and electrically evoked unilateral isometric knee extensions were followed in 16 healthy men during 56 days of horizontal bed rest and assessed at bed rest days 4, 7, 10, 17, 24, 38 and 56. Subjects were randomized to either an inactive control group (Ctrl, n = 8) or a resistive vibration exercise countermeasure group (RVE, n = 8). No changes were observed in neural activation, indicated by the amplitude of the surface electromyogram, or the initial rate of voluntary torque development in either group during bed rest. In contrast, for Ctrl, the force oscillation amplitude at 10 Hz stimulation increased by 48% (P < 0.01), the time to reach peak torque at 300 Hz stimulation decreased by 7% (P < 0.01), and the half relaxation time at 150 Hz stimulation tended to be slightly reduced by 3% (P = 0.056) after 56 days of bed rest. No changes were observed for RVE. Torque production at 10 Hz stimulation relative to maximal (150 Hz) stimulation was increased after bed rest for both Ctrl (15%; P < 0.05) and RVE (41%; P < 0.05). In conclusion, bed rest without exercise countermeasure resulted in intrinsic speed properties of a faster knee extensor group, which may have partly contributed to the preserved ability to perform fast voluntary contractions. The changes in intrinsic contractile properties were prevented by resistive vibration exercise, and voluntary motor performance remained unaltered for RVE subjects as well.
PMCID: PMC2358938  PMID: 18386049
Maximal rate of torque rise; Time course; Unloading; Force oscillation amplitude; EMG
10.  Effects of Head-Down Bed Rest on the Executive Functions and Emotional Response 
PLoS ONE  2012;7(12):e52160.
Prolonged bed rest may cause changes in the autonomic nervous system that are related to cognition and emotion. This study adopted an emotional flanker task to evaluate the effect of 45 days -6° head-down bed rest (HDBR) on executive functioning in 16 healthy young men at each of six time points: the second-to-last day before the bed rest period, the eleventh, twentieth, thirty-second and fortieth day during the bed rest period, and the eighth day after the bed rest period. In addition, self-report inventories (Beck Anxiety Inventory, BAI; Beck Depression Inventory, BDI; Positive Affect and Negative Affect Scale, PANAS) were conducted to record emotional changes, and the participants’ galvanic skin response (GSR), heart rate (HR) and heart rate variability (HRV) were assessed as measures of physiological activity. The results showed that the participants’ reaction time on the flanker task increased significantly relative to their responses on the second-to-last day before the period of bed rest, their galvanic skin response weakened and their degrees of positive affect declined during the bed rest period. Our results provide some evidence for a detrimental effect of prolonged bed rest on executive functioning and positive affect. Whether this stems from a lack of aerobic physical activity and/or the effect of HDBR itself remains to be determined.
PMCID: PMC3524097  PMID: 23284916
11.  Impact of 9 Days of Bed Rest on Hepatic and Peripheral Insulin Action, Insulin Secretion, and Whole-Body Lipolysis in Healthy Young Male Offspring of Patients With Type 2 Diabetes 
Diabetes  2009;58(12):2749-2756.
The aim of this study was to investigate the impact of 9 days of bed rest on insulin secretion, insulin action, and whole-body glucose and fat metabolism in first-degree relative (FDR) and matched control (CON) subjects.
A total of 13 FDR and 20 CON subjects participated in the study. All were studied before and after 9 days of bed rest using the clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. Glucose and glycerol turnover rates were studied using stable isotope kinetics.
Bed rest caused a significant decrease in whole-body insulin sensitivity in both groups. Hepatic insulin resistance was elevated in FDR subjects prior to bed rest and was significantly augmented by bed rest in FDR (P < 0.01) but not in CON (P = NS) subjects. The rate of whole-body lipolysis decreased during bed rest in both FDR and CON subjects, with no significant differences between the groups. Insulin resistance induced by bed rest was fully accounted for by the impairment of nonoxidative glucose metabolism in both groups (overall P < 0.001).
Whole-body insulin action in both insulin-resistant FDR and healthy CON subjects deteriorates with 9 days of bed rest, converging toward similar degrees of whole-body insulin resistance. FDR subjects exhibit hepatic insulin resistance (HIR), which, in contrast to CON subjects, deteriorates in response to physical inactivity. FDR subjects exhibit reduced insulin secretion when seen in relation to their degree of HIR but not peripheral insulin resistance.
PMCID: PMC2780872  PMID: 19720789
12.  Impact of Physical Inactivity on Subcutaneous Adipose Tissue Metabolism in Healthy Young Male Offspring of Patients With Type 2 Diabetes 
Diabetes  2010;59(11):2790-2798.
Physical inactivity is a risk factor for type 2 diabetes and may be more detrimental in first-degree relative (FDR) subjects, unmasking underlying defects of metabolism. Using a positive family history of type 2 diabetes as a marker of increased genetic risk, the aim of this study was to investigate the impact of physical inactivity on adipose tissue (AT) metabolism in FDR subjects.
A total of 13 FDR and 20 control (CON) subjects participated in the study. All were studied before and after 10 days of bed rest using the glucose clamp technique combined with measurements of glucose uptake, lipolysis, and lactate release from subcutaneous abdominal (SCAAT) and femoral (SCFAT) adipose tissue by the microdialysis technique. Additionally, mRNA expression of lipases was determined in biopsies from SCAAT.
Before bed rest, the FDR subjects revealed significantly increased glucose uptake in SCAAT. Furthermore, mRNA expression of lipases was significantly decreased in the SCAAT of FDR subjects. Bed rest significantly decreased lipolysis and tended to increase glucose uptake in the SCFAT of both CON and FDR subjects. In response to bed rest, SCAAT glucose uptake significantly increased in CON subjects but not in FDR subjects.
FDR subjects exhibit an abnormal AT metabolism including increased glucose uptake prior to bed rest. However, the differences between FDR and CON subjects in AT metabolism were attenuated during bed rest due to relatively more adverse changes in CON subjects compared with FDR subjects. Physical inactivity per se is not more deleterious in FDR subjects as compared with CON subjects with respect to derangements in AT metabolism.
PMCID: PMC2963537  PMID: 20823100
13.  Larks and owls and health, wealth, and wisdom 
BMJ : British Medical Journal  1998;317(7174):1675-1677.
To test the validity of Benjamin Franklin’s maxim “early to bed and early to rise makes a man healthy, wealthy, and wise.”
Cross sectional analysis of sleeping patterns in a nationally representative group of elderly people, and longitudinal investigation of mortality.
Eight areas in Britain (five in England, two in Scotland, and one in Wales).
1229 men and women aged 65 and over who in 1973-4 had taken part in a survey funded by the Department of Health and Social Security and for whom data on sleeping patterns, health, socioeconomic circumstances, and cognitive function had been recorded.
Main outcome measures
Self reported income, access to a car, standard of accommodation, performance on a test of cognitive function, state of health and mortality during 23 years of follow up.
356 people (29%) were defined as larks (to bed before 11 pm and up before 8 am) and 318 (26%) were defined as owls (to bed at or after 11 pm and up at or after 8 am). There was no indication that larks were richer than those with other sleeping patterns. On the contrary, owls had the largest mean income and were more likely to have access to a car. There was also no evidence that larks were superior to those with other sleeping patterns with regard to their cognitive performance or their state of health. Both larks and owls had a slightly reduced risk of death compared with the rest of the study sample, but this was accounted for by the fact that they spent less time in bed at night. In the study sample as a whole, longer periods of time in bed were associated with increased mortality. After adjustment for age, sex, the presence of illness, and other risk factors, people who spent 12 or more hours in bed had a relative risk of death of 1.7 (1.2 to 2.5) compared with those who were in bed for 9 hours. The lowest risk occurred in people who spent 8 hours in bed (adjusted relative risk 0.8; 0.7 to 1.0).
These findings do not support Franklin’s claim. A “late to bed and late to rise” lifestyle does not seem to lead to socioeconomic, cognitive, or health disadvantage, but a longer time spent in bed may be associated with increased mortality.
Key messagesProverbial advice about lifestyle has the authority of tradition and the merit of brevity, but it is rarely based on systematically collected evidenceIn a nationally representative cohort of elderly people there was no indication that those who lived by the maxim “early to bed and early to rise” were advantaged as regards state of health, material circumstances, or wisdomSleeping for more than 8 hours a night was associated with increased mortality, but it mattered little whether sleep was taken in the early or late part of the nightThere is no justification for early risers to affect moral superiority
PMCID: PMC28744  PMID: 9857121
14.  Day/Night Variability in Blood Pressure: Influence of Posture and Physical Activity 
American Journal of Hypertension  2013;26(6):822-828.
Blood pressure (BP) is highest during the day and lowest at night. Absence of this rhythm is a predictor of cardiovascular morbidity and mortality. Contributions of changes in posture and physical activity to the 24-hour day/night rhythm in BP are not well understood. We hypothesized that postural changes and physical activity contribute substantially to the day/night rhythm in BP.
Fourteen healthy, sedentary, nonobese, normotensive men (aged 19–50 years) each completed an ambulatory and a bed rest condition during which BP was measured every 30–60 minutes for 24 hours. When ambulatory, subjects followed their usual routines without restrictions to capture the “normal” condition. During bed rest, subjects were constantly confined to bed in a 6-degree head-down position; therefore posture was constant, and physical activity was minimized. Two subjects were excluded from analysis because of irregular sleep timing.
The systolic and diastolic BP reduction during the sleep period was similar in ambulatory (−11±2mmHg/−8±1mmHg) and bed rest conditions (−8±3mmHg/−4±2mmHg; P = 0.38/P = 0.12). The morning surge in diastolic BP was attenuated during bed rest (P = 0.001), and there was a statistical trend for the same effect in systolic BP (P = 0.06).
A substantial proportion of the 24-hour BP rhythm remained during bed rest, indicating that typical daily changes in posture and/or physical activity do not entirely explain 24-hour BP variation under normal ambulatory conditions. However, the morning BP increase was attenuated during bed rest, suggesting that the adoption of an upright posture and/or physical activity in the morning contributes to the morning BP surge.
PMCID: PMC3693479  PMID: 23535155
ambulatory; bed rest; blood pressure; circadian; hypertension; sleep.
15.  New Onset of Constipation during Long-Term Physical Inactivity: A Proof-of-Concept Study on the Immobility-Induced Bowel Changes 
PLoS ONE  2013;8(8):e72608.
The pathophysiological mechanisms underlining constipation are incompletely understood, but prolonged bed rest is commonly considered a relevant determinant.
Our primary aim was to study the effect of long-term physical inactivity on determining a new onset of constipation. Secondary aim were the evaluation of changes in stool frequency, bowel function and symptoms induced by this prolonged physical inactivity.
Ten healthy men underwent a 7-day run-in followed by 35-day study of experimentally-controlled bed rest. The study was sponsored by the Italian Space Agency. The onset of constipation was evaluated according to Rome III criteria for functional constipation. Abdominal bloating, flatulence, pain and urgency were assessed by a 100mm Visual Analog Scales and bowel function by adjectival scales (Bristol Stool Form Scale, ease of passage of stool and sense of incomplete evacuation). Daily measurements of bowel movements was summarized on a weekly score. Pre and post bed rest Quality of Life (SF-36), general health (Goldberg’s General Health) and depression mood (Zung scale) questionnaires were administered.
New onset of functional constipation fulfilling Rome III criteria was found in 60% (6/10) of participants (p=0.03). The score of flatulence significantly increased whilst the stool frequency significantly decreased during the week-by-week comparisons period (repeated-measures ANOVA, p=0.02 and p=0.001, respectively). Stool consistency and bowel symptoms were not influenced by prolonged physical inactivity. In addition, no significant changes were observed in general health, in mood state and in quality of life at the end of bed rest
Our results provide evidence that prolonged physical inactivity is relevant etiology in functional constipation in healthy individuals. The common clinical suggestion of early mobilization in bedridden patients is supported as well.
PMCID: PMC3748072  PMID: 23977327
16.  Turnover and splanchnic metabolism of free fatty acids and ketones in insulin-dependent diabetics at rest and in response to exercise. 
Journal of Clinical Investigation  1984;73(5):1367-1376.
Nine insulin-dependent diabetics and six healthy controls were studied at rest, during, and after 60 min of bicycle exercise at a work load corresponding to 45% of their maximal oxygen intake. The catheter technique was employed to determine splanchnic and leg exchange of metabolites. FFA turnover and regional exchange was evaluated using [14C]oleate infusion. Basal glucose (13.8 +/- 1.1 mmol/l), ketone body (1.12 +/- 0.12 mmol/l), and FFA (967 +/- 110 mumol/l) concentrations were elevated in the diabetics in comparison with controls. In the resting state, splanchnic ketone acid production in the diabetics was 6-10-fold greater than in controls. Uptake of oleic acid by the splanchnic bed was increased 2-3-fold, and the proportion of splanchnic FFA uptake converted to ketones (61%) was threefold greater than in controls. In contrast, splanchnic fractional extraction of oleic acid was identical in diabetics and controls. A direct relationship was observed between splanchnic uptake and splanchnic inflow (plasma concentration X hepatic plasma flow) of oleic acid that could be described by the same regression line in the diabetic and control groups. During exercise, splanchnic ketone production rose in both groups. In the control group the increase in ketogenesis was associated with a rise in splanchnic inflow and in uptake of oleic acid, a rise in splanchnic fractional extraction of oleate, and an increase in the proportion of splanchnic FFA uptake converted to ketone acids from 20-40%. In the diabetic group, the increase in ketogenesis occurred in the absence of a rise in splanchnic inflow or uptake of oleic acid, but was associated with an increase in splanchnic fractional extraction of oleic acid and a marked increase in hepatic conversion of FFA to ketones, so that the entire uptake of FFA was accountable as ketone acid output. Splanchnic uptake of oleic acid correlated directly with splanchnic oleic acid inflow in both groups, but the slope of the regression line was steeper than in the resting state. Plasma glucagon levels were higher in the diabetic group at rest and during exercise, while plasma norepinephrine showed a twofold greater increment in response to exercise in the diabetic group (to 1,400-1,500 pg/ml). A net uptake of ketone acids by the leg was observed during exercise but could account for less than 5% of leg oxidative metabolism in the diabetics and less than 1% in controls. Despite the increase in ketogenesis during exercise, a rise in arterial ketone acid levels was not observed in the diabetics until postexercise recovery, during which sustained increments to values of 1.8-1.9 mmol/l and sustained increases in splanchnic ketone production were observed at 30-60 min. The largest increment in blood ketone acids and in splanchnic ketone production above values observed in controls thus occurred in the diabetics after 60 min of recovery from exercise. We concluded that: (a) In the resting state, increased ketogenesis in the diabetic is a consequence of augmented splanchnic inflow of FFA and increased intrahepatic conversion of FFA to ketones, but does not depend on augmented fractional extraction of circulating FFA by the splanchnic bed. (b) Exercise-induced increases in ketogenesis in normal subjects are due to augmented splanchnic inflow and fractional extraction of FFA as well as increased intrahepatic conversion of FFA to ketones. (c) When exercise and diabetes are combined, ketogenesis increases further despite the absence of a rise in splanchnic inflow of FFA. An increase in splanchnic fractional extraction of FFA and a marked increase intrahepatic conversion of FFA to ketones accounts for the exaggerated ketogenic response to exercise in the diabetic. (d) Elevated levels of plasma glucagon and/or norepinephrine may account for the increased hepatic ketogenic response to exercise in the diabetic. (e) Ketone utilization by muscle increases during exercise but constitutes a quantitatively minor oxidative fuel for muscle even in the diabetic. (f) The accelerated ketogenesis during exercise in the diabetic continues unabated during the recovery period, resulting in an exaggerated postexercise ketosis.
PMCID: PMC425159  PMID: 6715541
17.  GLUT4 and Glycogen Synthase Are Key Players in Bed Rest–Induced Insulin Resistance 
Diabetes  2012;61(5):1090-1099.
To elucidate the molecular mechanisms behind physical inactivity–induced insulin resistance in skeletal muscle, 12 young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies obtained before and after. In six of the subjects, muscle biopsies were taken from both legs before and after a 3-h hyperinsulinemic euglycemic clamp performed 3 h after a 45-min, one-legged exercise. Blood samples were obtained from one femoral artery and both femoral veins before and during the clamp. Glucose infusion rate and leg glucose extraction during the clamp were lower after than before bed rest. This bed rest–induced insulin resistance occurred together with reduced muscle GLUT4, hexokinase II, protein kinase B/Akt1, and Akt2 protein level, and a tendency for reduced 3-hydroxyacyl-CoA dehydrogenase activity. The ability of insulin to phosphorylate Akt and activate glycogen synthase (GS) was reduced with normal GS site 3 but abnormal GS site 2+2a phosphorylation after bed rest. Exercise enhanced insulin-stimulated leg glucose extraction both before and after bed rest, which was accompanied by higher GS activity in the prior-exercised leg than the rested leg. The present findings demonstrate that physical inactivity–induced insulin resistance in muscle is associated with lower content/activity of key proteins in glucose transport/phosphorylation and storage.
PMCID: PMC3331744  PMID: 22403297
18.  Sex‐specific responses of bone metabolism and renal stone risk during bed rest 
Physiological Reports  2014;2(8):e12119.
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.
PMCID: PMC4246590  PMID: 25107989
Bed rest; bone density; bone metabolism; renal stone risk; sex differences
19.  Relationship between serum cystatin C and polycystic ovary syndrome 
Background: Polycystic ovary syndrome (PCOS) causes an increased risk of metabolic cardiovascular syndrome. Also, cystatin C serum levels are associated with the risk of cardiovascular events in metabolic syndrome patients.
Objective: To investigate the relationship between cystatin C in PCOS patients.
Materials and Methods: 35 women with PCOS were compared to 35 women with healthy matched age and body mass index. They all underwent tests to determine plasma levels of C-reactive protein (CRP), cystatin C, lipid profile and apo-lipoprotein. Blood pressure and demographic variables of each subject were obtained.
Results: Systolic and diastolic blood pressure were higher in PCOS patients compared to control group. Triglyceride and low-density lipoprotein cholesterol levels were higher in PCOS; contrariwise, high-density lipoprotein was lower from that of healthy volunteers. Cystatin and CRP levels were significantly higher in patients with PCOS in comparison with healthy subjects (p<0.0001). Among measured determinants, only PCOS status was independently associated with cystatin C.
Conclusion: Cystatin C was positively correlated with PCOS status concentrations but not with systolic and diastolic blood pressure, or any of the lipid profile variables or demographic characteristics. Indeed, no correlation was found between cystatin C and CRP levels. Therefore, cystatin C might be related to PCOS beyond its use as a marker of the renal function.
PMCID: PMC3941379  PMID: 24639696
Polycystic ovary syndrome; Cystatin C; C-reactive protein; Dyslipidemia; Blood pressure
20.  Four hour ambulation after angioplasty is a safe practice method 
During the last 3 decades, there were increasing tendency towards angioplasty because of its benefits. But, this procedure has its acute problems like bleeding and formation of hematoma in the removal place of the sheet. Based on researchers’ clinical experiences, patients need a time of 8-12 hours for bed rest after coronary angioplasty. Recognizing desirable time for bed rest after angioplasty and remove the arterial sheet forms the foundation of related researches in the world. Getting out of bed soon after angioplasty, causes more comfortable feelings, less hospitalization period, fewer side effects of prolonged bed rest and less hospitalization expenses. Regarding less time for bed rest after angioplasty, the aim of this study was to assess the effect of the time of getting out of bed after angioplasty on the complications after removing the sheet in coronary angioplasty patients.
This was an experimental clinical study conducted in one step and two groups. Samples were included 124 angioplasty patients (62 in each group) who were chosen randomly from the CCU of Shahid Chamran hospital of the Isfahan University of Medical Sciences in 2007. Data were gathered by observing and evaluating the patients, using a questionnaire and a checklist. After angioplasty, patients from the intervention group were taken out of bed in 4 hours and patients from the control group were taken out of bed in 8 hours. After taking out of bed, patients were examined for bleeding and formation of hematoma in the place of taking out the arterial sheet. Data were analyzed using descriptive and inferential statistics via SPSS software.
Results showed no meaningful difference between the two groups after getting out of bed (p > 0.05) regarding relative frequency of bleeding (p = 0.50), formation of hematoma (p = 0.34) and average diameter of hematoma (p = 0.39).
Results of this study showed that reducing the bed rest time to 4 hours after removing the arterial sheet of size 7 do not increase bleeding and formation of hematoma in the removal place of the sheet. So, those angioplasty patients who do not have critical clinical condition and their vital symptoms are stabilized will be able to get out of bed 4 hours after removing the sheet.
PMCID: PMC3093164  PMID: 21589772
Angioplasty; getting out of bed; removing the sheet; femoral arterial sheet; rest in bed
21.  Short-term Physical Inactivity Impairs Vascular Function 
The Journal of surgical research  2014;190(2):672-682.
Sedentarism, also termed physical inactivity, is an independent risk factor for cardiovascular diseases. Mechanisms thought to be involved include insulin resistance, dyslipidemia, hypertension, and increased inflammation. It is unknown whether changes in vascular and endothelial function also contribute to this excess risk. We hypothesized that short-term exposure to inactivity would lead to endothelial dysfunction, arterial stiffening and increased vascular inflammation.
Five healthy subjects (4 males and 1 female) underwent 5 days of bed rest (BR) to simulate inactivity. Measurements of vascular function [flow-mediated vasodilation (FMD) to evaluate endothelial function; applanation tonometry to assess arterial resistance], inflammation and metabolism were made before BR, daily during BR and after 2 recovery days. Subjects maintained an isocaloric diet throughout.
Bed rest led to significant decreases in brachial artery and femoral artery FMD [Brachial: 11 ± 3% pre-BR vs. 9 ± 2% end-BR, P=0.04; Femoral: 4 ± 1% vs. 2 ± 1%, P=0.04]. The central augmentation index increased with BR [−4 ± 9% vs. 5 ± 11%, P=0.03]. Diastolic blood pressure (DBP) increased [58 ± 7 mmHg vs. 62 ± 7 mmHg, P=0.02], while neither systolic blood pressure nor heart rate changed. 15-HETE, an arachidonic acid metabolite, increased but the other inflammatory and metabolic biomarkers were unchanged.
Our findings show that acute exposure to sedentarism results in decreased endothelial function, arterial stiffening, increased DBP, and an increase in 15-HETE. We speculate that inactivity promotes a vascular “deconditioning” state characterized by impaired endothelial function, leading to arterial stiffness and increased arterial tone. Although physiologically significant, the underlying mechanisms and clinical relevance of these findings need to be further explored.
PMCID: PMC4096607  PMID: 24630521
22.  Exercise electrocardiographic responses and serum cystatin C levels among metabolic syndrome patients without overt diabetes mellitus 
An impaired heart rate response during exercise (chronotropic incompetence) and an impaired heart rate recovery (HRR) after exercise are predictors of cardiovascular risk and mortality. Cystatin C is a novel marker for cardiovascular disease. We aimed to investigate exercise electrocardiographic responses in patients with metabolic syndrome who were without overt diabetes mellitus, in addition to the association of serum cystatin C levels with the exercise electrocardiographic test results.
Forty-three consecutive patients admitted to a cardiology outpatient clinic without angina pectoris were recruited if they met criteria for metabolic syndrome but did not have overt diabetes mellitus. Serum cystatin C levels were measured, and all participants underwent exercise electrocardiographic testing. Patients who were found to have ischemia had a coronary angiography procedure.
The mean cystatin C level of patients was higher in metabolic syndrome group than healthy controls (610.1 ± 334.02 vs 337.3 ± 111.01 μg/L; P < 0.001). The percentage of patients with ischemia confirmed by coronary angiography was 13.9% in the metabolic syndrome group. Cystatin C levels in the ischemic patients of the metabolic syndrome group were higher than that in nonischemic patients (957.00 ± 375.6 vs 553.8 ± 295.3 μg/L; P = 0.005). Chronotropic incompetence was observed in 30.2% of the patients with metabolic syndrome compared with 16.7% in the control group (P = 0.186). Chronotropic response indices were 0.8 ± 0.18 versus 0.9 ± 0.10 for the two groups, respectively (P = 0.259). HRR was significantly lower in the metabolic syndrome patients compared with the controls (20.1 ± 8.01 vs 25.2 ± 4.5 per min; P < 0.001), and the ST-segment adjustment relative to heart rate(ST/HR index ratio) was 1.4 ± 1.34 versus 0.4 ± 0.31 μV/beat (P < 0.001), respectively. Cystatin C was negatively correlated with the chronotropic response index (CRI) and HRR and was positively correlated with ST/HR index in the entire study population (R = −0.658, −0.346, 0.388, respectively; P < 0.05).
A substantial proportion of metabolic syndrome patients without overt diabetes mellitus had silent coronary ischemia in addition to impairment of objective exercise electrocardiographic parameters. In the metabolic syndrome patients without overt diabetes mellitus, cystatin C levels were found to be elevated and the elevation was more pronounced in the subgroup with silent ischemia. Cystatin C was also correlated with HRR and CRI.
PMCID: PMC3049540  PMID: 21415918
exercise electrocardiography; metabolic syndrome; silent ischemia; cystatin C
23.  Physical Inactivity Differentially Alters Dietary Oleate and Palmitate Trafficking 
Diabetes  2009;58(2):367-376.
OBJECTIVE— Obesity and diabetes are characterized by the incapacity to use fat as fuel. We hypothesized that this reduced fat oxidation is secondary to a sedentary lifestyle.
RESEARCH DESIGN AND METHODS— We investigated the effect of a 2-month bed rest on the dietary oleate and palmitate trafficking in lean women (control group, n = 8) and the effect of concomitant resistance/aerobic exercise training as a countermeasure (exercise group, n = 8). Trafficking of stable isotope–labeled dietary fats was combined with muscle gene expression and magnetic resonance imaging–derived muscle fat content analyses.
RESULTS— In the control group, bed rest increased the cumulative [1-13C]oleate and [d31]palmitate appearance in triglycerides (37%, P = 0.009, and 34%, P = 0.016, respectively) and nonesterified fatty acids (NEFAs) (37%, P = 0.038, and 38%, P = 0.002) and decreased muscle lipoprotein lipase (P = 0.043) and fatty acid translocase CD36 (P = 0.043) mRNA expressions. Plasma NEFA-to-triglyceride ratios for [1-13C]oleate and [d31]palmitate remained unchanged, suggesting that the same proportion of tracers enters the peripheral tissues after bed rest. Bed rest did not affect [1-13C]oleate oxidation but decreased [d31]palmitate oxidation by −8.2 ± 4.9% (P < 0.0001). Despite a decreased spontaneous energy intake and a reduction of 1.9 ± 0.3 kg (P = 0.001) in fat mass, exercise training did not mitigate these alterations but partially maintained fat-free mass, insulin sensitivity, and total lipid oxidation in fasting and fed states. In both groups, muscle fat content increased by 2.7% after bed rest and negatively correlated with the reduction in [d31]palmitate oxidation (r2 = 0.48, P = 0.003).
CONCLUSIONS— While saturated and monounsaturated fats have similar plasma trafficking and clearance, physical inactivity affects the partitioning of saturated fats toward storage, likely leading to an accumulation of palmitate in muscle fat.
PMCID: PMC2628610  PMID: 19017764
24.  The effect of supplemental oral phosphate on the bone mineral changes during prolonged bed rest 
Journal of Clinical Investigation  1971;50(12):2506-2518.
Five healthy young men were studied during 24-30 wk of continuous bed rest. During the first 12 wk of bed rest, untreated subjects increased calcium excretion in the urine by 109 mg/day and in the feces by 147 mg/day. The rate of total body calcium loss was 0.5-0.7% per month. Losses of central calcaneus mineral, assessed by gamma ray transmission scanning, occurred at a tenfold higher rate, whereas the mineral content of the radius did not change. Changes in phosphorus balance resembled the calcium pattern, and increased excretion of nitrogen and hydroxyproline also occurred during bed rest. Upon reambulation, the subjects' calcium balance became positive in 1 month and recovery of their calcaneus mineral was complete within 10-20 wk.
Treatment with potassium phosphate supplements (1327 mg P/day) entirely prevented the hypercalciuria of bed rest, but fecal calcium tended to increase. During the first 12 wk, calcium balance was slightly less negative (mean - 193 mg/day) than during bed rest without added phosphate (mean - 267 mg/day). This effect was not seen during the second 12 wk of bed rest. The patterns of magnesium excretion were similar to those of calcium. Fecal and urinary phosphorus excretions were doubled, and phosphorus balance became positive (+ 113 mg/day). Mineral loss from the central calcaneus was similar to that of untreated subjects. It is concluded that this form of phosphate supplementation reduces urinary calcium excretion but does not prevent bone loss during bed rest.
PMCID: PMC292200  PMID: 5129304
25.  Effects of 20 days of bed rest on the viscoelastic properties of tendon structures in lower limb muscles 
Objectives: The purpose of this study was to investigate the effects of 20 days' bed rest on the viscoelastic properties of human tendon structures in knee extensor and plantar flexor muscles in vivo.
Methods: Eight healthy men (age: 24±4 years, height: 172±9 m, body mass: 69±13 kg) carried out a 6° head-down bed rest for 20 days. Before and after bed rest, elongation (L) of the tendon and aponeurosis of vastus lateralis (VL) and medial gastrocnemius muscles (MG) during isometric knee extension and plantar flexion, respectively, were determined using real-time ultrasonic apparatus, while the subjects performed ramp isometric contraction up to the voluntary maximum, followed by ramp relaxation. The relationship between estimated muscle force (Fm) and tendon elongation (L) was fitted to a linear regression, the slope of which was defined as stiffness. The hysteresis was calculated as the ratio of the area within the Fm-L loop to the area beneath the load portion of the curve.
Results: L values above 100 N were significantly greater after bed rest for VL, while there were no significant differences in L values between before and after for MG. The stiffness decreased after bed rest for VL (70.3±27.4 v 50.1±24.8 N/mm, before and after bed rest, respectively; p = 0.003) and MG (29.4±7.5 v 25.6±7.8 N/mm, before and after bed rest, respectively; p = 0.054). In addition, hysteresis increased after bed rest for VL (16.5±7.1% v 28.2±12.9%, before and after bed rest, respectively; p = 0.017), but not for MG (17.4±4.4% v 17.7±6.1%, before and after bed rest, respectively; p = 0.925).
Conclusions: These results suggested that bed rest decreased the stiffness of human tendon structures and increased their hysteresis, and that these changes were found in knee extensors, but not the plantar flexors.
PMCID: PMC1724819  PMID: 15155437

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