Effects of the renin-angiotensin-aldosterone system on the cardiovascular system during 20-days bed rest

Long term change of renin-angiotensin-aldosterone system (RAAS) induced by bed rest and its effects on cardiovascular system are still controversial. The purpose of this study was to obtain a general conclusion on these questions by analyzing our two 20-days horizontal bed rest experiments in past two years with 18 subjects. Plasma renin activity and aldosterone were consistently increased during the bed rest, but angiotensin II was increased only during the early days. Decrease in urinary sodium excretion and increase in urinary potassium excretion were observed during day 3-8 and day 7-12, respectively. Mean arterial pressure increased during day 3-8. Pulse pressure was returned to pre-bed rest level by day 10 after an initial decrease. All these results indicated an activated RAAS and its active effects on cardiovascular and overall fluid regulating systems during our horizontal bed rest studies. Direct effect of change in gravitational force on renal pressure-sensitive cells or effects related to physical inactivity may explain our results.     

WISE 2005: chronic bed rest impairs microcirculatory endothelium in women

Sedentary behavior has deleterious effects on the cardiovascular system, including reduced endothelial functions. A 2-mo bed rest study in healthy women [women international space simulation for exploration (WISE) 2005 program] presented a unique opportunity to analyze the specific effects of prolonged inactivity without other vascular risk factors on the endothelium. We investigated endothelial properties before and after 56 days of bed rest in 8 subjects who performed no exercise (control group: No-EX) and in 8 subjects who regularly performed treadmill exercise in a lower body negative pressure chamber as well as resistance exercise (countermeasure group, EX). A functional evaluation of the microcirculation in the skin was assessed with laser Doppler. We studied endothelium-dependent and -independent vasodilation using iontophoresis of acetylcholine and sodium nitroprusside, respectively. We also measured circulating endothelial cells (CECs), an index of endothelial damage. In the No-EX group, endothelium-dependent vasodilation was significantly reduced (35.4 +/- 4.8% vs. 24.1 +/- 3.8%, P < 0.05) by bed rest with a significant increase in the number of CECs (3.6 +/- 1.4 vs. 10.6 +/- 2.7 ml(-1), P < 0.05). In the EX group, endothelium-dependent vasodilation and number of CECs were preserved. Our study shows that in humans prolonged bed rest causes impairment of endothelium-dependent function at the microcirculatory level, along with an increase in circulating endothelial cells. Microcirculatory endothelial dysfunction might participate in cardiovascular deconditioning, as well as in several bed rest-induced pathologies. We therefore conclude that the endothelium should be a target for countermeasures during periods of prolonged deconditioning.     

Mechanical unloading impairs keratinocyte migration and angiogenesis during cutaneous wound healing.

Although initially thought to improve an individual's ability to heal, mechanical unloading promoted by extended periods of bed rest has emerged as a contributing factor to delayed or aberrant tissue repair. Using a rat hindlimb unloading (HLU) model of hypogravity, we mimicked some aspects of physical inactivity by removing weight-bearing loads from the hindlimbs and producing a systemic cephalic fluid shift. This model simulates bed rest in that the animal undergoes physiological adaptations, resulting in a reduction in exercise capability, increased frequency of orthostatic intolerance, and a reduction in plasma volume. To investigate whether changes associated with prior prolonged bed rest correlate with impaired cutaneous wound healing, we examined wound closure, angiogenesis, and collagen content in day 2 to day 21 wounds from rats exposed to HLU 2 wk before excisional wounding. Wound closure was delayed in day 2 wounds from HLU rats compared with ambulatory controls. Although the levels of proangiogenic growth factors, fibroblast growth factor-2 (FGF-2), and vascular endothelial growth factor (VEGF) were similar between the two groups, wound vascularity was significantly reduced in day 7 wounds from HLU animals. To further examine this disparity, total collagen content was assessed but found to be similar between the two groups. Taken together, these results suggest that keratinocyte and endothelial cell function may be impaired during the wound healing process under periods of prolonged inactivity or bed rest.     

Use it or lose it--the hazards of bed rest and inactivity.

Professional experience and lay wisdom teach us the benefits of exercise and the hazards of idleness. Yet the myth persists that "bed rest is good for you" when ill or convalescing. Abundant scientific evidence in the past 50 years has demonstrated the specific damage done to each of the body''s organ systems by inactivity. Both aging and inactivity lead to strikingly similar kinds of deterioration. I summarize the data from military and veterans'' hospitals, rehabilitation experience, aerospace research, and gerontology and review the physiologic and metabolic changes of aging and inactivity, along with strategies to help prevent the iatrogenic complications of bed rest.     

New Onset of Constipation during Long-Term Physical Inactivity: A Proof-of-Concept Study on the Immobility-Induced Bowel Changes

Background

The pathophysiological mechanisms underlining constipation are incompletely understood, but prolonged bed rest is commonly considered a relevant determinant.

Aims

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.

Methods

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.

Results

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

Conclusions

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.     

Resistance training affects GLUT-4 content in skeletal muscle of humans after 19 days of head-down bed rest.

This study assessed the effects of inactivity on GLUT-4 content of human skeletal muscle and evaluated resistance training as a countermeasure to inactivity-related changes in GLUT-4 content in skeletal muscle. Nine young men participated in the study. For 19 days, four control subjects remained in a -6 degrees head-down tilt at all times throughout bed rest, except for showering every other day. Five training group subjects also remained at bed rest, except during resistance training once in the morning. The resistance training consisted of 30 isometric maximal voluntary contractions for 3 s each; leg-press exercise was used to recruit the extensor muscles of the ankle, knee, and hip. Pauses (3 s) were allowed between bouts of maximal contraction. Muscle biopsy samples were obtained from the lateral aspect of vastus lateralis (VL) muscle before and after the bed rest. GLUT-4 content in VL muscle of the control group was significantly decreased after bed rest (473 +/- 48 vs. 398 +/- 66 counts. min-1. microgram membrane protein-1, before and after bed rest, respectively), whereas GLUT-4 significantly increased in the training group with bed rest (510 +/- 158 vs. 663 +/- 189 counts. min-1. microgram membrane protein-1, before and after bed rest, respectively). The present study demonstrated that GLUT-4 in VL muscle decreased by approximately 16% after 19 days of bed rest, and isometric resistance training during bed rest induced a 30% increase above the value of GLUT-4 before bed rest.     

Electrical impedance measurements in the arm and the leg during a thirty day bed rest study

The need to detect, follow and understand the effects of gravity on body fluid distribution is a constant stimulus to the quest for new techniques in this area of research. One of these techniques is electrical bioimpedance spectroscopy (BIS). Although not new, this is a technique whose applications to biomedical research are fairly recent. What is new is the development of instrumentation that has made practical the use of impedance spectroscopy in the biomedical setting, particularly in studies involving human subjects. The purpose of this paper is to report impedance spectroscopy observations made on a subject who was submitted to bed rest for a period of thirty days. These observations were made as part of a study on muscle atrophy during a thirty day head down bed rest. Since bed rest studies are very costly in human and financial terms, and technically difficult to realize, we felt that even though the present study deals only with a single case it was worthy of reporting because it illustrates kinds of questions impedance spectroscopy may help to answer in microgravity research.     

Neuroendocrine and behavioral implications of endocrine disrupting chemicals in quail

Studies in our laboratory have focused on endocrine, neuroendocrine, and behavioral components of reproduction in the Japanese quail. These studies considered various stages in the life cycle, including embryonic development, sexual maturation, adult reproductive function, and aging. A major focus of our research has been the role of neuroendocrine systems that appear to synchronize both endocrine and behavioral responses. These studies provide the basis for our more recent research on the impact of endocrine disrupting chemicals (EDCs) on reproductive function in the Japanese quail. These endocrine active chemicals include pesticides, herbicides, industrial products, and plant phytoestrogens. Many of these chemicals appear to mimic vertebrate steroids, often by interacting with steroid receptors. However, most EDCs have relatively weak biological activity compared to native steroid hormones. Therefore, it becomes important to understand the mode and mechanism of action of classes of these chemicals and sensitive stages in the life history of various species. Precocial birds, such as the Japanese quail, are likely to be sensitive to EDC effects during embryonic development, because sexual differentiation occurs during this period. Accordingly, adult quail may be less impacted by EDC exposure. Because there are a great many data available on normal development and reproductive function in this species, the Japanese quail provides an excellent model for examining the effects of EDCs. Thus, we have begun studies using a Japanese quail model system to study the effects of EDCs on reproductive endocrine and behavioral responses. In this review, we have two goals: first, to provide a summary of reproductive development and sexual differentiation in intact Japanese quail embryos, including ontogenetic patterns in steroid hormones in the embryonic and maturing quail. Second, we discuss some recent data from experiments in our laboratory in which EDCs have been tested in Japanese quail. The Japanese quail provides an excellent avian model for testing EDCs because this species has well-characterized reproductive endocrine and behavioral responses. Considerable research has been conducted in quail in which the effects of embryonic steroid exposure have been studied relative to reproductive behavior. Moreover, developmental processes have been studied extensively and include investigations of the reproductive axis, thyroid system, and stress and immune responses. We have conducted a number of studies, which have considered long-term neuroendocrine consequences as well as behavioral responses to steroids. Some of these studies have specifically tested the effects of embryonic steroid exposure on later reproductive function in a multigenerational context. A multigenerational exposure provides a basis for understanding potential exposure scenarios in the field. In addition, potential routes of exposure to EDCs for avian species are being considered, as well as differential effects due to stage of the life cycle at exposure to an EDC. The studies in our laboratory have used both diet and egg injection as modes of exposure for Japanese quail. In this way, birds were exposed to a specific dose of an EDC at a selected stage in development by injection. Alternatively, dietary exposure appears to be a primary route of exposure; therefore experimental exposure through the diet mimics potential field situations. Thus, experiments should consider a number of aspects of exposure when attempting to replicate field exposures to EDCs.     

Metabolic disruptions induced by reduced ambulatory activity in free-living humans

Physical inactivity likely plays a role in the development of insulin resistance and obesity; however, direct evidence is minimal and mechanisms of action remain unknown. Studying metabolic outcomes that occur after transitioning from higher to lower levels of physical activity is the best tool to answer these questions. Previous studies have successfully used more extreme models of inactivity, including bed rest, or the cessation of exercise in highly trained endurance athletes, to provide novel findings. However, these models do not accurately reflect the type of inactivity experienced by a large majority of the population. Recent studies have used a more applicable model in which active (～10,000 steps/day), healthy young controls are asked to transition to an inactive lifestyle (～1,500 steps/day) for a 14-day period. The transition to inactivity resulted in reduced insulin sensitivity and increased central adiposity. This review will discuss the outcomes of these studies, their implications for the cause/effect relationship between central adiposity and insulin resistance, and provide rationale for why inactivity induces these factors. In addition, the experimental challenges of directly linking acute responses to inactivity to chronic disease will also be discussed.     

The value of juvenile animal studies: a Japanese industry perspective

Pharmaceuticals have been used on adults and children; however, they were previously investigated only by adult human clinical studies and adult animal nonclinical studies. The US FDA finalized the guidance of juvenile animal toxicity studies in 2006, and EMEA was finalized in 2008. At that point, juvenile animal toxicity studies were encouraged to investigate the safety of the pediatric population. In Japan, the awareness of the development of pediatric drugs is increasing, and many scientific meetings about juvenile animal studies are being held. A Japanese guideline for juvenile animal toxicity studies has been long awaited by many Japanese pharmaceutical companies because concrete directionality has not been available in Japan thus far. The Ministry of Health, Labour, and Welfare started to prepare the guideline for nonclinical safety studies in juvenile animals since October 2010. After completion of the Japanese guideline, guidelines would exist in the three regions: Japan, US, and Europe. Then, global development of pediatric pharmaceuticals would be accelerated effectively.     

Disuse and aging: same problem, different outcomes

Many of the changes that accompany physical inactivity coincide with those that occur during aging. These changes are generally grouped under the term of 'disuse' (or "lack of use" or "inappropriately modulated stimulation"). Studies of long-term space travel have revealed that weightlessness in space also induces changes resembling those of aging and physical inactivity. The relationship between disuse (due to bed rest, insufficient exercise, or lack of gravity) and aging has some definite practical implications. As life expectancy is lenghtened in all populations worldwide, the number of elderly with varying degrees of disability leading to reduced physical activity also increases. Changes induced by bed rest as a consequence of disease may also be superimposed on aging changes and further diminish physiologic reserves and accelerate pathology. Therefore, the study of disuse, irrespective of its etiology, may serve as a model for understanding not only some of the functional changes induced by lack of activity and/or gravity but also some of the disabilities of old age. Indeed, a better understanding of disuse phenomena will make it possible to establish programs of prevention and rehabilitation that will ameliorate both disuse and aging deficits.     

The current state of bone loss research: Data from spaceflight and microgravity simulators

Bone loss is a well documented phenomenon occurring in humans both in short‐ and in long‐term spaceflights. This phenomenon can be also reproduced on the ground in human and animals and also modeled in cell‐based analogs. Since space flights are infrequent and expensive to study the biomedical effects of microgravity on the human body, much of the known pathology of bone loss comes from experimental studies. The most commonly used in vitro simulators of microgravity are clinostats while in vivo simulators include the bed rest studies in humans and hindlimb unloading experiments in animals. Despite the numerous reports that have documented bone loss in wide ranges in multiple crew members, the pathology remains a key concern and development of effective countermeasures is still a major task. Thus far, the offered modalities have not shown much success in preventing or alleviating bone loss in astronauts and cosmonauts. The objective of this review is to capture the most recent research on bone loss from spaceflights, bed rest and hindlimb unloading, and in vitro studies utilizing cellular models in clinostats. Additionally, this review offers projections on where the research has to focus to ensure the most rapid development of effective countermeasures. J. Cell. Biochem. 114: 1001–1008, 2013. © 2012 Wiley Periodicals, Inc.     

Japan and human evolutionary research

The trends in evolutionary research in Japan have largely changed through the introduction of new methodologies such as molecular genetics and multivariate statistics since the 1960’s. The development of ecology and primatology brought another new wave into fields of physical anthropology. This paper reviews briefly general trends in anthropological research now on-going in Japan. Microevolutionary studies of the Japanese and neighboring populations which have a long history in Japan will be reviewed in more detail.     

Diagnosing Suicides of Resolve: Psychiatric Practice in Contemporary Japan

In Japan, suicide has long been depicted as an act of free will, even aestheticized in the cultural notion suicide of resolve. Amid the record-high Japanese suicide rates since the 1990s, however, Japanese psychiatrists have been working to medicalize suicide and, in the process, confronting this deeply ingrained cultural notion. Drawing on two years of fieldwork at psychiatric institutions around Tokyo, I examine how psychiatrists try to persuade patients of the pathological nature of their suicidal intentions and how patients respond to such medicalization. I also explore psychiatrists' ambivalent attitudes toward pathologizing suicide and how they limit their biomedical jurisdiction by treating only what they regard as biological anomaly, while carefully avoiding the psychological realm. One ironic consequence of this medicalization may be that psychiatrists are reinforcing the dichotomy between normal and pathological, "pure" and "trivial," suicides, despite their clinical knowledge of the tenuousness of such distinctions and the ephemerality of human intentionality. Thus, while the medicalization of suicide is cultivating a conceptual space for Japanese to debate how to bring the suicidal back onto the side of life, it scarcely seems poised to supplant the cultural discourse on suicide that has elevated suicide to a moral act of self-determination.     

Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies

Although it is no longer debatable that sedentary behaviors are an actual cause of many metabolic diseases, the physiology of physical inactivity has been poorly investigated for this purpose. Along with microgravity, the physiological adaptations to spaceflights require metabolic adaptations to physical inactivity, and that is exceedingly well-simulated during the ground-based microgravity bed-rest analogs. Bed rest thus represents a unique model to investigate the mechanisms by which physical inactivity leads to the development of current societal chronic diseases. For decades, however, clinicians and physiologists working in space research have worked separately without taking full awareness of potential strong mutual questioning. This review summarizes the data collected over the last 60 years on metabolic adaptations to bed rest in healthy subjects. Our aim is to provide evidence that supports the hypothesis that physical inactivity per se is one of the primary causes in the development of metabolic inflexibility. This evidence will focus on four main tenants of metabolic inflexiblity: 1) insulin resistance, 2) impaired lipid trafficking and hyperlipidemia, 3) a shift in substrate use toward glucose, and 4) a shift in muscle fiber type and ectopic fat storage. Altogether, this hypothesis places sedentary behaviors upstream on the list of factors involved in metabolic inflexibility, which is considered to be a primary impairment in several metabolic disorders such as obesity, insulin resistance, and type 2 diabetes mellitus.     

Bed rest reduces metabolic protein content and abolishes exercise-induced mRNA responses in human skeletal muscle

The aim was to test the hypothesis that 7 days of bed rest reduces mitochondrial number and expression and activity of oxidative proteins in human skeletal muscle but that exercise-induced intracellular signaling as well as mRNA and microRNA (miR) responses are maintained after bed rest. Twelve young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies taken before and after bed rest. In addition, muscle biopsies were obtained from six of the subjects prior to, immediately after, and 3 h after 45 min of one-legged knee extensor exercise performed before and after bed rest. Maximal oxygen uptake decreased by 4%, and exercise endurance decreased nonsignificantly, by 11%, by bed rest. Bed rest reduced skeletal muscle mitochondrial DNA/nuclear DNA content 15%, hexokinase II and sirtuin 1 protein content ～45%, 3-hydroxyacyl-CoA dehydrogenase and citrate synthase activity ～8%, and miR-1 and miR-133a content ～10%. However, cytochrome c and vascular endothelial growth factor (VEGF) protein content as well as capillarization did not change significantly with bed rest. Acute exercise increased AMP-activated protein kinase phosphorylation, peroxisome proliferator activated receptor-γ coactivator-1α, and VEGF mRNA content in skeletal muscle before bed rest, but the responses were abolished after bed rest. The present findings indicate that only 7 days of physical inactivity reduces skeletal muscle metabolic capacity as well as abolishes exercise-induced adaptive gene responses, likely reflecting an interference with the ability of skeletal muscle to adapt to exercise.     

Alendronate as an effective countermeasure to disuse induced bone loss

Microgravity, similar to disuse immobilization on earth, causes rapid bone loss. This loss is believed to be an adaptive response to the reduced musculoskeletal forces in space and occurs gradually enough that changes occurring during short duration space flight are not a concern. Bone loss, however, will be a major impediment for long duration missions if effective countermeasures are not developed and implemented. Bed rest is used to simulate the reduced mechanical forces in humans and was used to test the hypothesis that oral alendronate would reduce the effects of long duration (17 weeks) inactivity on bone. Eight male subjects were given daily oral doses of alendronate during 17 weeks of horizontal bed rest and compared with 13 male control subjects not given the drug. Efficacy was evaluated based on measurements of bone markers, calcium balance and bone density performed before, during and after the bed rest. The results show that oral alendronate attenuates most of the characteristic changes in bone that are associated with long duration bed rest and presumably space flight.     

Inferring the population expansions in peopling of Japan

Background

Extensive studies in different fields have been performed to reconstruct the prehistory of populations in the Japanese archipelago. Estimates the ancestral population dynamics based on Japanese molecular sequences can extend our understanding about the colonization of Japan and the ethnogenesis of modern Japanese.

Methodology/Principal Findings

We applied Bayesian skyline plot (BSP) with a dataset based on 952 Japanese mitochondrial DNA (mtDNA) genomes to depict the female effective population size (N_ef) through time for the total Japanese and each of the major mtDNA haplogroups in Japanese. Our results revealed a rapid N_ef growth since ∼5 thousand years ago had left ∼72% Japanese mtDNA lineages with a salient signature. The BSP for the major mtDNA haplogroups indicated some different demographic history.

Conclusions/Significance

The results suggested that the rapid population expansion acted as a major force in shaping current maternal pool of Japanese. It supported a model for population dynamics in Japan in which the prehistoric population growth initiated in the Middle Jomon Period experienced a smooth and swift transition from Jomon to Yayoi, and then continued through the Yayoi Period. The confounding demographic backgrounds of different mtDNA haplogroups could also have some implications for some related studies in future.