Radio-Adaptive Responses of Mouse Myocardiocytes

One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) Cs-137 gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Pro-apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value . 0.003) 4hr after H, but not after 4hr LH when compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive response that mitigates the reduction in genetic expression associated with single high-dose gamma radiation exposure. This radio-adaptive response may serve as a potential countermeasure to radiation-induced myocardial remodeling and preserve the cardiovascular health of astronauts; thus, reducing the risks of human space exploration

Effects of High Dietary HEME Iron and Radiation on Cardiovascular Function

The radiation related health risks to astronauts is of particular concern to NASA. Data support that exposure to radiation is associated with a number of disorders including a heightened risk for cardiovascular diseases. Independent of radiation, altered nutrient status (e.g. high dietary iron) also increases ones risk for cardiovascular disease. However, it is unknown whether exposure to radiation in combination with high dietary iron further increases ones cardiovascular risk. The intent of our proposal is to generate compulsory data examining the combined effect of radiation exposure and iron overload on sensitivity to radiation injury to address HRP risks: 1) Risk Factor of Inadequate Nutrition; 2) Risk of Cardiac Rhythm Problems; and 3) Risk of Degenerative Tissue or other Health Effects from Space Radiation. Towards our goal we propose two distinct pilot studies using the following specific aims: Vascular Aim 1: To determine the short-term consequences of the independent and combined effects of exposure to gamma radiation and elevated body iron stores on measures of endothelial function and cell viability and integrity. We hypothesize that animals that have high body iron stores and are exposed to gamma radiation will show a greater reduction in endothelial dependent nitric oxid production and larger pathological changes in endothelial integrity than animals that have only 1 of those treatments (either high iron stores or exposure to gamma radiation). Vascular Aim 2: Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with endothelial cell function. We hypothesize that modifications of epigenetic control and posttranslational expression of proteins associated with endothelial cell function will be differentially altered in rats with high body iron stores and exposed to gamma radiation compared to rats with only 1 type of treatment. Cardiac Aim 1: To determine the short-term consequences of the independent and combined effects of gamma radiation and elevated body iron stores on measures of cardiac structure. We hypothesize that modifications to cardiac structure and function will be greater in rats with high body iron stores and exposed to gamma radiation than in rats that have only 1 of those treatments. Cardiac Aim 2: Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with cardiac structure and function. We hypothesize that modifications of epigenetic control and posttranslational expression of proteins associated with cardiac contractile function will be differentially altered in rats with high body iron stores and exposed to gamma radiation compared to rats with only 1 type of treatment

Cardiovascular Adaptations in the Spaceflight Environment

No abstract availabl

Induction of a Radio-Adaptive Response by Low-dose Gamma Irradiation in Mouse Cardiomyocytes

One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) 137Cs gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value < or = 0.003) 4hr after H, but not after 4hr LH compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive response that mitigates the reduction in genetic expression associated with single high-dose gamma radiation exposure. This radio-adaptive response may serve as a potential countermeasure to radiation-induced myocardial remodeling and preserve the cardiovascular health of astronauts; thus, reducing the risks of human space exploration

A Data Mining Project to Identify Cardiovascular Related Factors That May Contribute to Changes in Visual Acuity Within the US Astronaut Corps

Many of the cardiovascular-related adaptations that occur in the microgravity environment are due, in part, to a well-characterized cephalad-fluid shift that is evidenced by facial edema and decreased lower limb circumference. It is believed that most of these alterations occur as a compensatory response necessary to maintain a "normal" blood pressure and cardiac output while in space. However, data from both flight and analog research suggest that in some instances these microgravity-induced alterations may contribute to cardiovascular-related pathologies. Most concerning is the potential relation between the vision disturbances experienced by some long duration crewmembers and changes in cerebral blood flow and intra-ocular pressure. The purpose of this project was to identify cardiovascular measures that may potentially distinguish individuals at risk for visual disturbances after long duration space flight. Toward this goal, we constructed a dataset from Medical Operation tilt/stand test evaluations pre- (days L-15-L-5) and immediate post-flight (day R+0) on 20 (3 females, 17 males). We restricted our evaluation to only crewmembers who participated in both shuttle and space station missions. Data analysis was performed using both descriptive and analytical methods (Stata 11.2, College Station, TX) and are presented as means +/- 95% CI. Crewmembers averaged 5207 (3447 - 8934) flight hours across both long (MIR-23 through Expedition16) and short (STS-27 through STS-101) duration missions between 1988 and 2008. The mean age of the crew at the time of their most recent shuttle flight was 41 (34-44) compared to 47 (40-54) years during their time on station. In order to focus our analysis (we did not have codes to separate out subjects by symptomotology) , we performed a visual inspection of each cardiovascular measures captured during testing and plotted them against stand time, pre- to post-flight, and between mission duration. It was found that pulse pressure most clearly differentiated the two mission types. Statistical analysis confirmed that pulse pressure was significantly higher before [45.6; (42.1 to 49.1)] and after [50.7; (46.9 to 54.6)] time on station compared with their most recent shuttle flight [31.6 (27.8 to 35.4), and 32.2 (28.3 to 36.0) respectively] even after correcting differences in age and cumulative number of mission hours. Without knowing the identity of which long duration crewmembers demonstrated visual changes, we were limited to examining whether certain crew regulate components of pulse pressure, systolic and diastolic blood pressure, differently due to microgravity exposure. To that end, we stratified crew into tertiles based on either their pre-flight measure of systolic or diastolic blood pressure. Those crew in the highest tertile for both systolic (lower tertile (n=8; 103-111), middle tertile (n=7; 113-121), and upper tertile (n=5; 125-136) and diastolic blood pressure (lower tertile (n=8; 58-64), middle tertile (n=7; 67-73), and upper tertile (n=5; 75-81) demonstrated less variability in pulse pressure between R+0 and L-10 (Figure 2). Interestingly, those crewmembers with the highest resting systolic blood pressure demonstrated either no change or in some instances an increase in total peripheral resistance, where those in the lower tertiles had lower values of total peripheral resistance compared to pre-flight levels. In this study, it was found that crewmembers in the highest tertile for both systolic and diastolic blood pressure demonstrated less variability in pulse pressure and that the decrease in variability was due in part to lower levels of compliance as indicated by similar or higher levels of total peripheral resistance after compared with before flight levels. Whether there is a relation between blood pressure regulation and total peripheral resistance in crew presenting with negative changes in visual acuity remains unknown

Lower Limb Venous Compliance is Different Between Men and Women Following 60 Days of Head-Down Bedrest but Is Not Associated with Venoconstriction Dysfunction

Space flight-induced orthostatic intolerance (OI) is more prevalent in female (F) than male (M) astronauts. The mechanisms explaining the higher incidence of OI in F are unclear. We tested the hypothesis that venous compliance would be higher in F more than M following 6 deg head-down bed rest (BR) and would be associated with constrictor dysfunction. Using 2-D ultrasound, dorsal hand (DHV) and dorsal foot (DFV) vein compliances were determined in 24 subjects (10 F, 14 M; 35 +/- 1 yr) by measuring mean diameter response to increasing congestion pressure (0, 20, 30, and 40 mmHg) before and after 60 d of BR. Constrictor function was assessed by intravenous infusions of Ketorolac (KE; 1.5 ig/min) Phenylephrine (PE; 3160 ng/min), and L-NMMA (50 ig/min). The effects of BR between F vs. M and hand vs. foot were determined using mixed-effects linear regression. DFV but not DHV compliance changed in response to BR (p=0.012). Mean DFV increased significantly (0.903 mm to 1.191mm) in F but decreased in M (1.353 mm to 1.154 mm). DFV constrictor response was not different between sexes in response to BR (KE; p=0.647, PE; p=0.717, and L-NMMA; p=0.825). These BR data suggest that the higher incidence of OI in F astronauts may be related to increased lower limb venous compliance, contributing to blood pooling upon standing. Notably, changes to DFV compliance was not accompanied by impaired constrictor function

Development of Gradient Compression Garments for Protection Against Post Flight Orthostatic Intolerance

Orthostatic intolerance after space flight is still an issue for astronaut health. No in-flight countermeasure has been 100% effective to date. NASA currently uses an inflatable anti-gravity suit (AGS) during reentry, but this device is uncomfortable and loses effectiveness upon egress from the Shuttle. The Russian Space Agency currently uses a mechanical counter-pressure garment (Kentavr) that is difficult to adjust alone, and prolonged use may result in painful swelling at points where the garment is not continuous (feet, knees, and groin). To improve comfort, reduce upmass and stowage requirements, and control fabrication and maintenance costs, we have been evaluating a variety of gradient compression, mechanical counter-pressure garments, constructed from spandex and nylon, as a possible replacement for the current AGS. We have examined comfort and cardiovascular responses to knee-high garments in normovolemic subjects; thigh-high garments in hypovolemic subjects and in astronauts after space flight; and 1-piece, breast-high garments in hypovolemic subjects. These gradient compression garments provide 55 mmHg of compression over the ankle, decreasing linearly to ~35 mmHg at the knee. In thigh-high versions the compression continues to decrease to ~20 mmHg at the top of the leg, and for breast-high versions, to ~15 mmHg over the abdomen. Measures of efficacy include increased tilt survival time, elevated blood pressure and stroke volume, and lower heart-rate response to orthostatic stress. Results from these studies indicate that the greater the magnitude of compression and the greater the area of coverage, the more effective the compression garment becomes. Therefore, we are currently testing a 3-piece breast-high compression garment on astronauts after short-duration flight. We chose a 3-piece garment consisting of thigh-high stockings and shorts, because it is easy to don and comfortable to wear, and should provide the same level of protection as the 1-piece breast-high garments evaluated in hypovolemic test subjects

Cassava: adding value for Africa - Strategic market initiatives that support wealth creation for women along the Cassava Value Chains in Southwest, Nigeria.

Empowering and creating wealth for cassava producing and processing smallholder farmers (of which women constitute the majority) through value addition and competitive market led opportunities for inclusive growth in agriculture is very important to counter poverty and ensure food security. This study attempts to examine the extent to which Cassava: Adding Value for Africa (C:AVA) project in Nigeria has created market led opportunities for smallholder farmers of cassava roots in Southwest Nigeria from 2008 to 2010. Data were collected through interview schedule administered on 237 randomly selected farmers who are participants in C:AVA project registered with the Agricultural Development Project (ADP) in Ogun, Ondo States and Justice, Development and Peace Movement (JDPM). Catholic Diocese of Abeokuta from Ogun State and Ondo State respectively. Data were analyzed descriptively by using measures such as frequency distribution, table, percentages and Chi-Square. The study revealed that 60% of the respondents were men and 40% were women. Men were more educated that women with 28.6% of women farmers having no formal education when compared with 10.3% of men. The difference in income between the third and fourth quartile was very high compared with other quartiles and the mean income earned by male farmers was more than twice the mean income earned by female farmers. With regards to level of production there was an increase in the yield of cassava roots on the farms surveyed from the average national range of 10-12 tonnes/ha in 2008 to an average range of 20-25 tonnes/ha in 2010. These improved varieties resulted in an average yield advantage of about 65% over local varieties. Owing to the observable increase in yield, farmers in the study area increased the hectares under cassava from an average of 0.5 - 1.5 ha in 2008 to an average of 10.0-20.0 ha in 2010. The average annual income of women farmers increased from $1000 in 2008 to an additional average income of$1700 in 2010. Chi-square analysis revealed significant associations (p<0.05) between yield of improved varieties (X2=29.187), gender (X2=50.632), value addition (X2=32.547), improved technologies (X2=29.507); Types of market (X2=14.743), group membership (X2=10.973), capacity building (X2=68.490) with income. The study concluded that C:AVA has provided systematic development of specialization in which women cassava roots producers/ processors produce specifically for multiple markets to ensure wealth and household food security for women and their households