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125 records · Page 7

Effects of Bone Morphogenic Proteins on Engineered Cartilage

A report describes experiments on the effects of bone morphogenic proteins (BMPs) on engineered cartilage grown in vitro. In the experiments, bovine calf articular chondrocytes were seeded onto biodegradable polyglycolic acid scaffolds and cultured in, variously, a control medium or a medium supplemented with BMP-2, BMP-12, or BMP-13 in various concentrations. Under all conditions investigated, cell-polymer constructs cultivated for 4 weeks macroscopically and histologically resembled native cartilage. At a concentration of 100 ng/mL, BMP-2, BMP-12, or BMP-13 caused (1) total masses of the constructs to exceed those of the controls by 121, 80, or 62 percent, respectively; (2) weight percentages of glycosaminoglycans in the constructs to increase by 27, 18, or 15, respectively; and (3) total collagen contents of the constructs to decrease to 63, 89, or 83 percent of the control values, respectively. BMP-2, but not BMP-12 or BMP-13, promoted chondrocyte hypertrophy. These observations were interpreted as suggesting that the three BMPs increase the growth rates and modulate the compositions of engineered cartilage. It was also concluded that in vitro engineered cartilage is a suitable system for studying effects of BMPs on chondrogenesis in a well-defined environment.

Gooch, Keith, J.↗

Tissue Doppler Imaging Combined with Advanced 12-Lead ECG Analysis Might Improve Early Diagnosis of Hypertrophic Cardiomyopathy in Childhood

Optimization of early diagnosis of childhood hypertrophic cardiomyopathy (HCM) is essential in lowering the risk of HCM complications. Standard echocardiography (ECHO) has shown to be less sensitive in this regard. In this study, we sought to assess whether spatial QRS-T angle deviation, which has shown to predict HCM in adults with high sensitivity, and myocardial Tissue Doppler Imaging (TDI) could be additional tools in early diagnosis of HCM in childhood. Methods: Children and adolescents with familial HCM (n=10, median age 16, range 5-27 years), and without obvious hypertrophy but with heredity for HCM (n=12, median age 16, range 4-25 years, HCM or sudden death with autopsy-verified HCM in greater than or equal to 1 first-degree relative, HCM-risk) were additionally investigated with TDI and advanced 12-lead ECG analysis using Cardiax(Registered trademark) (IMED Co Ltd, Budapest, Hungary and Houston). Spatial QRS-T angle (SA) was derived from Kors regression-related transformation. Healthy age-matched controls (n=21) were also studied. All participants underwent thorough clinical examination. Results: Spatial QRS-T angle (Figure/ Panel A) and septal E/Ea ratio (Figure/Panel B) were most increased in HCM group as compared to the HCM-risk and control groups (p less than 0.05). Of note, these 2 variables showed a trend toward higher levels in HCM-risk group than in control group (p=0.05 for E/Ea and 0.06 for QRS/T by ANOVA). In a logistic regression model, increased SA and septal E/Ea ratio appeared to significantly predict both the disease (Chi-square in HCM group: 9 and 5, respectively, p less than 0.05 for both) and the risk for HCM (Chi-square in HCM-risk group: 5 and 4 respectively, p less than 0.05 for both), with further increased predictability level when these 2 variables were combined (Chi-square 10 in HCM group, and 7 in HCM-risk group, p less than 0.01 for both). Conclusions: In this small material, Tissue Doppler Imaging and spatial mean QRS-T angle deviation, particularly when combined, appear to be sensitive in predicting the risk for developing childhood HCM. Large-scale, prospective studies are needed to confirm this hypothesis.

Femlund, E.↗

Deployment of an Advanced Electrocardiographic Analysis (A-ECG) to Detect Cardiovascular Risk in Career Firefighters

INTRODUCTION Sudden cardiac death is the leading cause of line of duty death among firefighters, accounting for approximately 45% of fatalities annually. Firefighters perform strenuous muscular work while wearing heavy, encapsulating personal protective equipment in high ambient temperatures, under chaotic and emotionally stressful conditions. These factors can precipitate sudden cardiac events like myocardial infarction, serious dysrhythmias, or cerebrovascular accidents in firefighters with underlying cardiovascular disease. Screening for cardiovascular risk factors is recommended but not always followed in this population. PHASER is a project charged with identifying and prioritizing risk factors in emergency responders. We have deployed an advanced ECG (A-ECG) system developed at NASA for improved sensitivity and specificity in the detection of cardiac risk. METHODS Forty-four professional firefighters were recruited to perform comprehensive baseline assessments including tests of aerobic performance and laboratory tests for fasting lipid profiles and glucose. Heart rate and conventional 12-lead ECG were obtained at rest and during incremental treadmill exercise testing (XT). In addition, a 5-min resting 12-lead A-ECG was obtained in a subset of firefighters (n=18) and transmitted over a secure networked system to a physician collaborator at NASA for advanced-ECG analysis. This A-ECG system has been proven, using myocardial perfusion and other imaging, to accurately identify a number of cardiac pathologies including coronary artery disease (CAD), left ventricular hypertrophy, hypertrophic cardiomyopathy, non-ischemic cardiomyopathy, and ischemic cardiomyopathy. RESULTS Subjects mean (SD) age was 43 (8) years, weight 91 (13) kg, and BMI of 28 (3) kg/square meter. Maximum oxygen uptake (VO2max) was 39 (9) ml/kg/min. This compares with the 45th %ile in healthy reference values and a recommended standard of 42 ml/kg/min for firefighters. The metabolic threshold (VO2Theta) above which lactate accumulates was 23 (8) ml/kg/min. The chronotropic index, a measure of cardiovascular strain during XT was 35 (8) /L compared with reference values for men of 40 /L. Total cholesterol, LDL-C and HDL-C were 202 (34),126 (29), and 55 (15) mg/dl, respectively. Fifty-one percent of subjects had .3 cardiovascular risk factors, 2 subjects had resting hypertension (BP.140/90), and 23 had pre-hypertension (.120/80 but <140/90). Seven had exaggerated exercise induced hypertension but only one had ST depression on XT ECG, at least one positive A-ECG score for CAD, and documented CAD based on cardiology referral. While all other subjects, including those with fewer risk factors, higher aerobic fitness, and normal exercise ECGs, were classified as healthy by A-ECG, there was no trend for association between risk factors and any of 20 A-ECG parameters in the grouped data. CONCLUSIONS A-ECG screening correctly identified the individual with CAD although there was no trend for A-ECG parameters to distinguish those with elevated BP or multiple risk factors but normal XT ECG. We have demonstrated that a new technology, advanced-ECG, can be introduced for remote firefighter risk assessment. This simple, time and cost-effective approach to risk identification that can be acquired remotely and transmitted securely can detect individuals potentially at risk for line-of-duty death. Additional research is needed to further document its value.

Dolezal, B. A.↗

Femoral Blood Flow and Cardiac Output During Blood Flow Restricted Leg Press Exercise

Low load blood flow restricted resistance exercise (LBFR) causes muscle hypertrophy that may be stimulated by the local ischemic environment created by the cuff pressure. However, local blood flow (BF) during such exercise is not well understood. PURPOSE: To characterize femoral artery BF and cardiac output (CO) during leg press exercise (LP) performed at a high load (HL) and low load (LL) with different levels of cuff pressure. METHODS: Eleven subjects (men/women 4/7, age 31.4+/-12.8 y, weight 68.9+/-13.2 kg, mean+/-SD) performed 3 sets of supine left LP to fatigue with 90 s of rest in 4 conditions: HL (%1-RM/cuff pressure: 80%/0); LL (20%/0); LBFR(sub DBP) (20%/1.3 x diastolic blood pressure, BP); LBFR(sub SBP) (20%/1.3 x supine systolic BP). The cuff remained inflated throughout the LBFR exercise sessions. Artery diameter, velocity time integral (VTI), and stroke volume (SV) were measured using Doppler ultrasound at rest and immediately after each set of exercise. Heart rate (HR) was monitored using a 3-lead ECG. BF was calculated as VTI x vessel cross-sectional area. CO was calculated as HR x SV. The data obtained after each set of exercise were averaged and used for analyses. Multi-level modeling was used to determine the effect of exercise condition on dependent variables. Statistical significance was set a priori at p< 0.05. RESULTS: Artery diameter did not change from baseline. BF increased (p<0.05) after exercise in each condition except LBFR(sub SBP) in the order of HL (12.73+/-1.42 cm3,mean+/-SE) > LL (9.92+/-0.82 cm3) > LBFR(sub dBP)(6.47+/-0.79 cm3) > LBFR(sub SBP) (3.51+/-0.59 cm3). Blunted exercise induced increases occurred in HR, SV, and CO after LBFR compared to HL and LL. HR increased 45% after HL and LL and 28% after LBFR (p<0.05), but SV increased (p<0.05) only after HL. Consequently, the increase (p<0.05) in CO was greater in HL and LL (approximately 3 L/min) than in LBFR (approximately 1 L/min). CONCLUSION: BF during LBFR(sub SBP) was 1/3 of that observed in LL, which supports the hypothesis that local ischemia stimulates the LBFR hypertrophic response. As the cuff did not compress the artery, the ischemia may have occurred because of the blunted rise in CO or because arterial BP cannot overcome the cuff pressure. As LBFR(sub DBP) effectively reduced BF and CO with cuff pressures less than systolic BP, future studies should investigate the hypertrophic potential of LBFR at even lower cuff pressures.

Everett, M. E.↗

Deployment of an Advanced Electrocardiographic Analysis (A-ECG) to Detect Cardiovascular Risk in Career Firefighters

INTRODUCTION: Sudden cardiac death is the leading cause of line of duty death among firefighters, accounting for approximately 45% of fatalities annually. Firefighters perform strenuous muscular work while wearing heavy, encapsulating personal protective equipment in high ambient temperatures, under chaotic and emotionally stressful conditions. These factors can precipitate sudden cardiac events like myocardial infarction, serious dysrhythmias, or cerebrovascular accidents in firefighters with underlying cardiovascular disease. PURPOSE: The purpose of this study was to deploy and then evaluate the contribution of resting advanced ECG (A-ECG) in addition to other screening tools (family history, lipid profiles, and cardiopulmonary exercise tests, XT) in assessment of an individual fs cardiac risk profile. METHODS: Forty-four career firefighters were recruited to perform comprehensive baseline assessments including tests of aerobic performance, fasting lipids and glucose. Five-min resting 12-lead A-ECGs were obtained in a subset of firefighters (n=21) and transmitted over a secure networked system to a NASA physician collaborator. Using myocardial perfusion and other imaging as the gold standard, A-ECG scoring has been proven useful in accurately identifying a number of cardiac pathologies including coronary artery disease (CAD), left ventricular hypertrophy, hypertrophic cardiomyopathy, and non-ischemic and ischemic cardiomyopathy. RESULTS: Subjects f mean (SD) age was 43 (8) years, weight 91 (13) kg, and BMI 28 (3) kg/m2. Fifty-one percent of subjects had .3 cardiovascular risk factors. One subject had ST depression on XT ECG, at least one positive A-ECG score for CAD, and documented CAD based on cardiology referral. While all other subjects, including those with fewer risk factors, higher aerobic fitness, and normal exercise ECGs, were classified as healthy by A-ECG, there was no trend for association between risk factors and any of 20 A-ECG parameters in the grouped data.

Dolezal, B. A.↗

NASA Astronaut Urinary Conditions Associated with Spaceflight

INTRODUCTION: Spaceflight is associated with many factors which may promote kidney stone formation, urinary retention, and/or Urinary Tract Infection (UTI). According to ISS mission predictions supplied by NASA's Integrated Medical Model, kidney stone is the second and sepsis (urosepsis as primary driver) the third most likely reason for emergent medical evacuation from the International Space Station (ISS). METHODS: Inflight and postflight medical records of NASA astronauts were reviewed for urinary retention, UTI and kidney stones during Mercury, Gemini, Apollo, Mir, Shuttle, and ISS expeditions 1-38. RESULTS: NASA astronauts have had 7 cases of kidney stones in the 12 months after flight. Three of these cases occurred within 90 to 180 days after landing and one of the seven cases occurred in the first 90 days after flight. There have been a total of 16 cases (0.018 events per person-flights) of urinary retention during flight. The event rates per mission are nearly identical between Shuttle and ISS flights (0.019 vs 0.021 events per person-flights). In 12 of the 16 cases, astronauts had taken at least one space motion sickness medication. Upon further analysis, it was determined that the odds of developing urinary retention in spaceflight is 3 times higher among astronauts who took promethazine. The female to male odds ratio for inflight urinary retention is 11:14. An astronaut with urinary retention is 25 times more likely to have a UTI with a 17% infection rate per mission. There have been 9 reported UTIs during spaceflight. DISCUSSION: It is unclear if spaceflight carries an increased post-flight risk of kidney stones. Regarding urinary retention, the female to male odds ratio is higher during flight compared to the general population where older males comprise almost all cases due to prostatic hypertrophy. This female prevalence in spaceflight is even more concerning given the fact that there have been many more males in space than females. Terrestrial medications with a known side effect of urinary retention are also associated with urinary retention during flight. However, not all cases of urinary retention surrounded medication use inflight. It is also known that UTI is a terrestrial cause of urinary retention. Furthermore, the treatment of urinary retention with a urinary catheter may be more likely to initiate a UTI in space than on the ground, as aseptic techniques can be particularly challenging with an inexperienced provider in a free-floating environment. Inflight urinary retention and UTI have proven to be highly associated and urinary risks should be considered collectively when planning for space flight.

Law, Jennifer↗

Transcriptomic Changes in Peripheral Blood Mononuclear Cells of International Space Station Crewmembers

In space, living organisms are exposed to numerous stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures. This study is part of the Functional Immune Project, intended to determine alterations in crewmembers` immunobiology before, during, and after spaceflight. For this project, blood samples were collected from International Space Station (ISS) crewmembers at the following time points: i) at two pre-flight time points of 180 days (L180) and 45 days (L45) before launch. ii) During flight, blood was drawn at approximately the midpoint (mid-flight, MF) of the mission, and shortly before egress from the ISS (late-flight, LF). iii) Post-flight blood samples were collected within 24 hrs (R0), 30 days (R30) and 90 days (R90) after landing. For each crewmember, blood was also drawn from a matching test subject on the ground at the corresponding time point. For both the ISS crewmembers and the ground control subjects, total RNA was isolated from peripheral blood mononuclear cells (PBMC) and mRNA was analysed using next generation RNA-sequencing (NGS). Differentially expressed genes were determined by performing contrast analysis. Using the ground control subjects of all of the time points combined as a control, a number of dysregulated genes were identified in astronauts at MF, LF and R0, including downregulations of SMAD7 and CDKN1A at MF and LF. Some of the genes such as SERPINE1 and VEGFA were downregulated at MF and LF, but upregulated at R0, while others such as NKG7 were down regulated at all of the 3 time points. Pathway analysis of these differentially expressed genes indicated that the NF-κB pathway was chronically activated in space. Analysis of the consequent diseases suggested potential associations with not only immune dysfunction, but also other health risks including osteoarthritis, cardiac hypertrophy and neuroinflammation.

Maria Moreno-Villanueva↗

Transcriptomic Changes in Peripheral Blood Mononuclear Cells of International Space Station Crewmembers

In space, living organisms are exposed to numerous stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures. This study is part of the Functional Immune Project, intended to determine alterations in crewmembers` immunobiology before, during, and after spaceflight. For this project, blood samples were collected from International Space Station (ISS) crewmembers at the following time points: i) Blood was drawn at two pre-flight time points of 180 days (L180) and 45 days (L45) before launch. ii) During flight, blood was drawn at approximately the midpoint (mid-flight, MF) of the mission, and shortly before egress from the ISS (late-flight, LF). iii) Post-flight blood samples were collected within 36 hours (R0), 30 days (R30) and 90 days (R90) after landing. For each crewmember, blood was also drawn from a matching test subject on the ground at the corresponding time point. For both the ISS crewmembers and the ground control subjects, total RNA was isolated from peripheral blood mononuclear cells (PBMC) and mRNA was analysed using next generation RNA-sequencing (NGS). Differentially expressed genes were determined by performing contrast analysis. Using the ground control subjects of all time points combined as a control, a number of dysregulated genes were identified in astronauts at MF, LF and R0, including downregulations of SMAD7 and CDKN1A at MF and LF. Some of the genes such as SERPINE1 and VEGFA were downregulated at MF and LF, but upregulated at R0, while others such as NKG7 were down regulated at all 3 time points. Pathway analysis of these differentially expressed genes indicated that the NF-κB pathway was chronically activated in space. Analysis of the consequent diseases suggested potential associations with not only immune dysfunction, but also other health risks including osteoarthritis, cardiac hypertrophy and neuroinflammation.

Maria Moreno-Villanueva↗

Skeletal muscle plasticity: cellular and molecular responses to altered physical activity paradigms

The goal of this article is to examine our current understanding of the chain of events known to be involved in the adaptive process whereby specific genes and their protein products undergo altered expression; specifically, skeletal muscle adaptation in response to altered loading states will be discussed, with a special focus on the regulation of the contractile protein, myosin heavy chain gene expression. This protein, which is both an important structural and regulatory protein comprising the contractile apparatus, can be expressed as different isoforms, thereby having an impact on the functional diversity of the muscle. Because the regulation of the myosin gene family is under the control of a complex set of processes including, but not limited to, activity, hormonal, and metabolic factors, this protein will serve as a cellular "marker" for studies of muscle plasticity in response to various mechanical perturbations in which the quantity and type of myosin isoform, along with other important cellular proteins, are altered in expression.

Non-NASA Center↗

Autocrine and/or paracrine insulin-like growth factor-I activity in skeletal muscle

Similar to bone, skeletal muscle responds and adapts to changes in loading state via mechanisms that appear to be intrinsic to the muscle. One of the mechanisms modulating skeletal muscle adaptation it thought to involve the autocrine and/or paracrine production of insulinlike growth factor-I. This brief review outlines components of the insulinlike growth factor-I system as it relates to skeletal muscle and provides the rationale for the theory that insulinlike growth factor-I is involved with muscle adaptation.

Review, Tutorial↗

Mechanical stimulation improves tissue-engineered human skeletal muscle

Human bioartificial muscles (HBAMs) are tissue engineered by suspending muscle cells in collagen/MATRIGEL, casting in a silicone mold containing end attachment sites, and allowing the cells to differentiate for 8 to 16 days. The resulting HBAMs are representative of skeletal muscle in that they contain parallel arrays of postmitotic myofibers; however, they differ in many other morphological characteristics. To engineer improved HBAMs, i.e., more in vivo-like, we developed Mechanical Cell Stimulator (MCS) hardware to apply in vivo-like forces directly to the engineered tissue. A sensitive force transducer attached to the HBAM measured real-time, internally generated, as well as externally applied, forces. The muscle cells generated increasing internal forces during formation which were inhibitable with a cytoskeleton depolymerizer. Repetitive stretch/relaxation for 8 days increased the HBAM elasticity two- to threefold, mean myofiber diameter 12%, and myofiber area percent 40%. This system allows engineering of improved skeletal muscle analogs as well as a nondestructive method to determine passive force and viscoelastic properties of the resulting tissue.

Non-NASA Center↗

Long-term insulin-like growth factor-I expression in skeletal muscles attenuates the enhanced in vitro proliferation ability of the resident satellite cells in transgenic mice

Insulin-like growth factor-I (IGF-I) overexpression for 1-month in mouse skeletal muscle increases satellite cell proliferation potential. However, it is unknown whether this beneficial enhancement by IGF-I expression would persist over a longer-term duration in aged mice. This is an important issue to address if a prolonged course of IGF-I is to be used clinically in muscle-wasting conditions where satellite cells may become limiting. Using the IGF-I transgenic (IGF-I Tg) mouse that selectively expresses the IGF-I transgene in striated muscles, we found that 18-months of continuous IGF-I overexpression led to a loss in the enhanced in vitro proliferative capacity of satellite cells from Tg skeletal muscles. Also 18-month-old IGF-I Tg satellite cells lost the enhanced BrdU incorporation, greater pRb and Akt phosphorylations, and decreased p27(Kip1) levels initially observed in cells from 1-month-old IGF-I Tg mice. The levels of those biochemical markers reverted to similar values seen in the 18-months WT littermates. These findings, therefore, suggest that there is no further beneficial effect on enhancing satellite cell proliferation ability with persistent long-term expression of IGF-I in skeletal muscles of these transgenic mice.

Non-NASA Center↗

Treatment of hypertension with perindopril reduces plasma atrial natriuretic peptide levels, left ventricular mass, and improves echocardiographic parameters of diastolic function

BACKGROUND: Hypertension is a major independent risk factor for cardiac deaths, and diastolic dysfunction is a usual finding during the course of this disease. HYPOTHESIS: This study was designed to investigate the effects of chronic therapy with perindopril on left ventricular (LV) mass, left atrial size, diastolic function, and plasma level of atrial natriuretic peptide (ANP) in patients with hypertension. METHODS: Twenty four patients who had not been previously taking any antihypertensive medication and without prior history of angina pectoris, myocardial infarction, congestive heart failure, dysrhythmias, valvular heart disease, or systemic illnesses received 4-8 mg/day of perindopril orally. Echocardiographic studies were acquired at baseline and 6 months after the initiation of therapy. RESULTS: Systolic and diastolic blood pressure decreased from 174 +/- 19.7 and 107.5 +/- 7.8 mmHg to 134 +/- 10.6 and 82 +/- 6.7 mmHg, respectively (p < 0.001). Left ventricular mass decreased from 252.4 +/- 8.3 to 205.7 +/- 7.08 g and left atrial volume from 20.4 +/- 5.1 to 17.6 +/- 5.2 ml, respectively (p < 0.001). Transmitral Doppler early and atrial filling velocity ratio (E/A) increased from 0.69 +/- 0.06 to 0.92 +/- 0.05 m/s and plasma ANP level decreased from 71.9 +/- 11.7 to 35.3 +/- 7.8 pg/ml (p < 0.001). Reduction of LV mass correlated positively with a reduction in ANP levels (r = 0.66, p < 0.0005). CONCLUSIONS: Perindopril caused a significant reduction of LV mass, left atrial volume, and plasma ANP levels, as well as improvement in Doppler parameters of LV filling in this group of patients with hypertension.

NASA Program Biomedical Research and Countermeasur↗

Mechanical load induces sarcoplasmic wounding and FGF release in differentiated human skeletal muscle cultures

The transduction mechanism (or mechanisms) responsible for converting a mechanical load into a skeletal muscle growth response are unclear. In this study we have used a mechanically active tissue culture model of differentiated human skeletal muscle cells to investigate the relationship between mechanical load, sarcolemma wounding, fibroblast growth factor release, and skeletal muscle cell growth. Using the Flexcell Strain Unit we demonstrate that as mechanical load increases, so too does the amount of sarcolemma wounding. A similar relationship was also observed between the level of mechanical load inflicted on the cells and the amount of bFGF (FGF2) released into the surrounding medium. In addition, we demonstrate that the muscle cell growth response induced by chronic mechanical loading in culture can be inhibited by the presence of an antibody capable of neutralizing the biological activity of FGF. This study provides direct evidence that mechanically induced, sarcolemma wound-mediated FGF release is an important autocrine mechanism for transducing the stimulus of mechanical load into a skeletal muscle growth response.

NASA Center JSC↗

The presence of lysylpyridinoline in the hypertrophic cartilage of newly hatched chicks

The presence of lysylpyridinoline (LP) as a nonreducible cross-link in appreciable quantities has primarily been limited to the mineralized tissues, bone and dentin. However, the results reported here show that LP is not only present in the hypertrophic cartilage of the tibiotarsus isolated from newly hatched broiler chicks, but it is approx. 4-fold as concentrated as hydroxylysylpyridinoline (HP). Bone and articular cartilage surrounding the hypertrophic cartilage do not contain measurable quantities of LP. Purified LP has a fluorescent scan similar to purified HP and literature values, confirming that we indeed were measuring LP. Also, the cartilage lesion produced by immature chondrocytes from birds with tibial dyschondroplasia had LP but the HP:LP ratio was > 1. Thus, the low HP:LP ratio could be a marker for hypertrophic cartilage in avians.

NASA Discipline Musculoskeletal↗