WHITE BLOOD CELLS, EXERCISE, AND CHILDREN: INITIAL MECHANISMS

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding the dynamic changes in body composition in the perinatal and early neonatal period has been a major of focus of neonatal research for over a century. At no time in the life of humans is energy expenditure for growth so large and the process of new tissue development so rapid. Measurements of body composition and energy expenditure are essential if we are to gain insights into the mechanisms of how interventions like assisted exercise influence body composition in premature babies. For many reasons involving technical, ethical, and feasibility factors, making accurate measurements of both body composition and energy expenditure has remained a singular challenge in this field (1), and the armamentarium available for these important indexes of growth are limited in the context of the newborn. Current techniques include: anthropometry, total body electrical conductance, tracer dilution, total body potassium, bioelectrical impedance, magnetic resonance imaging and spectroscopy, acoustic plethysmography, air displacement, Dual Energy X-ray Absorptiometry (DEXA), Quantitative ultrasound (QUS), and regional ultrasonography of skeletal muscle and fat mass (2-8). Of these methods, some combination of DEXA, QUS, and regional ultrasonography is the most promising and feasible. QUS and muscle ultrasound are noninvasive, can be performed at the bedside (no need to transport the infant), have no ionizing radiation, and can be performed multiple times during the course of an intervention study. However, the determinants of QUS are complex and their relationship to bone structure and density have yet to be fully clarified. Both QUS and muscle sonography provide data on regions of the body, and it may not be possible to extrapolate the regional data to total body bone mineral density or muscle mass-a key outcome when considering the impact of assisted exercise. In contrast, DEXA can measure both bone mineralization and body composition, and these measurements can be made for the whole body and regionally. But the disadvantages of DEXA are also substantial: the baby must be studied with a minimum of movement artifact (often, a daunting challenge for a typical, unsedated neonate), and the baby must be transported to the DEXA unit rendering it difficult to perform multiple measurements in a growing, hospitalized premature baby. Finally, DEXA does involve a minimal (probably negligent) dose of ionizing radiation which can hinder recruitment. Thus, to optimize our measurements of body composition and bone mineralization in the prospective study, we plan a Methods Validation Study designed to compare the three following techniques: " DEXA " Bone Quantitative Ultrasound " Muscle Ultrasound As a result of this study, we will be able to determine the optimal combination of these three methods, or, if possible, information from QUS and muscle ultrasonagraphy alone are powerful enough to meet our objectives. DEXA: is a scanning technique that measures the differential attenuation of two x-rays as they pass through the body. DEXA has become the state-of-the-art method to estimate body composition for research purposes in adult humans [e.g., (9)]. DEXA scans measure total and regional body bone mineral content (BMC), bone mineral density (BMD), fat-free mass (FFM), and fat mass (FM). DEXA scanning has been used in infants, and our Project Consultant, Dr. Winston Koo, has done much of the pioneering work in establishing the instrumental, clinical, and analaytical approaches necessary for reproducible and accurate use of DEXA scanning for the measurement of body composition in infants (10; 11). QUS: Metabolic bone disease is a relatively common event in preterm infants because the greatest period of bone mineral accretion ordinarily occurs during the last trimester of pregnancy, and this is difficult to reproduce in the extrauterine environment (12; 13). Currently, its diagnosis is based primarily on biochemical evaluation of serum alkaline phosphatase and radiological evidence of osteopenia and/or fractures, and in some cases, on measurements of bone mineralization by DEXA (14). The use of DEXA in the clinical setting, however, is limited by its relatively high cost and the need to transport the patient to the instrument, making it relatively unfeasible for very small or sick infants, i.e., the very ones most at risk of developing metabolic bone disease. QUS measurement of bone SOS has recently become a viable alternative, and there is a substantial body of literature demonstrating its utility in assessing bone strength in infants (15-20), children (21) and adults (22; 23). QUS is predicated on the concept that the propagation of sound waves through a medium depends upon the physical properties of that medium (Figure 3). Therefore, the denser the medium, the faster the sound waves propagate through it. In addition to bone density, bone SOS is also determined by other bone properties, such as cortical thickness, elasticity and micro-architecture, and may, in conjunction with DEXA, provide a more clinically relevant picture of bone strength (24; 25). QUS is relatively inexpensive, portable, noninvasive, involves no ionizing radiation, and has, in initial studies, been shown to correlate accurately with measurements by DEXA (26; 27). Muscle Ultrasound: A major goal of this study is to assess muscle and fat mass in the newborn and preterm infant. Ultrasound (US) imaging is a useful technique for visualization of skeletal muscle tissue (28), and has been extensively used in adults (29) and more recently in children (30) and infants (31) [where it is increasingly used to measure volume of the diaphragm as well (32)]. US imaging is a portable, noninvasive method that does not involve ionizing radiation. Clear visualization of the muscle boundaries is possible since the epimysium surrounding the muscle is highly reflective and the bone echo is strong and distinct. This gives the added advantage of directly quantitating lean muscle mass compared to more indirect methods like skinfold thickness, which can include the skin and subcutaneous fat (33). In a recent New England Journal of Medicine report (34), muscle ultrasound was used to assess muscle hypertrophy in a baby with a myostatin gene mutation, and it has been used successfully to gauge cardiac and skeletal muscle mass in small animals such as the rat and small shorebirds (35; 36). A key question is whether regional measurement of bone strength or muscle/fat distribution, as will be done by the QUS and muscle ultrasound techniques, can be useful in gauging total body lean and fat distribution. We will be able to answer this question in the proposed Methods Validation Study. We have reason to be optimistic, for example, our Project Consultant Dr. Winston Koo and coworkers (37) showed in the piglet model that bone mineral content variables obtained from DEXA of the humerus and femur were highly correlated with whole body DEXA results.