bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Therapy for Heart Transplantation‐Associated Coronary Arteriosclerosisa
Authors: ISOBE MITSUAKI , SUZUKI JUN‐ICHI , MORISHITA RYUICHI , KANEDA YASUFUMI , AMANO JUN
Published: July 2010

Abstract: Cardiac allograft arteriosclerosis, which limits the long‐term survival of recipients, cannot be prevented by conventional therapies. The arteriopathy is characterized by diffuse intimal thickening made up of proliferative smooth muscle cells. To test the hypothesis that cell cycle‐regulatory genes play crucial roles in the development of this arteriopathy in vivo gene therapy targeting cell division cycle (cdc) 2 kinase was attempted in murine cardiac allografts using hemagglutinating virus of Japan (HVJ)‐liposome method. Antisense cdc 2 kinase oligodeoxynucleotide (ODN) was transfected into the allografts by intraluminal injection during the operation and the allografts were harvested at 4 weeks after transplantation. Coronary intimal thickening had developed in sense ODN‐treated allografts and ICAM‐1 and VCAM‐1 were enhanced in these arteries. PDGF mRNA was also detected. Antisense cdc 2 kinase ODN inhibited intimal hyperplasia. These data indicate that antisense cdc 2 kinase modulates gene expression and inhibits smooth muscle cell proliferation of graft arteries.
Role of Endothelin‐1 in Atherosclerosisa
Authors: FAN JIANGLIN , UNOKI HIROYUKI , IWASA SATOSHI , WATANABE TERUO
Published: July 2010

Abstract:Increased evidence has shown that endothelin‐1 (ET‐1) derived from the arterial cells is involved in the development of atherosclerosis. ET‐1 and ET receptors are upregulated in both human and experimental animal atherosclerotic lesions. Plasma ET‐1 levels are significantly elevated in hypercholestolemic subjects and cholesterol‐fed animals. We hypothesized that plasma lipoproteins such as LDL and HDL retained in the arterial wall can affect ET‐1 production and secretion, thereby sustaining vascular functions. Using a two‐chamber culture system, we have demonstrated that endothelial cells (ECs) show a polar secretion of ET‐1; the majority of ET‐1 are secreted toward the basal side of the vessels. Furthermore, we found that LDL enhances whereas HDL inhibits the ET‐1 secretion from ECs in a polarized pattern. In order to demonstrate ET receptor distribution in the lesion, we recently studied both human and apoE‐KO mice. Our study showed that there is an increased expression of ETB receptors in foamy macrophages in the lesions. More importantly, medial smooth muscle cells (SMCs) beneath the foam cell lesions exhibited a higher intensity of ETB receptor immunoreactivity than those located in foam cell‐free areas. In such an area, ET‐1 immunoreactivity is also increased. These results suggest that accumulation of foamy macrophages may modulate the shift of ET receptor subtypes from ETA to ETB in SMCs and an enhanced ET system mediated by ETB receptors may play a pivotal role in the progression of atherosclerosis. This notion has been further supported by a recent finding that administration of ET receptor antagonists resulted in a significant reduction of atherosclerosis in apoE‐KO mice.
Receptors and Lipid Transfer Proteins in HDL Metabolism
Authors: SILVER DAVID L. , JIANG XIAN‐CHENG , ARAI TAKESHI , BRUCE CAN , TALL ALAN R.
Published: July 2010

Abstract: It is believed that HDL exerts its anti‐atherogenic effects through the process of delivering cholesterol from peripheral tissues back to the liver for removal from the body (i.e., reverse cholesterol transport). The metabolic life cycle of HDL lipid and apolipoproteins during reverse cholesterol transport involves both its modification in plasma by lipid transfer proteins and the clearance from plasma of HDL lipid and protein mediated by hepatic cell surface proteins. We review recent work from our laboratory that focuses on specific metabolic steps in reverse cholesterol transport and the results of altering these steps on plasma HDL levels and atherosclerosis. Recently, SR‐BI was shown to be an authentic HDL receptor mediating the selective uptake of HDL lipids into cells without degradation of HDL proteins. We discuss the evidence for additional receptor activity mediating HDL protein catabolism in the liver from studies in obese (ob/ob) mice, which have markedly increased HDL due to a defect in hepatic catabolism of apoA‐I and apoA‐II. In addition, we review recent findings that phospholipid transfer protein deficiency in mice results in markedly reduced HDL levels. Lastly, we highlight our findings that overexpression of SR‐BI in LDL receptor‐deficient mice results in decreased atherosclerosis.
Lipid Lowering Reduces Proteolytic and Prothrombotic Potential in Rabbit Atheromaa
Authors: AIKAWA MASANORI , LIBBY PETER
Published: July 2010

Abstract: Thrombus formation at sites of atheromatous plaque disruption cause most acute coronary events such as myocardial infarction and unstable angina. Lesional macrophages and smooth muscle cells produce matrix metalloproteinases (MMPs) and tissue factor (TF), the molecules likely contribute to plaque rupture and thrombus formation. Recent clinical studies have suggested that lipid lowering can reduce the incidence of acute coronary events. We have recently determined the effects of long‐term dietary lipid lowering on atheroma of high‐cholesterol‐fed rabbits. Lipid lowering diminished macrophage accumulation, reduced expression and activity of MMPs, and increased interstitial collagen accumulation in rabbit atheroma. Expression and activity of TF in atheroma also substantially decreased during lipid lowering. Dietary lipid lowering also promoted accumulation of mature smooth muscle cells expressing less MMPs and TF in the plaque's fibrous cap. These results suggest potential mechanisms by which lipid lowering reduces acute coronary events in patients by decreasing proteolytic and prothrombotic activity within the atheroma.
Mechanisms of Vascular Atrophy and Fibrous Cap Disruption
Authors: CLOWES ALEXANDER W. , BERCELI SCOTT A.
Published: July 2010

Abstract: The process of plaque destabilization and rupture remains an area of intense investigation. While reductions in lumen cross‐sectional area induced by early, non‐occlusive lesions are compensated by remodeling and expansion of the artery, further plaque enlargement leads to an uncompensated reduction in lumen area and an increase in surface shearing forces. We hypothesize that these local increases in wall shear stress lead to a reduction in smooth muscle cell proliferation and increase in cell death. Using a primate prosthetic graft model, we have observed that alterations in nitric oxide and platelet‐derived growth factor metabolism are important regulators of intimal growth and regression. We suggest that these factors may also be influential in the process of fibrous cap atrophy and plaque rupture.
Characterization of Atherosclerotic Plaques by Magnetic Resonance Imaging
Authors: FAYAD ZAHI , FUSTER VALENTIN
Published: July 2010

Abstract: The study of atherosclerotic disease during its natural history and after therapeutic intervention will enhance our understanding of the progression and regression of this disease and will aid in selecting the appropriate medical treatments or surgical interventions. Several invasive and non‐invasive imaging techniques are available to assess atherosclerotic vessels. Most of these techniques are strong in identifying the morphological features of the disease, such as lumenal diameter and stenosis or wall thickness, and in some cases provide an assessment of the relative risk associated with the atherosclerosis. However, none of these techniques can fully characterize the composition of the atherosclerotic plaque in the vessel wall and, therefore, are incapable of identifying the vulnerable plaques. High‐resolution, multi‐contrast, magnetic resonance (MR) can non‐invasively image vulnerable plaques, characterize plaques in terms of lipid and fibrous content, and identify the presence of thrombus or calcium. Application of MR imaging opens up whole new areas for diagnosis, prevention, and treatment (e.g., lipid‐lowering drug regimens) of atherosclerosis.
Transcriptional Regulation of Smooth Muscle Phenotypic Modulation
Authors: NAGAI RYOZO , KOWASE KEIKO , KURABAYASHI MASAHIKO
Published: July 2010

Abstract: Phenotypic modulation of vascular smooth muscle cell plays a pivotal role in the development of vascular pathology, such as atherosclerosis and restenosis after angioplasty. We have identified the zinc finger protein BTEB2 as a DNA binding protein that regulates the nonmuscle myosin heavy chain (SMemb) promoter. BTEB2 is expressed in fetal aorta but not in adult aorta and is induced in the neointima in response to vascular injury. BTEB2 also activates a number of vascular disease‐associated genes, such as tissue factor, PAI‐1 (plasminogen activator inhibitor‐1), and Egr‐1 gene. We have further isolated and characterized the human BTEB2 gene. Functional studies using 5′‐deletion and site‐directed mutation constructs demonstrated that phorbol ester induces Egr‐1, which can activate the BTEB2 promoter through binding to ‐32 from the transcription start site. These results suggest that phenotypic modulation of vascular smooth muscle cells occurring in response to mitogen stimulation may be mediated by BTEB2 through Egr‐1 induction.
Endothelial Dysfunction, Hemodynamic Forces, and Atherogenesisa
Authors: GIMBRONE MICHAEL A. , TOPPER JAMES N. , NAGEL TOBI , ANDERSON KEITH R. , GARCIA‐CARDEÑA GUILLERMO
Published: July 2010

Abstract: Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of cardiovascular diseases such as atherosclerosis. The localization of atherosclerotic lesions to arterial geometries associated with disturbed flow patterns suggests an important role for local hemodynamic forces in atherogenesis. There is increasing evidence that the vascular endothelium, which is directly exposed to various fluid mechanical forces generated by pulsatile blood flow, can discriminate among these stimuli and transduce them into genetic regulatory events. At the level of individual genes, this regulation is accomplished via the binding of certain transcription factors, such as NFκB and Egr‐1, to shear‐stress response elements (SSREs) that are present in the promoters of biomechanically inducible genes. At the level of multiple genes, distinct patterns of up‐ and downregulation appear to be elicited by exposure to steady laminar shear stresses versus comparable levels of non‐laminar (e.g., turbulent) shear stresses or cytokine stimulation (e.g., IL‐1β). Certain genes upregulated by steady laminar shear stress stimulation (such as eNOS, COX‐2, and Mn‐SOD) support vasoprotective (i.e., anti‐inflammatory, anti‐thrombotic, anti‐oxidant) functions in the endothelium. We hypothesize that the selective and sustained expression of these and related “atheroprotective genes” in the endothelial lining of lesion‐protected areas represents a mechanism whereby hemodynamic forces can influence lesion formation and progression.
Molecular Basis of Angiogenesis: Role of VEGF and VE‐Cadherin
Authors: CARMELIET PETER , COLLEN DESIRE
Published: July 2010

Abstract: The formation of new blood vessels (angiogenesis) is essential for embryonic development and contributes to the pathogenesis of numerous disorders. In contrast, insufficient angiogenesis may lead to tissue ischemia and failure. The recent discovery of novel angiogenic molecules has initiated efforts to improve tissue perfusion via therapeutic angiogenesis. However, rational design of such treatment strategies mandates a better understanding of the molecular mechanisms of angiogenesis. In this brief review, the role of a prime angiogenic candidate, namely vascular endothelial growth factor (VEGF) and its homologues, in physiological and pathological angiogenesis will be discussed with particular attention to myocardial ischemia and heart failure. In addition, a novel interaction between the junctional protein vascular endothelial‐cadherin (VE‐cadherin) and VEGF, essential for the endothelial survival function of VEGF, will be reviewed.
Differentiation‐Induced Transmigration of HL60 Cells across Activated HUVEC Monolayer Involves E‐selectin‐Dependent Mechanisma
Authors: YOSHIDA MASAYUKI , CHIEN LEE‐JUNG , YASUKOCHI YUKIO , NUMANO FUJIO
Published: July 2010

Abstract: The leukocyte‐endothelial adhesive interaction is one of the key mechanisms during inflammation. The human promyelocytic cell line HL60 has been used in a number of studies to characterize leukocyte‐endothelial interactions, especially selectin‐mediated adhesion. HL60 also has been used in studies to characterize the myeloid cell function during differentiation. In this study, we investigated the adhesive interactions of HL60 to vascular endothelium, either in its undifferentiated state or after dimethylsulfoxide‐induced granulocytic differentiation. Granulocytic differentiation of HL60 cells significantly enhanced their transmigration across cytokine‐activated (IL‐1β 10 U/ml, 4 h) HUVEC monolayer. Interestingly, this enhanced transmigration of differentiated HL60 cells was inhibited by pretreatment of the monolayers with anti‐E‐selectin mAb as well as anti‐ICAM‐1 mAb or anti‐VE‐cadherin mAb, suggesting a potential role for E‐selectin in transendothelial migration. Further study of this enhanced transmigration mechanism may elucidate the regulation of selectin‐mediated leukocyte‐endothelial interactions.
Magnetic Resonance Imaging in Human Body Composition Research: From Quantitative to Qualitative Tissue Measurement
Authors: ROSS ROBERT , GOODPASTER BRET , KELLEY DAVID , BOADA FERNANDO
Published: July 2010

Abstract: Incremental improvements in our knowledge of human body composition are abetted by advances in research technology. Indeed, magnetic resonance imaging (MRI) represents a technological advance that has profoundly influenced body composition research. Routine applications of MRI include the measurement of whole‐body and regional adipose tissue distribution, quantification of lean tissue and its principal constituent skeletal muscle, and the measurement of visceral adipose tissue. MRI is now the method of choice for calibration of field methods designed to measure body fat and skeletal muscle in vivo. Common to these applications is the measurement of tissue quantity. More recently proton (1H) and sodium (23Na) MRI protocols have been developed that measure the quality (lipid and sodium concentration) of skeletal muscle tissue. These unique applications of MRI represent a major advance in the study of altered muscle composition in vivo, with numerous applications in both applied and clinical medicine. In this review we provide a brief overview of routine applications of MRI in body composition research, followed by a focus on more recent applications of MRI that employ fast‐imaging sequences for qualitative measurement of human skeletal muscle.
Observation of Intramyocellular Lipids by1H‐Magnetic Resonance Spectroscopy
Authors: BOESCH CHRIS , KREIS ROLAND
Published: July 2010

Abstract: Magnetic resonance (MR) methods are increasingly being used to investigate the physiology of human muscle. Although MR imaging (MRI) reveals the morphology of muscles in great detail, for example, for determining their volume and fiber orientation, MR spectroscopy (MRS) provides information on the chemical composition of the tissue. Depending on the observed nucleus, MRS allows the observation of high‐energy phosphates (31P‐MRS), glycogen (13C‐MRS), or intramyocellular lipids (1H‐MRS), to give only a few examples. 1H‐MRS of human skeletal muscle requires special techniques because1H nuclei in water or adipose tissue are far more concentrated than in any other metabolite of human tissue. The strong signal from water can be suppressed by special prepulses, whereas large signals from fat in adipose tissue can be reduced by carefully selecting the region of interest. Until recently, it was presumed that only a few metabolites would be visible underneath the large resonances of water and subcutaneous fat. Meanwhile, it was clear that 1H‐MR spectra of human muscle reveal much metabolic and structural information. The determination of intramyocellular lipids (IMCL) by 1H‐MRS was initiated by the observation of two compartments of triacylglycerols with a resonance‐frequency shift of approximately 0.2 ppm. The two resonances can be attributed to CH2 protons of lipids in fat cells, and to lipids inside muscle cells (IMCL).1H‐MRS examinations are noninvasive and, therefore, can be repeated many times and with a high temporal resolution. MRS has the potential to replace biopsy to follow‐up IMCL levels; however, biopsy still has the advantage that other methods, such as molecular biology, can be applied to the sample. It can be shown that IMCL levels (expressed in mMol/kg wet weight and volume %) are muscle specific and vary with diet and physical activity. In addition, it has been reported that IMCL levels are correlated with insulin sensitivity. A comparison of different methods for assessing IMCL levels, including MRS, chemical analysis, and morphometry, revealed a satisfactory correlation among them and a superior correlation of MRS with the average of the three methods. The observation of IMCL levels by means of 1H‐MRS is extremely promising, but several methodological limitations and pitfalls need to be considered.
Dual‐Energy X‐ray Absorptiometry Measurements of the Body Composition of Pigs of 90‐ to 130‐Kilograms Body Weight
Authors: MITCHELL A. D. , SCHOLZ A. M. , PURSEL V. G.
Published: July 2010

Abstract: We used the pig as an in vivo model for evaluating the effects of extreme body depth on the measurement of body composition by dual‐energy X‐ray absorptiometry (DXA). One group of 17 pigs weighed an average of 90 kg and had a maximum body depth of approximately 30 cm; another group of 54 pigs weighed 123 kg on average and had a maximum body depth of about 35 centimeters. In the larger pigs, DXA tended to measure a higher percentage of total body fat relative to the chemical analysis than in the smaller pigs. In both groups, but more predominantly in the larger pigs, there were areas in the bone of extreme thickness and/or density that were excluded from the analysis, which caused underestimation of bone mineral content and total tissue mass.
Hydrational Status Assessed by Bioelectrical Impedance Spectroscopy and Dilution Methods in Patients with Classical Dengue Fever
Authors: KLASSEN P. , MAZARIEGOS M. , DEURENBERG P. , SOLOMONS N. W. , FÜRST P.
Published: July 2010

Abstract: The effects of an episode of acute classical dengue fever on extracellular water (ECW), intracellular water (ICW), and total body water (TBW) were measured in nine patients using conventional dilution techniques; and the findings were compared with the outcome variables from whole body impedance spectroscopy (BIS), extracellular fluid resistance (Recf), and intracellular fluid resistance (Ricf). The patients were assessed on admission with febrile presentation (DI), at discharge after the defervescence of the fever cycle at about five days postadmission (DII), and seven days thereafter (DIII). As a reference group, 15 persons without acute or chronic illness were enrolled. Total body water was unaltered during the course of disease and was not different from that in normal healthy subjects. However, body water shifted from the intracellular to the extracellular compartment in patients from the acute phase to convalescence, as reflected in the ratios of ECW/TBW and ECW/ICW. These ratios were significantly higher in convalescent dengue patients (DIII) than in the reference group (p < 0.05). Increasing ECW, from the acute phase of the disease to convalescence, was associated with a significant decrease in Recf (719 ± 95, 693 ± 89, 643 ± 81 Ω; p < 0.0001) and in Recf/Ricf (p < 0.01). Recf and Recf/Ricf were higher in the acute phase (DI) of dengue fever compared to controls (p < 0.05). We conclude that dengue fever is characterized by a relative expansion of ECW during the course of disease and convalescence. BIS was sensitive in determining the hydrational profile in dengue fever patients.
Using Localized Impedance Measurements to Study Muscle Changes in Injury and Disease
Authors: AARON R. , SHIFFMAN C. A.
Published: July 2010

Abstract: We measured localized impedance on the surface of the thigh to determine the properties of underlying muscle; these include ρ1, the resistivity for current flowing parallel to the fibers, and θavg, the average phase along the thigh (normalized to a standard length). The results for a modest sampling of nominally healthy subjects show that the θavg values are substantially higher than the whole body phases encountered in standard bioimpedance analysis. When the sample is augmented to include subjects undergoing hemodialysis and/or recovering from serious illness or leg injury, the behavior of the position dependence of the phase θ(z) and the ρ1 vs. θavg average distribution both strongly indicate a correlation between very low phase angles and injury or disease. Furthermore, measurements on a subject in a weight training program after injury provide evidence of a monotone increase in ρ1 with increasing strength. Measurements on dialysis patients during treatment show a nonlinear response of thigh muscle to the degree of fluid removal and wide disparities between individuals.
Comparison of Whole Body and Segmental Bioimpedance Methodologies for Estimating Total Body Water
Authors: WOTTON M. J. , THOMAS B. J. , CORNISH B. H. , WARD L. C.
Published: July 2010

Abstract: We compared the whole body (WB) and segmental bioelectrical impedance analysis (BIA) methodologies in a group of healthy adults (n= 25). It has been suggested that the segmental methodology may overcome the difficulty in generating a single algorithm to predict total body water (TBW) in all groups whether healthy or not. We measured TBW, using D2O dilution, and WB and segmental BIA parameters. Cole‐Cole analysis was used to determine the impedance at the characteristic frequency (Zc). The correlation between TBW (by D2O dilution) and segmental BIA measures (multiple regression, r= 0.90, p < 0.001, SEE = 3.1 L) was not significantly higher than the correlation between TBW (D2O dilution) and WB BIA measures (simple regression, r= 0.85, p < 0.001, SEE = 3.6 L). Others have observed this “lack of improvement” in a group of healthy subjects. The true value of the segmental BIA methodology may lie in applications involving groups with altered distributions of segmental and compartmental fluid.
Assessment of Body Volume Using Three‐Dimensional Photonic Scanning
Authors: WELLS J.C. K. , DOUROS I. , FULLER N. J. , ELIA M. , DEKKER L.
Published: July 2010

Abstract:Measurement of body volume (BV) can be used to estimate body composition using two‐ or multicomponent models. The traditional approach, underwater weighing (UWW), is awkward and unsuitable for many subjects. A newer alternative, whole body air displacement plethysmography (ADP), is less demanding but still unsuitable for young children, who may not remain still during the measurement. We have, therefore, considered whether a novel approach, three‐dimensional photonic scanning, is a viable alternative. Duplicate measurements of body volume were obtained in 22 adults (11 of each sex; mean [SD] BMI, 21.8 [2.5] kg/m2) by UWW, ADP, and a Hamamatsu Bodyline Scanner (HBS) (Hamamatsu, Japan). Subjects wore a tight‐fitting swimming costume for all three measurements, which were performed within one day of each other. Scans lasted 10 seconds, with the subject standing in a predefined position. The body surface skin was reconstructed using a B‐spline‐fitting model. In UWW, lung volume (LV) was measured simultaneously with underwater weight. In ADP and HBS, LV was predicted from weight and height. Results were compared using correlation and Bland and Altman analysis. Correlation analysis indicated that the scanner successfully ranked subjects in terms of BV. However, Bland and Altman analysis demonstrated that, relative to both UWW and ADP, HBS measured BV without bias but with limits of agreement between individuals of >2 liters, equivalent to approximately 20% fat. Scan precision was 0.57 liters, or 4.1% fat. Although HBS cannot yet measure BV with sufficient accuracy to predict fatness, much of the error is probably due to difficulties in standardizing LV during the scan. Simultaneous measurement of LV with volume by HBS is expected to improve limits of agreement substantially. Occlusion is also an important source of error. The method offers many advantages over alternative techniques, because the measurement is brief, noninvasive, and suitable for repeat measurements.
Body Composition Modeling: Application to Exploration of the Resting Energy Expenditure Fat‐free Mass Relationship
Authors: HEYMSFIELD STEVEN B. , GALLAGHER DYMPNA , WANG ZIMIAN
Published: July 2010

Abstract: There are now many published methods for predicting resting energy expenditure (REE) from measured body mass and composition. Although these published reports extend back almost a century, new related studies appear on a regular basis. It remains unclear what the similarities and differences are between these many methods and what, if any, advantages the newly introduced REE prediction models offer. These issues led us to develop an organizational system for REE prediction methods with the ultimate aim of clarifying prevailing ambiguities in the field. Our classification scheme is founded on the mathematical function type (descriptive and mechanistic) and body composition level (whole body → molecular) used in REE prediction model development. The model is applied in an exploration of the well‐established empirical relationship between REE and fat‐free body mass (FFM). The developed relationships indicate that REE vs. FFM is a curvilinear relationship in mammals as a whole, that the relationship can be described as a linear function in humans, and that the simple linear regression line coefficients can be reconstructed from established tissue‐system level component relationships. Our classification system, the first founded on a conceptual basis, highlights similarities and differences between the many diverse REE body composition prediction methods, provides a framework for teaching REE‐body composition relationships to students, and suggests important future research opportunities.
Factors Influencing Body Composition of Premature Infants at Term‐Adjusted Age
Authors: ATKINSONA STEPHANIE A. , RANDALL‐SIMPSON JANIS
Published: July 2010

Abstract: We investigated the influence of body size at birth, feeding of mother's milk versus formula, or standard‐term formula versus energy‐ or nutrient‐enriched formula on the growth and whole body bone mineral content (BMC), lean and fat mass (using dual‐energy X‐ray absorptiometry) of low‐birth‐weight (LBW) infants to term‐adjusted age. LBW infants who were appropriate for gestational age were lighter and shorter than term‐born infants (n= 46) but had a higher percent fat mass (19–28% vs. 15 ± 7%). For LBW infants fed standard formula or mother's milk after hospital discharge, the mean BMC expressed either as a function of weight (17 ± 2, 19 ± 2 vs. 20 ± 2 g/kg) or length (1.1 ± 0.2, 1.1 ± 0.2 vs. 1.5 ± 0.2 g/cm) was more than 1 SD below term infant values. However, infants fed a nutrient‐enriched formula from hospital discharge had BMC within 1 SD below term infants. Infants who were born small, compared to appropriate for gestational age, compared to infants of similar birth weight had lower percent body fat (16 ± 6 vs. 19 ± 5) and lower BMC (47 ± 3 vs. 62 ± 5 g) at term age. Both size at birth and diet influence patterns of growth and body composition in early life in very‐low‐birth‐weight (VLBW) infants. The long‐term significance of these variable growth patterns in VLBW infants in early life requires further investigation.
Body Composition in Healthy Aging
Authors: BAUMGARTNER R. N.
Published: July 2010

Abstract: Health risks in elderly people cannot be evaluated simply in conventional terms of body fatness or fat distribution. Elderly people have less muscle and bone mass, expanded extracellular fluid volumes, and reduced body cell mass compared to younger adults. These nonfat components of body composition play critical roles, influencing cognitive and physical functional status, nutritional and endocrine status, quality of life, and comorbidity in elderly people. Different patterns of “disordered body composition” have different relationships to these outcomes and may require different, tailored approaches to treatment that combine various exercise regimens and dietary supplements with hormone replacement or appetite‐stimulating drugs. Skeletal muscle atrophy, or “sarcopenia,” is highly prevalent in the elderly population, increases with age, and is strongly associated with disability, independent of morbidity. Elders at greatest risk are those who are simultaneously sarcopenic and obese. The accurate identification of sarcopenic obesity requires precise methods of simultaneously measuring fat and lean components, such as dual‐energy X‐ray absorptiometry.
Menopause‐Related Changes in Body Fat Distribution
Authors: TOTH MICHAEL J. , TCHERNOF ANDRÉ , SITES CYNTHIA K. , POEHLMAN ERIC T.
Published: July 2010

Abstract: Menopause‐related changes in body fat distribution may partially explain the greater risk of cardiovascular and metabolic disease during the postmenopausal years. To date, however, the effect of the menopause transition on body fat distribution remains unclear. Cross‐sectional and longitudinal studies using waist circumference or the waist‐to‐hip ratio show no effect of menopause on body fat distribution. By contrast, studies using dual‐energy X‐ray absorptiometry showed increased trunk fat in postmenopausal women. Moreover, studies using computed tomography (CT) and magnetic resonance imaging (MRI) show that postmenopausal women have greater amounts of intra‐abdominal fat compared to premenopausal women. Collectively, these studies suggest that the menopause transition is associated with an accumulation of central fat and, in particular, intra‐abdominal fat. Whether menopause‐related differences in trunk or intra‐abdominal fat are independent of age and/or adiposity, however, is unclear. Thus, we recently examined the effect of menopausal status on body composition and abdominal fat distribution in 53 middle‐aged, premenopausal women (47 ± 3 years) and 28 early postmenopausal women (51 ± 4 years). Postmenopausal women had 36% more trunk fat (p < 0.01), 49% greater intra‐abdominal fat area (p < 0.01), and 22% greater subcutaneous abdominal fat area (p < 0.05) than premenopausal women. The menopause‐related difference in intra‐abdominal fat persisted (p < 0.05) after statistical adjustment for age and fat mass, whereas no differences were noted in trunk or abdominal subcutaneous fat. A similar pattern of differences in trunk, subcutaneous, and intra‐abdominal fat was observed in subsamples of pre‐ and postmenopausal women matched for age or fat mass. Our data and that of others suggest that early postmenopausal status is associated with a preferential increase in intra‐abdominal fat that is independent of age and total adiposity. Thus, CT and MRI should be used when examining menopause‐related changes in body fat distribution.
Total Body Calcium in Obese Women: Validation of Dual‐Energy X‐ray Absorptiometry against in Vivo Neutron Activation Analysis
Authors: LAFERRÈRE B. , FUNKHOUSER A. , THORNTON J. , PI‐SUNYER F. X.
Published: July 2010

Abstract: In vivo neutron activation analysis (IVNA) allows in vivo measurement of total body calcium and is considered the gold standard technique. Dual‐energy X‐ray absorbtiometry (DXA) estimates total body calcium. Although there are a few comparisons of the two techniques, there are none with obese women. The present study compared the estimation of total body calcium by DXA with the measurement of Ca by IVNA in 69 obese women. Sixty‐nine obese women (age 44 ± 10 years, body weight [BW] 93 ± 10.4 kg, body mass index [BMI] 35 ± 4, fat mass 42 ± 7 kg, 48 pre‐ and 21 postmenopausal, 30 Caucasian and 39 African‐American) were recruited for a six‐month body composition study without weight loss intervention. Total body (TB) Ca was measured by IVNA (CaIVNA) and by DXA (CaDXA) at baseline (n= 69) and again at six months (n= 40). At baseline, CaDXA was significantly higher than CaIVNA (1018 ± 130 g vs. 706 ± 92 g, p= 0.0001). The difference remained after six months (1028 ± 153 g vs. 715 ± 96 g). There was a small but significant increase in TBCa at six months by both DXA (16.5 ± 40, p < 0.02) and IVNA (8 ± 22 g, p < 0.03). However, this change was not significantly different between the two methods (p= 0.2365). The correlation between the two methods was very high (r= 0.937) and was independent of either race or menopausal status (p= 0.5163). We generated a regression equation: CaIVNA= 0.659 × CaDXA+ 34.77; SEE = 32.2, R= 0.937. We present a model integrating the effect of weight and height on the relationship between CaIVNA and CaDXA. The higher the BMI, the bigger the difference between CaIVNA and CaDXA. In our population with a mean BMI of 35.3, CaIVNA= 69% CaDXA.
Effect of Recombinant Human Growth Hormone on Regional Tissue Distribution in Growth Hormone‐Deficient Males
Authors: BELL W. , DAVIES J. S. , EVANS W. D. , SCANLON M. F.
Published: July 2010

Abstract: Dual‐energy X‐ray absorptiometry was used to analyze the regional tissue distribution of bone mineral mass (BMM), fat mass (FM), and lean tissue mass (LTM) in the arms, trunk, and legs of 23 male growth hormone‐deficient (GHD) males. Patients were assigned randomly to treatment (n= 11) and control (n= 12) groups. During the first six months, the treatment group received recombinant growth hormone (rhGH) and the control group placebo. During the second six months, both groups received rhGH. Following treatment there was a trend for BMM to be lost in the arms and legs, with gains at the trunk. Fat mass was lost mainly from the trunk. Proportionally more LTM was distributed to the arms and legs than to the trunk. Treatment was more effective in the first six months than the second. The correlation between the waist‐hip ratio and trunk fat was poor, suggesting that its use in patients with GHD may be misleading.
The Prognostic Value of Body Protein in Patients with Lung Cancer
Authors: KADAR LIANNA , ALBERTSSON MARIA , AREBERG J. , LANDBERG T. , MATTSSON S.
Published: July 2010

Abstract: Lung cancer is a major cause of death in many countries. To improve the results of treatment, more individualized therapy is necessary; for this, it is necessary to identify new prognostic factors. In 21 patients with lung cancer (17 with non‐small‐cell lung cancer and 4 with small‐cell lung cancer) that had received radiation treatment, the amount of body protein was estimated with in vivo neutron activation analysis. Patients in whom body protein decreased had recurrences of the disease earlier and a poorer survival than patients whose body protein increased. A clear relationship was seen between changes in the body's protein content and recurrence‐free survival. To better evaluate the prognostic value of body protein content in patients with lung cancer, a larger number of patients and a longer follow‐up period are needed.
Molecular Identification and Characterization of G Protein‐Coupled Receptors for Lysophosphatidic Acid and Sphingosine 1‐Phosphate
Authors: AN SONGZHU
Published: July 2010

Abstract:Lysophospholipid mediators, lysophosphatidic acid (LPA) and sphingosine 1‐phosphate (S1P), play important roles in diverse biological processes, including cell proliferation, survival, cytoskeleton changes, migration, wound healing, angiogenesis, tumor invasion, and embryonic development. The recent breakthrough in cloning and identification of several G‐protein‐coupled receptors for LPA and S1P has provided tools to dissect the complex mechanisms by which these lysophospholipids exert their (patho)physiological functions. Here, strategies and efforts in cloning and identifying the Edg family receptors for LPA and S1P are reviewed. Reporter gene assays used to take advantage of signaling properties of LPA and S1P, and to overcome intrinsic difficulties unique to this system, are described. From these experimental approaches, important lessons can be learned and applied to future studies of signal transduction of lysophospholipid receptors.
Pharmacological Characterization of Phospholipid Growth‐Factor Receptors
Authors: TIGYI GABOR , FISCHER DAVID J. , BAKER DANIEL , WANG DE‐AN , YUE JUNMING , NUSSER NORA , VIRAG TAMAS , ZSIROS VERONIKA , LILIOM KAROLY , MILLER DUANE , PARRILL ABBY
Published: July 2010

Abstract:The phospholipid growth‐factor (PLGF) terminology is proposed to describe a group of endogenous glycerol‐ and sphingolipid mediators that regulate cell proliferation through plasma membrane receptors. In addition to LPA and SPP, multiple PLGFs are present in blood plasma and serum. PLGF activity is regulated by its stimulus‐coupled production and by endogenous inhibitors. In addition to LPA and SPP, alkenyl‐glycerophosphate, cyclic‐phosphatidic acid, and sphingosylphosphorylcholine were detected in biological fluids using mass spectrometry. Heterologous desensitization studies indicate the expression of multiple LPA‐activated receptors in a variety of cell types, which are differentially activated by the different PLGFs. Northern blot and RT‐PCR results reinforce the coexpression of PSP24α and different members of the EDG1‐7 receptors in the same cell. Stable heterologous expression of the PSP24α, EDG2, and EDG4 receptors in HEK293 cells show distinct PLGF specificities and dose‐response properties for each receptor subtype. Thus, both the controlled availability of the different agonists/inhibitors and the regulated expression of their receptors regulate the biological effects of PLGFs.
Phospholipase D
Authors: EXTON JOHN H.
Published: July 2010

Abstract:Phospholipase D is an ubiquitous enzyme that hydrolyzes phosphatidylcholine to phosphatidic acid and choline. Its cellular actions are related to the production of phosphatidic acid and include alterations to cell growth, shape, and secretion. There are two mammalian phospholipase D genes whose products (PLD1 and PLD2) are alternatively spliced. both forms have two highly conserved HKD motifs that are essential for catalysis and dimerization. PLD1 is regulatedin vitroandin vivoby protein kinase C and small GTPases of the Rho and ARF families, whereas PLD2 shows a higher basal activity with little or no response to these proteins. the cellular locations and specific functions of the two PLD isoforms remain to be established.
A Novel Polyisoprenyl Phosphate Signaling Cascade in Human Neutrophils
Authors: LEVY BRUCE D. , SERHAN CHARLES N.
Published: July 2010

Abstract:Activation of neutrophil (PMN) surface receptors can evoke inflammation and tissue injury via aberrant release of excess effectors. The molecular mechanisms involved in host protection and control of PMN responses have yet to be defined. As Billah and coworkers (1989) and Exton (1997), for example, have pointed out, phospholipase D (PLD) signaling is known to play a pivotal role in PMN activation. Here, we determined the relationship between polyisoprenyl phosphate (PIPP) remodeling and PLD signaling and their impact in activation of PMN receptors by “proinflammatory” (leukotriene B4), and “anti‐inflammatory” (aspirin‐triggered lipoxin A4) ligands. Activation of the leukotriene B4receptor initiated a rapid (within seconds) decrement in presqualene diphosphate (PSDP), activation of PLD and production of superoxide anions. This contrasts with activation of the LXA4receptor by an aspirin‐triggered lipoxin A4mimetic that before leukotriene B4gave an inverse relationship with rapidly increasing PSDP levels, and inhibition of both PLD activity and superoxide generation. PSDP proved to be a potent and direct‐acting inhibitor of PLD (rhPLD1b: Ki = 5.9 nM), a property not shared by structurally related endogenous lipids. This PIPP also interacted withSrchomology domains, selectively targeting SH2 and not SH3 domains. These results indicate a role for ligand‐driven rapid PIPP remodeling as an early switch and “stop” signaling event that controls PMN. Moreover, they indicate that PSDP directly down‐regulates PMN signaling events via select protein‐targeted interactions controlling intracellular responses relevant in inflammation.
Eicosanoid Regulation of Angiogenesis in Human Prostate Carcinoma and Its Therapeutic Implications
Authors: NIE DAOTAI , TANG KEQIN , SZEKERES KAROLY , LI LI , HONN KENNETH V.
Published: July 2010

Abstract:Cancer of the prostate is the most commonly diagnosed cancer in America. There are several lines of evidence implicating the involvement of arachidonate 12‐lipoxygenase, an enzyme metabolizing arachidonic acid to form 12(S)‐hydroxyeicosatetraenoic acid (HETE), in prostate cancer progression. First, as prostate cancer reaches a more advanced stage, the level of 12‐lipoxygenase expression is increased. Second, overexpression of 12‐lipoxygenase in human prostate cancer cells stimulates angiogenesis and tumor growth. Third, an inhibitor of 12‐lipoxygenase has been found effective against metastatic prostate tumor growth, and the inhibition of 12‐lipoxygenase is related with the reduction of tumor angiogenesis. Collectively, these studies suggest that 12‐lipoxygenase regulates tumor angiogenesis in prostate cancer and that inhibition of 12‐lipoxygenase is a novel therapeutic approach for the treatment of prostate cancers.
Mechanisms of Lysolipid Phosphate Effects on Cellular Survival and Proliferation
Authors: GOETZL EDWARD J. , LEE HSINYU , DOLEZALOVA HANA , KALLI KIMBERLY R. , CONOVER CHERYL A. , HU YU‐LONG , AZUMA TOSHI , STOSSEL THOMAS P. , KARLINER JOEL S. , JAFFE ROBERT B.
Published: July 2010

Abstract: The specificity of cellular effects of lysolipid phosphate (LLP) growth factors is determined by binding to endothelial differentiation gene‐encoded G protein‐coupled receptors (EDG Rs), which transduce diverse proliferative and effector signals. The primary determinants of cellular responses to LLPs are the generative and biodegradative events, which establish steady‐state concentrations of each LLP at cell surfaces, and the relative frequency of expression of each EDG R. There are major differences among types of cells in the net effective generation of the LLPs, lysophosphatidic acid (LPA) and sphingosine 1‐phosphate (S1P), and in their profile of expression of EDG Rs. The less well characterized secondary determinants of cellular specificity of LLPs are high‐affinity binding proteins with carrier and cell‐presentation functions, cell‐selective regulators of expression of EDG Rs, and cellular factors that govern coupling of EDG Rs to G protein transductional pathways. The roles of components of the LLP‐EDG R system in normal physiology and disease processes will be definitively elucidated only after development of animal models with biologically meaningful alterations in genes encoding EDG Rs and the discovery of potent and selective pharmacological probes.
Sphingolipid Regulation of Female Gonadal Cell Apoptosis
Authors: MORITA YUTAKA , TILLY JONATHAN L.
Published: July 2010

Abstract: Ceramide and sphingosine‐1‐phosphate (S1P) are sphingosine‐based lipid signaling molecules that have been implicated as key mediators of cellular growth, differentiation, and apoptosis. The cellular response depends on cell type, on the absence or presence of other signals initiated by the same or another stimulus, and on the subcellular location of sphingomyelin hydrolysis leading to ceramide generation. Consistent with mounting evidence implicating components of the sphingomyelin pathway as mediators of cellular life and death in nonreproductive tissues, recent data have indicated that sphingolipid‐based signaling events are also prominent features of cellular development and apoptosis in the fetal and postnatal female gonads. This area of investigation represents a new research avenue of considerable significance for both basic biology and clinical medicine because of the massive levels of developmental death that occur normally in the female germ line, especially during gametogenesis, as well as of the central role of oocyte apoptosis in female gonadal failure resulting from pathologic insults.
Evaluation of Plasma Lysophospholipids for Diagnostic Significance Using Electrospray Ionization Mass Spectrometry (ESI‐MS) Analyses
Authors: XIAO YIJIN , CHEN YONGHONG , KENNEDY ALEXANDER W. , BELINSON JEROME , XU YAN
Published: July 2010

Abstract: We previously reported that lysophosphatidic acid (LPA) represents a potential biomarker for ovarian and other gynecologic cancers. To further improve the accuracy and potentially increase the sensitivity and specificity of the assay, we developed an electrospray ionization mass spectrometry (ESI‐MS)‐based method to analyze LPA and related lysophospholipids. LPA, lysophosphatidylinositol (LPI), lysophosphatidylserine (LPS), and lysophosphatidylcholine (LPC) could be detected with high sensitivity (in low pmol range) using this method. Standard curves were established for quantitative analysis. LPA and closely related lysophospholipids isolated from thin‐layer chromatography (TLC) plates were analyzed directly by ESI‐MS. This ESI‐MS‐based assay allows simultaneous detection and quantitation of all different species of LPAs and LPIs in a sample over a range of at least 5–300 pmol. Moreover, this test was at least 50 times more sensitive when a multiple reaction monitoring (MRM) mode was used. Using these protocols in a limited set of analyses, we found that both LPA and LPI were elevated in patients with ovarian cancer.
Sphingosine‐1‐phosphate Inhibits Haptotactic Motility by Overproduction of Focal Adhesion Sites in B16 Melanoma Cells through EDG‐Induced Activation of Rho
Authors: YAMAMURA S. , HAKOMORI S. , WADA A. , IGARASHI Y.
Published: July 2010

Abstract: We investigated the molecular mechanism by which Sph‐1‐P affects the FN‐dependent haptotactic motility of serum‐starved mouse melanoma B16/F10 cells. We found that EDG‐5‐induced Rho activation followed by enhanced tyrosine phosphorylation of FAK and paxillin, and β1‐integrin activation leading to overexpression of focal adhesion sites, as well as increment of stress fiber formation, must be the molecular basis of inhibition of haptotactic cell motility by Sph‐1‐P.
RT‐PCR‐Based Detection of Occult Disseminated Tumor Cells in Peripheral Blood and Bone Marrow of Patients with Solid Tumors: An Overview
Authors: ZIPPELIUS A. , PANTEL K.
Published: July 2010

Abstract: Despite recent progress in early detection and local curative therapy, patients with primary epithelial cancer quite frequently relapse with incurable metastasis. Early disseminated tumor cells that may be seminal for distant failure and are undetectable by current diagnostic methods have been identified by immunocytochemical techniques in bone marrow of cancer patients using monoclonal antibodies against cytokeratins. Recently, promising new molecular approaches, namely, reverse transcriptase‐polymerase chain reaction (RT‐PCR) assays, have been suggested as a potential technique for the detection of minimal residual tumor burden by targeting mRNA transcribed from epithelial genes in bone marrow, peripheral blood, or lymph nodes. Several studies using RT‐PCR thus far indicate a highly sensitive and specific staging tool, although the prognostic value is still controversial. However, limitations may arise from ectopic expression of marker mRNA in hematopoietic cells and deficient expression in circulating tumor cells. The present review focuses on the relevant literature and demonstrates the range of current applications of RT‐PCR‐based assays for detecting disseminated tumor cells in peripheral blood and bone marrow of patients with solid tumors. We will both summarize technical evaluations of published molecular approaches and discuss the widely disparate results on PCR findings in clinical studies.