bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Basis of Gynecological Cancer
Authors: SPANDIDOS D. A. , DOKIANAKIS D. N. , KALLERGI G. , AGGELAKIS E.
Published: July 2010

Abstract: Alterations in the cellular genome affecting the expression or function of genes controlling cell growth and differentiation are considered to be the main cause of cancer. Genes that cause cancer are of two distinct types: oncogenes and onco‐suppressor genes. The normal proto‐oncogene can be converted into an active oncogene by deletion or point mutation in its coding sequence, gene amplification, and by specific chromosome rearrangements. Mutations and abnormal expression in ras, myc, c‐erbB‐2, and other oncogenes have been reported in several types of gynecological cancer. Onco‐suppressor genes are involved in gynecological cancer, their functions are localized in different phases of the cell cycle. Structural changes and deletions of these genes can cause cancer. Mutations in the p53, BRCA1, DCC, and PTEN genes have been reported in gynecological cancers such as ovarian, cervical, and endometrial cancer. Human papillomaviruses are of major interest because specific types (HPV‐16, ‐18, and several others) have been identified as causative agents in at least 90% of cancers of the cervix. In this study we summarize the available information regarding the implication of specific oncogenes, onco‐suppressor genes, and HPV in the development of female genital malignancies.
Maternal Hypothalamic‐Pituitary‐Adrenal Axis in Pregnancy and the Postpartum Period: Postpartum‐Related Disorders
Authors: MASTORAKOS G. , ILIAS I.
Published: July 2010

Abstract: During pregnancy, placenta‐derived CRH increases exponentially in the plasma. Circulating levels of CRH‐binding protein decrease considerably in the last trimester of pregnancy, resulting in further elevation of bio‐available plasma CRH. The adrenal glands during pregnancy gradually become hypertrophic because of the increase in ACTH, which parallels that of CRH. Thus, pregnancy is a transient period of relative hypercortisolism. The activation of the hypothalamic‐pituitary‐adrenal axis during pregnancy has been proposed to function as a biological clock. In this model, the placenta is perceived as a stress‐sensitive organ and placental CRH as a timing starter, determining a preterm, term, or postterm labor. During pregnancy, as well as during the immediate postpartum period, the hypothalamic maternal CRH secretion is suppressed, because of the circulating levels of cortisol. Hypothalamic CRH secretion normalizes within 12 weeks. This transient postpartum maternal hypothalamic CRH suppression, together with the steroid withdrawal that follows parturition, might be causally related to the mood disorders and the vulnerability to autoimmune diseases such as thyroiditis or rheumatoid arthritis often observed during the postpartum period.
Antenatal Assessment for the Detection of Fetal Asphyxia: An Evidence‐Based Approach Using Indication‐Specific Testing
Authors: VINTZILEOS ANTHONY M.
Published: July 2010

Abstract: One of the most important advances in perinatal health care is the use of antepartum fetal testing. Antepartum fetal testing methods may include inexpensive tests such as fetal kick counts or tests that can be quite expensive such as non‐stress tests, fetal biophysical profiles, and Doppler assessments as well as invasive tests such as amniocentesis or cordocentesis. Clinical experience, combined with recent literature, suggest that there is no ideal test for all high‐risk fetuses and that some antepartum fetal tests may be more appropriate than others, depending on the underlying pathophysiology or the indication for testing.1 Because many different pathophysiological processes lead to fetal acidemia and in‐utero death, indication‐specific testing may be not only logical, but also cost‐effective. In this article, specific guidelines of antepartum fetal testing are presented. These indication‐specific guidelines are based on the underlying pathophysiological processes that place the fetus at risk and also on the need to use the fewest number of tests without compromising safety.
Mechanisms of Perinatal Cerebral Injury in Fetus and Newborn
Authors: DELIVORIA‐PAPADOPOULOS MARIA , MISHRA OM PRAKASH
Published: July 2010

Abstract: Cerebral hypoxia in the fetus and newborn results in neonatal morbidity and mortality as well as long‐term sequelae such as mental retardation, seizure disorders, and cerebral palsy. In the developing brain, determinants of susceptibility to hypoxia should include the lipid composition of the brain cell membrane, the rate of lipid peroxidation, the presence of antioxidant defenses, and the development and modulation of excitatory amino acid neurotransmitter receptors such as the N‐methyl‐d‐aspartate (NMDA) receptor, the intracellular Ca2+, and the intranuclear Ca2+‐dependent mechanisms. In addition to the developmental status of these cellular components, the response of these potential mechanisms to hypoxia determines the fate of the hypoxic brain cell in the developing brain. Using electron spin resonance spectroscopy of alpha‐phenyl‐N‐tert‐butyl‐nitrone spin adducts, studies from our laboratory demonstrated that tissue hypoxia results in increased free radical generation in the cortex of fetal guinea pigs and newborn piglets. Pretreatment with MgSO4 significantly decreased the hypoxia‐induced increase in free radical generation in the term fetal brain. We also showed that brain tissue hypoxia modifies the NMDA receptor ion‐channel recognition and modulatory sites. Furthermore, a higher increase in NMDA receptor agonist‐dependent Ca2+ in synaptosomes was demonstrated. The increase in intracellular Ca2+ may activate several enzymatic pathways such as phospholipase A2 and metabolism of archidonic acid by cyclooxygenase and lipoxygenase, conversion of xanthine dehydrogenase to xanthine oxidase by proteases, and activation of nitric oxide synthase. Using inhibitors of each of these enzymes such as cyclooxygenase (indomethacin), lipoxygenase (nordihydroguaiaretic acid), xanthine oxidase (allopurinol), and nitric oxide synthase (N‐nitro‐l‐arginine), studies have shown that these enzyme reactions result in oxygen free radical generation, membrane peroxidation, and cell membrane dysfunction in the hypoxic brain. Specifically, generation of nitric oxide free radicals during hypoxia may lead to nitration and nitrosylation of specific membrane proteins and receptors, resulting in dysfunction of receptors and enzymes. We conclude that hypoxia‐induced modification of the NMDA receptor leading to increased intracellular Ca2+ results in free radical generation and cell injury. We suggest that during hypoxia the increased intracellular Ca2+ may lead to increased intranuclear Ca2+ concentration and alter nuclear events including transcription of specific apoptotic genes and activation of endonucleases, resulting in programmed cell death.
Angiogenic Factors in the Perinatal Period: Diversity in Biological Functions Reflected in Their Serum Concentrations Soon after Birth
Authors: MALAMITSI‐PUCHNER ARIADNE , TZIOTIS JOHN , PROTONOTARIOU EFTHIMIA , SARANDAKOU ANGELIKI , CREATSAS GEORGE
Published: July 2010

Abstract: These studies investigated whether serum levels of the angiogenic factors angiogenin, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) change soon after birth due to the elimination of the placenta and to diminished angiogenic but increased adaptational demands in extrauterine life. Also investigated was whether serum levels correlate with sex, birth weight, or mode of delivery. Serum from healthy mothers and their healthy full‐term infants at birth (umbilical cord, UC), day 1 (N1) and day 4 (N4) postpartum was analyzed by enzyme immunoassays. Angiogenin levels were higher in maternal serum and rose significantly from UC to N1 and N4, possibly because of the elimination of the placenta, which produces an angiogenin inhibitor. bFGF and VEGF maternal levels were lower than fetal and neonatal ones. Although neonatal bFGF levels did not differ from fetal levels, possibly reflecting diminished angiogenesis ex utero, VEGF levels increased in neonatal serum, possibly signifying adaptational demands. Neither factor depended on sex, mode of delivery, or birth weight. Thus, significant differences from normal reference values of the studied factors might reflect ill‐defined situations of the placenta and fetus/newborn serving as early diagnostic markers.
Contraception in Women at High Risk or with Established Cardiovascular Disease
Authors: PITSAVOS CHRISTOS , STEFANADIS CHRISTODOULOS , TOUTOUZAS PAVLOS
Published: July 2010

Abstract: Oral contraceptives are one of the most effective and widely used reversible contraceptive methods. Over 90 million women worldwide, including over 44 million in developing countries, are now using oral contraceptives. Despite their advantages, there is concern about the links between combined oral contraceptives and the risk of cardiovascular disease. The risk attributable to oral contraceptive use in women <35 years of age is small, even if they smoke, but there are substantially increased risks in older women who both smoke and use oral contraceptives. Differences between oral contraceptive types in the relative risk of venous thromboembolism contribute little to the total cardiovascular mortality associated with oral contraceptive use, even though the total number of cardiovascular events is increased. It is important to consider the user's age and smoking status when determining oral contraceptive‐attributable risks. Hormonal oral contraceptives have changed and now contain lower doses of estrogen and progestagen.
Surface Morphology of the Human Endometrium: Basic and Clinical Aspects
Authors: NIKAS GEORGE , MAKRIGIANNAKIS ANTONIS , HOVATTA OUTI , JONES HOWARD W.
Published: July 2010

Abstract: The human endometrium is an extremely sensitive target for steroid hormones. During the menstrual cycle, this tissue undergoes dynamic changes that are reflected on the surface morphology of the epithelium and that can be followed by scanning electron microscopy. The morphologic changes peak at the midsecretory phase, with the formation of the so‐called pinopodes. Increasing evidence suggests that these pinopodes are accurate markers for endometrial receptivity, and their detection may be of high clinical utility in the preparation of endometrium before embryo transfer. This article recapitulates published figures of endometrial ultrastructure and presents some unpublished data from ongoing studies.
Premature Ovarian Failure Is Not Premature Menopause
Authors: KALANTARIDOU SOPHIA N. , NELSON LAWRENCE M.
Published: July 2010

Abstract: Normal menopause occurs at an average age of 50 and results from ovarian follicle depletion. Normal menopause is an irreversible condition, whereas premature ovarian failure is characterized by intermittent ovarian function in half of these young women. These young women produce estrogen intermittently and sometimes even ovulate despite the presence of high gonadotropin levels. Indeed, pregnancy has occurred after a diagnosis of premature ovarian failure. On pelvic ultrasound examination, follicles were equally likely to be detected in patients more than 6 years after a diagnosis of premature ovarian failure as in patients less than 6 years after the diagnosis. Thus, the probability of detecting a follicle appears to remain stable during the normal reproductive lifespan of these young women. Indeed, pregnancy was reported in a 44‐year‐old woman 16 years after a diagnosis of premature ovarian failure. No treatment to restore fertility in patients with premature ovarian failure has proved to be safe and effective in prospective controlled studies. Theoretically, these unproved therapies might even prevent one of these spontaneous pregnancies from occurring.
Idiopathic Juvenile Osteoporosis
Authors: KRASSAS G. E.
Published: July 2010

Abstract: Osteoporosis in childhood is uncommon, and it may be secondary to a spectrum of diverse conditions. When such causes have been excluded, some patients remain who have a congenital disease (osteoporosis imperfecta) or a disease in which the etiology is obscure, called idiopathic juvenile osteoporosis (IJO). The cause of IJO is unknown, and the diagnosis is based both on the exclusion of other diseases and on its own positive fractures. The basic strategy of treatment is to protect the spine until remission occurs. Sex steroids are contraindicated. Bisphosphonates, calcitriol, fluoride, and calcitonin have been administered therapeuticlly, but the results were equivocal. Usually the disease remits by itself.
Current and Potential Application of GnRH Agonists in Gynecologic Practice
Authors: TZAFETTAS JOHN M.
Published: July 2010

Abstract: The development of GnRH‐a (analogues or agonists) is a major leap forward in the treatment of various hormone‐dependent diseases in medicine. Their introduction in reproductive endocrinology, in in vitro fertilization/embryo transfer (IVF/ET) and other assisted reproduction techniques had a revolutionary impact. They have been effective in other gynecologic conditions including fibroids, endometriosis, anovulatory disorders, precocious puberty, dysfunctional uterine bleeding, and operative hysteroscopy. Medical castration induced by GnRH‐a has become first‐line therapy in metastatic breast cancer. Their long‐term use, though, has been associated with a variety of adverse effects such as bone loss and decreased cardioprotection. “Steroid add‐back” therapy in these cases apparently is an effective alternative. It may allow their safe long‐term application beyond 6 months, averting unpleasant side‐effects and maintaining bone mass and cardioprotection.
Doing Time: The Emergence of Irreversibility
Authors: BOXER PHILIP J. , COHEN BERNARD
Published: July 2010

Abstract: By considering an enterprise to be a system of agents that observe and construct theories about themselves immediately raises issues of closure. These in turn pose questions about the identity and evolution of that which is exhibiting such closure. We address these questions by assigning enterprises to a class of systems whose models are triply articulated. The existential articulation provides an account of the possible behaviors of the enterprise's agents and of their interoperation. The referential articulation specifies outcomes that its agents are required to satisfy. The deontic articulation imposes constraints on the composition of the other two articulations that are sufficient to ensure that the enterprise effectively implements its specified requirements. Any of these articulations may be under‐determined in that they admit more than one elaboration. The behavioral closure of an enterprise is a kind of composition (formally, a category theoretic limit construction) of its three articulations. If the enterprise is its own observer, then the articulations are its models of itself. The enterprise has many opportunities for error in constructing this model. In particular, it may find that it cannot choose among its under‐determined articulations in such a way that their composition is internally consistent. Such errors necessitate changes to its model, which may be denoted as steps in an irreversible trajectory through a space of such models. This approach seems to provide a conceptual bridge across the gulf between systems theory and psychoanalysis, and has provided valuable insights into strategy formulation within large enterprises.
Regenerative Process in Life and Mind
Authors: CARIANI PETER
Published: July 2010

Abstract:The functional organization of the nervous system is discussed from the standpoint of organizational closure and regenerative process in order to draw parallels between life and mind. Living organization entails continual regeneration of material parts and functional relations (self‐production). Similarly, dynamic stability of informational states in brains may entail coherent self‐regenerating patterns of neural signals. If mind is the functional organization of the nervous system, then mental states can be seen as switchings between alternative sets of stable, self‐regenerative neural signal productions. In networks of neurons, signaling resonances can be created through recurrent, reentrant neural circuits that are organized to implement a heterarchy of correlational operations. Neural representations are dynamically built‐up through an interplay between externally‐impressed, incoming sensory signals and internally‐generated circulating signals to form pattern‐resonances. Semiotic aspects of resonance states involve semantic sensori‐motor linkages to and through the external environment and pragmatic linkages to evaluative mechanisms that implement internal goal states. It is hypothesized that coherent regenerative signaling may be an organizational requirement for a material system to support conscious awareness. In this view general anesthetics and seizures abolish awareness by temporarily disrupting the organizational coherence of regenerative neural signaling.
A Classification of Closure Concepts
Authors: SALTHE S. N.
Published: July 2010

Abstract: Closure has been used in various ways. I propose a classification based on the specification hierarchy formalism, wherein ideas are represented as subclasses, or restrictions, of other ideas, beginning with the most generally applicable concept and working inward to more particular applications. This exercise is part of a revival of nineteenth century natural philosophy. The classification also represents a self‐referential developmental system in which the classification itself emerges from the evolutionary process it describes. Since one form of closure builds upon a previously attained form, development traces a loss of evolutionary potential even as each closure gives access into a new, emergent, realm.
Importance of Diversity: Reconciling Natural Selection and Noncompetitive Processes
Authors: JOHNSON NORMAN L.
Published: July 2010

Abstract: To better understand selection processes in evolutionary systems (ecological to economic to social to artificial systems), the origins and role of diversity are examined in two systems that show increased group functionality (better performance, efficiency, robustness, adaptability, stability, etc.). Diversity was chosen as a clarifying concept, because it appears to have been largely ignored, or misunderstood. One system is a model of group selection within an ecosystem. The other is the group solution of a sequential problem using self‐organizing dynamics in the absence of any selection. A comparison of the two systems show that while diversity is essential to both, improvement by natural selection is derived from consuming diversity, whereas improvement by noncompetitive self‐organization is decreased by any reduction in diversity. The resulting perspective is that natural selection is a mechanism that increases the functionality of the individual (or groups within a larger system); noncompetitive self‐organization of the system, without need for selection, increases the functionality of the whole above that of the individual or group. The two extreme roles for diversity are reconciled if natural selection is not strongly expressed in these systems‐“survival of the fittest” becomes “survival of the adequate”‐so that noncompetitive processes can occur. The resulting view of a mature ecosystem is an elastic web of interactions in which natural selection is dormant or retains the status quo. The processes of natural selection for individual or group improvement are activated only if environment changes are sufficient to break the elastic interconnections, as might occur in punctuated equilibria.
Closure, Identity, and the Emergence of Formal Causation
Authors: MORENO ALVARO
Published: July 2010

Abstract:The aim of this paper is to characterize a type of causality relevant to study the closure of complex systems that we callformal causation. By this term we understand the existence of a new (not materially inherent) causal relation among constituents, generated through an autonomous process of closure. Once a certain level of organization is reached, material systems can generate internal constraints that, through recursive processes, construct their own identity. We study two different forms of closure: closure in dissipative systems and closure in template self‐replication. Finally, these two forms merge and bring forth a new one: informational closure, We show how complex forms of organization are based on informational closure, which is an explicit, recorded type of formal causation allowing a functional articulation between individual organizations and larger, collective and historical (meta)organizations.
Closure in the Emergence and Evolution of Life: Multiple Discourses or One?
Authors: WEBER BRUCE H.
Published: July 2010

Abstract: Evolutionary theory formulated in terms of complex systems dynamics shows interesting convergences with the approaches of developmental systems theory and biosemiotics, especially when applied to the problem of the origin of life. Although starting from difference conceptual assumptions, all three approaches agree on the importance of closure in the form of semi‐permeable chemical and informational boundaries and a more circumscribed role for DNA.
The Rosetta Stone of Stability
Authors: MINCH ERIC
Published: July 2010

Abstract:A number of proposals to augment the classical theory of natural selection turn on the need to consider the role of neutral genetic modifications, as well as on the role of patterns of physicochemically stable substructures. There are similarities between this opposition and that within cognitive science, where the dynamic and computational approaches emphasize complementary aspects of perceptual‐motor development. This paper summarizes the relevant arguments of the various schools of evolutionary and cognitive theory, as well as the various calls that have been made for unification or complementarity of explanations. An extended concept of stability is then proposed, which bridges the gap between thermodynamic equilibrium and semantic closure.
Remarks on Autocatalysis and Autopoiesis
Authors: McMULLIN BARRY
Published: July 2010

Abstract: The notions of collective autocatalysis and of autopoiesis are clearly related; equally clearly, they are not quite the same. The purpose of this paper is to try to clarify the relationship. Specifically I suggest that autopoiesis can be at least roughly characterized as collective autocatalysis plus spatial individuation. Although some mechanism of spatial confinement or concentration is probably necessary to the effective operation of any collectively autocatalytic reaction network, autopoiesis requires, in addition, that the mechanism for maintaining this confinement should itself be a product of the reaction network‐and should thus (?) be capable of separating or individuating otherwise identically organized networks. I suggest an informal heuristic test to discriminate the (merely) collectively autocatalytic from the (properly) autopoietic. Finally, in the light of this, I review a variety of published abstract or model systems, Alchemy, α‐universes, Tierra, and SCL.
Code‐Duality and the Epistemic Cut
Authors: HOFFMEYER JESPER
Published: July 2010

Abstract: Howard Pattee has claimed that an epistemic cut separates the world from observers and therefore from organisms. The epistemic cut imputes a linguistic mode of operation to living systems. Among evolutionary systems‐theorists on the other hand there seems to be a tendency to consider living systems as just one among many other kinds of evolutionary systems that, in principle, can all be described on the basis of thermodynamics or infodynamics. This paper searches a third position, in which the epistemic cut position is defended without adopting Patteee's distinction between a dynamic and a linguistic mode. It is observed that even the dynamic mode in living systems is always a semiotic mode although index‐ and analog‐coded rather than symbolic and digitally coded. The analog‐coded messages corresponds to a kind of tacit knowledge hidden in macromolecular structure and shape (e.g., molecular complementarity), and in organismic architecture and communication, that is, in the semiotic interactions of the body.
Closure, Function, Emergence, Semiosis, and Life: The Same Idea? Reflections on the Concrete and the Abstract in Theoretical Biology
Authors: EMMECHE CLAUS
Published: July 2010

Abstract: In this note epistemological problems in general theories about living systems are considered; in particular, the question of hidden connections between different areas of experience, such as folk biology and scientific biology, and hidden connections between central concepts of theoretical biology, such as function, semiosis, closure, and life.
Complementarity and Closure
Authors: ETXEBERRIA ARANTZA
Published: July 2010

Abstract: This paper compares two different accounts of closure to explain biological organization: as an organization enabled by an informational control on dynamics (Pattee) and as an internal closure of a dynamic nature (Varela). The two of them adopt different versions of a principle of complementarity to relate symbolic and dynamic explanations.
Genomes and Form: The Case for Teleomorphic Recursivity
Authors: VON STERNBERG RICHARD
Published: July 2010

Abstract:The genotype‐phenotype (genome‐form) distinction is considered by many to be fundamental to modern evolutionary thinking. Indeed, the premises that: DNA solely constitutes the genotype; that the phenotype is a transient product of the genotype, with the latter not only describing, but also implementing the construction of the former; and that the constructed materials and systems of the cell have no impact on the genotype, have become dogmas. Yet a vast body of data from molecular genetics reveals that cellular systems, directly and indirectly, alter the genome. Some of these data are reviewed. Proteins can influence mutations along the chromosomes, heritably modify the information content of DNA sequences, and, in some instances, reorganize the germline or somatic genome via DNA engineering pathways. These data suggest that theconstructed(proteins, chromatin arrays, and metabolic pathways) has an important role in shaping thedescriptor. Insofar as it is biochemically possible for states adopted by cellular structures to be stabilized and eventuallymemorizedby engineering chromosomes, semantic closure can be transcended‐meaning can be transferred from the domain of form to the genome, and this presumably ongoing process is termedteleomorphic recursivity. Throughout the paper, I implicitly argue that the genome‐form partition is strictly a formal one, with no deeply material basis.
The Internalist Stance: A Linguistic Practice Enclosing Dynamics
Authors: MATSUNO KOICHIRO
Published: July 2010

Abstract:Natural dynamics, as manifested in evolutionary processes, refer to material bodies in movement in the present progressive mode. Any interacting material body in the present progressive mode must be sentient to others because there can be no global agency coordinating it to others in a globally synchronous manner. The internalist perspective, or the worm's eye view, referring primarily to the present progressive mode, renders local material bodies, large or small, subject to an inevitable inconsistency among local representations of neighborhood events registered in the local present perfect tense. Any sentient material body experiencing this inconsistency subsequently transforms itself into an inconsistency‐free representation. The descriptive scheme unique to the internalist stance is internal and dynamic in the sense that it constantly strives to update constituent local representations, attempting to eliminate any inconsistencies residing within antecedent local representations. Compared to external descriptions of invariable universals grounded upon the Cartesian epistemic split, which are complementary to dynamics, internal description serves as a linguistic means of embodying natural dynamics even without recourse to the notion called forces. This makes our language powerful enough to enclose natural dynamics of material bodies in the empirical domain.
Genomic Searches for Genes That Influence Atherosclerosis and Its Risk Factors
Authors: HIXSON JAMES E. , BLANGERO JOHN
Published: July 2010

Abstract: We are performing genomic searches in randomly ascertained families to identify new quantitative trait loci (QTLs) that influence atherosclerosis and its risk factors. The genetic markers used for genomic searches are random microsatellite markers distributed throughout the human chromosomes. These markers are used for linkage analysis with variance component methods to identify QTLs for measured phenotypes related to lipid metabolism and atherosclerosis. We conducted such a genomic search in 477 participants of the San Antonio Family Heart Study. This genomic search identified QTLs on chromosomes 3 and 4 that influence LDL size class, an important risk factor of atherosclerosis. In addition to lipid risk factors, we measured a variety of gene products involved in atherogenesis in the arterial wall (such as adhesion molecules and components of hemostasis). We found QTLs for serum levels of soluble P‐selectin on chromosome 15 (LOD = 3.8) and chromosome 12 (LOD = 2.6).
Genetic Analysis of Essential Hypertension in Japanese Populations
Authors: OGIHARA TOSHIO , KATSUYA TOMOHIRO , HIGAKI JITSUO
Published: July 2010

Abstract: The reverse genetic approach, which examines genetic factors underlying the root of pathogenesis first, is a powerful tool to clarify the genetic cause of essential hypertension. Using the rat cross model, studies of the genetically hypertensive inbred rat model indicated several candidate loci on the rat chromosome responsible for blood pressure, but failed to identify the exact causal gene. Moreover, it was not certain that the rat data really reflect the human case. Thus, we shifted our focus to human genetics and carried out case control studies using the candidate gene approach. We mainly focused on gene components of the renin‐angiotensin system as candidates, finding that angiotensinogen gene polymorphisms are genetic predisposing factors for hypertension. However, the results obtained from case‐control studies using Japanese subjects were not consistent, suggesting that there was a problem in control sampling. In our recent study, we recruited more than 5,000 residents of an urban community as a general population and examined the association between genetic factors and their health status. Our results indicate that angiotensin‐converting enzyme gene polymorphism is a male‐specific genetic risk for essential hypertension. In light of our previous investigations, we present a discussion concerning the design of future studies of the genetics of hypertension.
Inflammation and Atherosclerosis: Atherosclerotic Lesions in Takayasu Arteritis
Authors: NUMANO FUJIO , KISHI YUKIO , TANAKA AKIRA , OHKAWARA MIHO , KAKUTA TSUNEKAZU , KOBAYASHI YASUSHI
Published: July 2010

Abstract: Takayasu arteritis is a chronic vasculitis, mainly involving the aorta and its main branches as well as the coronary and pulmonary arteries, causing stenosis and/or obstruction due to thrombus formation or dilatation due to aneurysmal formation and/or rupture of the involved arteries. These characteristic anomalies resulted from ischemia of retinal arteries due to the obstruction of cervical vessels. In Western countries this disease is also known as “pulseless disease,” because the pulse is frequently absent due to the obstruction of subclavian or brachial arteries. The pathogenesis of this morbid condition is still unknown. Epidemiologically, it is found mostly in female patients and is more prevalent in Asian and Latin American countries. Affected areas consist of a mixture of both active, productive inflammatory lesions, and old fibrous lesions. Autoimmune processes stimulated by viral infection and other unknown causative factors may play an important role under these pathophysiological conditions because HLA analysis revealed a statistically significant high frequency of haplotype A24‐B52‐DR2 in these patients in Japan. Documentation of atherosclerotic complications in young female patients with Takayasu arteritis who are generally free from traditional atherosclerosis risk factors may be clinical evidence that inflammation is indeed an important risk factor in atherogenesis.
Oxidized‐LDL and Atherosclerosis: Role of LOX‐1
Authors: KITA TORU , KUME NORIAKI , YOKODE MASAYUKI , ISHII KENJI , ARAI HIDENORI , HORIUCHI HISANORI , MORIWAKI HIDEAKI , MINAMI MANABU , KATAOKA HIROHARU , WAKATSUKI YOSHIO
Published: July 2010

Abstract: The accumulation of substantial numbers of monocyte/macrophages and activated T lymphocytes in focal areas of the arterial intima appears to be a hallmark of atherosclerosis. Our report demonstrated that lysophosphatidylcholine (lyso‐PC), a polar phospholipid component that is increased in atherosclerotic lipoproteins, such as oxidized LDL and remnant lipoproteins in diabetic and Type 3 hyperlipidemia, can upregulate adhesion molecules for monocytes and T lymphocytes, and growth factors, such as heparin‐binding epidermal growth factor‐like growth factor and PDGF A and B chains. Recently, we identified the novel receptor for oxidized LDL, named LOX‐1. We summarize the importance of the interaction between oxidized LDL and its receptor, LOX‐1, in terms of early stage atherogenesis.
CD36 in Atherosclerosis: The Role of a Class B Macrophage Scavenger Receptor
Authors: NICHOLSON ANDREW C. , FEBBRAIO MARIA , HAN JIHONG , SILVERSTEIN ROY L. , HAJJAR DAVID P.
Published: July 2010

Abstract: CD36, an 88 kD transmembrane glycoprotein, is an important receptor for oxidized lipoproteins. Unlike the LDL receptor, expression of CD36 is upregulated by this pro‐atherogenic particle, and binding and uptake perpetuates a cycle of lipid accumulation and receptor expression. This effect is, in part, mediated by the transcription factor, peroxisome proliferator activated receptor‐γ (PPARγ), and its ligands. We have found that specific inhibitors of protein kinase C (PKC) reduce basal mRNA expression of CD36 and block induction of CD36 mRNA and protein by oxidized LDL (OxLDL) and a PPARγ ligand. In addition, PKC inhibitors block both PPARγ mRNA and protein expression. These results suggest that activation of CD36 gene expression by OxLDL involves activation and translocation of PKC with subsequent PPARγ activation. More recently, we have generated a mouse null for CD36, and crossed it with the atherogenic Apo E null strain. Evaluation of lesion development in these animals will allow us to assess the in vivo contribution of CD36 to the pathogenesis of atherosclerosis.
Animal Models for Hyperinsulinemia and Insulin Resistance
Authors: ABE HIDEKI , YAMADA NOBUHIRO
Published: July 2010

Abstract: The direct effect of endogenous insulin on the atherosclerotic process has not been well understood. To clarify this question, we performed pancreas transplantation in Wistar Shionogi (WS) rats. Hyperinsulinemia was not related to coronary risk factors such as dyslipidemia and hypertension in transplanted rats. After 9 months of transplantation, the cholesterol ester contents of the aortas of transplanted WS rats were significantly higher than in the control rats. The effects of insulin resistance on coronary risk factors were examined in mice deficient in insulin substrate‐1‐deficient (IRS‐1) mice, a non‐obese animal model of insulin resistance. Blood pressure and plasma triglyceride levels were significantly higher in IRS‐1‐deficient mice than in normal mice. Impaired endothelium‐dependent vascular relaxation was also observed in IRS‐1‐deficient mice. Furthermore, lipoprotein lipase activity was lower than in normal mice, suggesting impaired lipolysis was involved in the increased plasma triglyceride levels under insulin‐resistant conditions.
Signaling Angiogenesis via p42/p44 MAP Kinase Cascade
Authors: PAGÈS GILLES , MILANINI JULIE , RICHARD DARREN E. , BERRA EDURNE , GOTHIÉ EMMANUEL , VIÑALS FRANCESC , POUYSSÉGUR JACQUES
Published: July 2010

Abstract: Vascular endothelial growth factor (VEGF), a potent agonist secreted by virtually all cells, controls migration and division of vascular endothelial cells. Disruption of one VEGF allele in mice has revealed a dramatic lethal effect in early embryogenesis, suggesting a key role in vasculogenesis. We analyzed the regulation of VEGF mRNA in normal and transformed CCL39 fibroblasts and then dissected the VEGF promoter to identify the signaling pathway(s) controlling the activation of this promoter in response to growth factors, oncogenes, and hypoxic stress. We demonstrated that the p42/p44 MAP kinase signaling cascade controls VEGF expression at least at two levels. In normoxic conditions, MAPKs activate the VEGF promoter at the proximal (−88/−66) region where Sp‐1/AP‐2 factors bind. Activation of p42/p44 MAPKs is sufficient to turn on VEGF mRNA. At low O2 tension, hypoxia inducible factor‐1α (HIF‐1α), a limiting factor rapidly stabilized and phosphorylated, plays a key role in the expression of several genes including VEGF. We demonstrated that p42/p44MAPKs stoichiometrically phosphorylate HIF‐1αin vitro and that HIF‐1‐dependent VEGF gene expression is strongly enhanced by the exclusive activation of p42/p44MAPKs. Finally, we demonstrated that the regulation of p42/p44MAPK activity is critical for controlling proliferation and growth arrest of vascular endothelial cells at confluency. These results point to at least three major targets of angiogenesis where p42/p44 MAP kinases exert a determinant action.
Blood Vessels from Bone Marrowa
Authors: CAMPBELL JULIE H. , EFENDY JOHNNY L. , HAN CHIH‐ LU , CAMPBELL GORDON R.
Published: July 2010

Abstract: Lengths of silastic tubing were inserted into the peritoneal cavity of rats or rabbits. By two weeks the free‐floating implants had become covered by a capsule consisting of several layers of “macrophage”‐derived myofibroblasts and collagen matrix overlaid by a single layer of mesothelial cells. The tubing was removed from the harvested implant and the tissue everted. This now resembled an artery with an inner lining of mesothelial cells (the “intima”), a “media” of myofibroblasts, and an outer collagenous “adventitia.” The tube of living tissue was grafted by end‐to‐end anastomoses into the transected carotid artery or abdominal aorta of the same animal in which the tissue had been grown, where it remained patent for four months and developed structures resembling elastic lamellae. The myofibroblasts developed a high volume fraction of myofilaments and became responsive to contractile and relaxing agents similar to smooth muscle cells of the adjacent artery wall.
Construction of Recombinant Adenoviral Vector of Annexin II
Authors: ISHII HIDETO , YOSHIDA MASAYUKI , HAJJAR KATHERINE A. , YASUKOCHI YUKIO , NUMANO FUJIO
Published: July 2010

Abstract: Annexin II is a member of the annexin family of calcium‐dependent phospholipid binding proteins expressed in vascular endothelium. Recently this molecule was reported to play a role in control of fibrinolysis on the endothelial surface. To examine the role of annexin II in vascular endothelium critically, we developed a recombinant adenoviral vector containing the annexin II cDNA. A full‐length annexin II cDNA was inserted into a shuttle vector, pAdRSV4, and co‐transfected into 293 cells with a replication‐deficient type 5 adenovirus, pJM17. Resulting plaques were isolated and checked for protein expression. The verified clone (AdRSV‐ANII) was further analyzed. Characterization of this vector will facilitate the investigation of the mechanism of fibrinolysis on vascular endothelium.
Enhanced Expression of Osteopontin by High Glucose: Involvement of Osteopontin in Diabetic Macroangiopathya
Authors: TAKEMOTO MINORU , YOKOTE KOUTARO , YAMAZAKI MASASHI , RIDALL AMY L. , BUTLER WILLIAM T. , MATSUMOTO TARO , TAMURA KEN , SAITO YASUSHI , MORI SEIJIRO
Published: July 2010

Abstract: Atherosclerotic vascular disease is a major complication of diabetic patients. Osteopontin has recently been implicated in the development of atherosclerosis. In the present study, we have investigated the effects of high glucose on expression of osteopontin in cultured rat aortic smooth muscle cells. High concentrations of glucose increased osteopontin secretion from the cells, and the increased secretion was completely inhibited by an inhibitor of protein kinase C, GF109203X. Northern blot analysis confirmed the enhanced effect of glucose on expression of osteopontin mRNA. Promoter activity of osteopontin, measured using the osteopontin promoter/luciferase expression vector system, was increased by high glucose, and the enhanced effect was completely inhibited by GF109203X. Glucosamine also increased the promoter activity of osteopontin. Azaserine, an inhibitor of glutamine:fructose‐6‐phosphate amidotransferase, the key enzyme of the hexosamine pathway, profoundly inhibited high glucose‐mediated increase in the promoter activity. Taken together, these data indicate that high glucose enhances the expression of osteopontin at the transcriptional level possibly through the activation of protein kinase C as well as the hexosamine pathway. Our results suggest that osteopontin could play a role in the development of diabetic vascular complications.
Assessment of Background Hydrogen by the Monte Carlo Computer Code MCNP‐4A during Measurements of Total Body Nitrogen
Authors: RYDE S. J. S. , AL‐AGEL F. A. M. , EVANS C. J. , HANCOCK D. A.
Published: July 2010

Abstract: The use of a hydrogen internal standard to enable the estimation of absolute mass during measurement of total body nitrogen by in vivo neutron activation is an established technique. Central to the technique is a determination of the H prompt gamma ray counts arising from the subject. In practice, interference counts from other sources‐e.g., neutron shielding‐are included. This study reports use of the Monte Carlo computer code, MCNP‐4A, to investigate the interference counts arising from shielding both with and without a phantom containing a urea solution. Over a range of phantom size (depth 5 to 30 cm, width 20 to 40 cm), the counts arising from shielding increased by between 4% and 32% compared with the counts without a phantom. For any given depth, the counts increased approximately linearly with width. For any given width, there was little increase for depths exceeding 15 centimeters. The shielding counts comprised between 15% and 26% of those arising from the urea phantom. These results, although specific to the Swansea apparatus, suggest that extraneous hydrogen counts can be considerable and depend strongly on the subject's size.
Calibration of the Brookhaven National Laboratory Delayed Gamma Neutron Activation Facility to Measure Total Body Calcium
Authors: MA R. , STAMATELATOS I. E. , YASUMURA S.
Published: July 2010

Abstract: Differences in body size and shape can cause large variances in the in vivo results of neutron activation analysis. To introduce corrections for body size for the delayed gamma neutron activation facility at Brookhaven National Laboratory, “reference man”‐sized and “reference woman”‐sized phantoms were constructed. Simulation results using the Monte Carlo Neutron and Photon Transport code also provided correction factors for people of different sizes. For individuals with a body mass index (BMI = weight (kg)/height (m)2) between 20 and 30, no correction was required. At BMIs greater than 30, the effects of neutron attenuation were significant and a correction factor of CF =−0.0192 × BMI + 1.5635 can be applied.
Assessing Regional Muscle Mass with Segmental Measurements of Bioelectrical Impedance in Obese Women during Weight Lossa,b
Authors: LUKASKI HENRY C.
Published: July 2010

Abstract: Tetrapolar bioelectrical impedance analysis (BIA) offers the possibility of determining the bioconductor volume in discrete segments of the body, because the resistivities of bone, fat, and skeletal muscle differ considerably. We tested this hypothesis by measuring BIA and anthropometry of defined segments of the right thighs of women before and during a controlled weight‐loss program. Eight women, aged 22 to 32 years, with a body mass index of 37.8 ± 1.6 (mean ± SE) kg/m2 underwent determinations of body composition with dual‐energy X‐ray absorptiometry (DXA) and regional BIA measurements (800 μA at 50 kHz) before the program, and monthly thereafter for four months during weight loss. BIA measurements were made with spot‐detector electrodes positioned 10 cm apart on the anterior of the thigh, and source electrodes placed on the right hand and foot. The physical volume of the thigh segment decreased by 29 ± 3% (p < 0.0001), with a modest change in its electrical volume (8 ± 0.2%; p < 0.05) during weight loss. Muscle (181 ± 49 g; p < 0.05) and fat mass (702 ± 95 g; p < 0.001) also declined. The electrical or bioconductor volume correlated with DXA determinations of muscle mass (r= 0.91, p < 0.0001), whereas physical volume correlated with fat mass (r= 0.95, p < 0.0001). These findings support the hypothesis that BIA is a valid method to assess regional muscle mass in humans.
Bioelectrical Impedance Spectroscopy in Health and Disease: Correspondence between Whole Body and Segmental Bioelectrical Impedance Spectroscopy Indices in Patients with Classical Dengue Fever
Authors: MAZARIEGOS MANOLO , KLASSEN PETRA , SOLOMONS NOEL W. , FÜRST PETER
Published: July 2010

Abstract: Bioelectrical impedance spectroscopy (BIS) can provide estimates of body composition for both whole body (WB) and body segments (BS). In normal, healthy subjects, BS measurements may be expected to serve as surrogates for WB indices; however, very little is known about this correspondence in people suffering from acute illnesses. The aim of this study was to evaluate the degree of this correspondence in patients with an acute, systemic illness, such as classical dengue fever. Ten adult patients were examined upon admision to the community hospital on the Pacific Coast of Guatemala and after clinical recovery about two weeks later, and compared with a group of healthy subjects living in the same region. BIS was measured with a Xitron 4000B analyzer (Xitron Technologies Inc., San Diego, CA, USA). BS measurements were carried out using Organ et al.'s approach. The BIS data were modeled with the manufacturer's software: extra‐ (Recf) and intracellular‐ (Ricf) resistances, and the Recf/Ricf ratio. BIS BS measurements correlate closely with WB in both the acute and the recovery stages of dengue fever, with the leg showing the highest degree of correspondence and the trunk the lowest. Recf indices, per se, generally showed higher correspondence than Ricf or the Recf/Ricf ratio.
Gamma Resonance Absorption: New Approach in Human Body Composition Studies
Authors: WIELOPOLSKI L. , VARTSKY D. , PIERSON R. , GOLDBERG M. , HEYMSFIELD S. , YASUMURA S. , MELNYCHUK S. T. , SREDNIAWSKI J.
Published: July 2010

Abstract:The main stream of body elemental analysis is based on the delayed, prompt, and inelastic neutron interactions with the main elements found in the human body, and subsequent analysis of the measured delayed or prompt gamma ray spectra. This methodology traditionally was, and still is, applied for whole body analysis and requires relatively high radiation doses. A new method, based on gamma nuclear resonance absorption (GNRA), is being established at Brookhaven National Laboratory as part of its body composition program. The method is element specific with a high tomographic spatial‐resolution capability, at a small fraction of the radiation dose used in the current system. The new system, with its components and capabilities, is described below.