bluuebunny/crossref_metadata_2025 huggingface dataset:
Preneoplastic Prostate Lesions
Authors: NELSON WILLIAM G. , DE MARZO ANGELO M. , DEWEESE THEODORE L. , LIN XIAOHUI , BROOKS JAMES D. , PUTZI MATTHEW J. , NELSON CHAD P. , GROOPMAN JOHN D. , KENSLER THOMAS W.
Published: July 2010

Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti‐oxidants, and various micronutrients, but the specific roles dietary agents play in promoting or preventing PCA remain controversial. We have collected evidence to suggest that GSTP1, the gene encoding the π‐class glutathione S‐transferase (GST), may serve a “caretaker” function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, in almost all PCA cases, PCA cells fail to express GSTP1 polypeptides, and lack of GSTP1 expression most often appears to be the result of somatic “CpG island” DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of prostatic epithelial neoplasia (PIN) lesions, thought to represent PCA precursors. We have recently learned that a new candidate early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. These findings have formed the basis for a new model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. When cells with defective GSTP1 genes appear amongst the PIA cells, such cells become vulnerable to oxidants and electrophiles that inflict genome damage that tends to promote neoplastic transformation to PIN and PCA cells. Subsequently, PIN and PCA cells with defective GSTP1 genes remain vulnerable to similar stresses tending to promote malignant progression. This new model for prostatic carcinogenesis has implications for the design of new prostate cancer prevention strategies. Rational prevention approaches might include: (i) restoration of GSTP1 expression via treatment with inhibitors of CpG methylation, (ii) compensation for inadequate GSTP1 activity via treatment with inducers of general GST activity, and (iii) abrogation of genome‐damaging stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic (particularly oxidant) stresses.
Bridging Epidemiology and Demography
Authors: WALLACE ROBERT B.
Published: July 2010

Abstract: Epidemiology and demography, although both encumbering several theoretical constructs, are generally applied, problem‐solving disciplines concerned with the nature and trajectories of defined groups. There are differences between the two disciplines in substantive interests and methodological traditions, however both have comprehensive perspectives and both are deeply concerned with the health, social, and economic well‐being of human populations. One way to promote productive interdisciplinary research is to apply or develop scientific theories that exploit the complementary interests and methods of the two disciplines. Several candidate theories and themes are suggested here, including (1) the life course approach as applied to the biology of longevity; (2) the “modernized” Malthusian dilemma; (3) the demographic transition within developing countries; (4) the theory of evolution and its social and biological implications; (5) reciprocal effects of ecological and environmental characteristics on population health and well‐being; and (6) systems theory as an approach to population complexity. Other approaches to fostering interdisciplinary investigation between these disciplines include joint course work, specifically targeted research funding initiatives and collaborative development of new population theory. The latter may be particularly important from several perspectives: uniting disciplines to jointly approach common and important scientific problems, providing existing frameworks with which to generate new scientific questions, and promoting enhanced scientific rigor by more tightly linking methods with hypotheses.
Social Inequalities in Health
Authors: GOLDMAN NOREEN
Published: July 2010

Abstract:Differentials in health and longevity by socioeconomic status and by the nature of social relationships have been found in innumerable studies in the social and medical sciences. Three categories of explanations for the observed patterns have been proposed: causal mechanisms through which the social environment affects health status or the risk of dying; selection or reverse causal pathways whereby a person's health status affects their social position; and artifactual mechanisms, such as measurement error. The general consensus among researchers is that the observed disparities in health are driven largely by a complex set of causal processes rather than by selection or by artifactual mechanisms. This paper explores the set of arguments and strategies that researchers have used to arrive at this conclusion. As part of this undertaking, we assess whether inferences regarding the minor contribution of selection to the overall association between social factors and health are justifiable. In addition, we identify current avenues of research that are providing new insights into the causal pathways linking social factors and health.
Epidemiologic Tools for Today and Tomorrow
Authors: HARTGE PATRICIA
Published: July 2010

Abstract: As the premier population sciences, epidemiology and demography face common challenges as the U.S. population ages, as the genomic revolution unfolds, and as computing power changes the scale of analysis by several orders of magnitude. Each discipline does need to develop new tools to address the changing research questions, and the best strategy for success includes increased collaboration between the disciplines. The paradigms of each discipline still offer important insights into the problems of both disciplines, so cross‐training would be a simple step to begin enlarging the tool box for population science.
How to Unify Knowledge
Authors: Wilson Edward O.
Published: July 2010

Abstract: The central question of general scholarship is whether all of knowledge is intrinsically consilient, that is, whether it can be united by a continuous skein of cause‐and‐effect explanation and across levels of increasingly complex organization. The answer lies in the recognition that the traditional line separating the great branches of learning (natural sciences, social sciences, and humanities) is not a barrier or even a line, but rather a broad domain of poorly explored material phenomena now being cooperatively entered from all sides. The key to bridge‐building is the discovery and analysis of human nature, which consists of the epigenetic rules—the hereditary regularities in mental development. Their study is now well under way, at the biological, social science, and humanities levels. Examples of epigenetic rules include the origin of color vocabularies, incest avoidance, optimum arousal in artistic design, and response to the natural environment. The convergence of the great branches of learning is mostly an empirical process, light on formal logic and theory in its initial stages. The value of the consilience program is that at long last we appear to have acquired the means either to establish the intrinsic truth of the fundamental unity of knowledge, or to discard it. I will argue the likelihood of its existence and early establishment.
Prolegomenon to a General Biology
Authors: Kauffman Stuart A.
Published: July 2010

Abstract: This chapter is a slightly modified version of Chapter 1 of my book, Investigations. I discuss “autonomous agents,” the origin of life, autocatalytic sets of polymers, work cycles, puzzles about evolutionary theory, and the birth of a general biology dealing with biospheres anywhere in the universe.
Biological Constraint, Cultural Variety, and Psychological Structures
Authors: Kagan Jerome
Published: July 2010

Abstract:Although biological processes bias humans to develop particular cognitive, affective, and behavioral forms, the cultural context of growth shapes these forms in particular ways. Psychologists have been indifferent to the nature of the mental structures that mediate the varied psychological functions that are the usual target of inquiry. This paper argues that schemata for perceptual events, motor programs, and semantic networks are distinct, although interdependent, forms that rest on different neurophysiologies. The biological constraints are weakest on the semantic networks that are influenced by the history, economy, religion, geography, and social structure of the society. These factors influence how cultures classify names for emotions, categories of self‐membership, and popular metaphors for human nature. One class of schemata is derived from changes in body tone. Temperamental variation in the susceptibility to changes in body tone has relevance for understanding personality and a vulnerability to anxiety disorders.
Toward a Biology of Personality and Emotion
Authors: Davidson Richard J.
Published: July 2010

Abstract:For most of this past century, scholarship on the topics of personality and emotion has emerged from the humanities and social sciences. In the past decade, a remarkable change has occurred in the influence of neuroscience on the conceptualization and study of these phenomena. This article argues that the categories that have emerged from psychiatric nosology and descriptive personality theory may be inadequate, and that new categories and dimensions derived from neuroscience research may produce a more tractable parsing of this complex domain. The article concludes by noting that the discovery of these biological differences among individuals does not imply that the origins of these differences lie in heritable influences. Experiential shaping of the brain circuitry underlying emotion is powerful. The neural architecture provides the final common pathway through which culture, social factors, and genetics all operate together.
Some Practical Suggestions for Teaching Science in the Liberal Arts
Authors: Pollack Robert
Published: July 2010

Abstract: At the undergraduate level, science is held at a distance from the liberal arts by common agreement among professors from both sides of a wall erected for them by the Enlightenment some centuries ago. There is today no intellectual argument put forth for maintaining the wall; the arguments in its defense are largely cultural and political and therefore in the final analysis fiscal, if not venal. Here are some concrete suggestions for how that wall might be brought down.
Fibrinogen: Evolution of the Structure‐Function Concept
Authors: BLOMBÄCK BIRGER
Published: July 2010

Abstract: Coagulation of blood is such an evident phenomenon that its observation can be traced back to earliest historical times. The great philosophers and physicians of antiquity discussed and provided interesting explanations. However, it was not until the end of the seventeenth century that the structural component of the blood clot was described by Malpighi as a white fibrous substance. In the middle of the nineteenth century this was identified as a constituent of pathological thrombi and given the name fibrin. At about that time its precursor in blood, fibrinogen, was isolated in a highly purified form by Hammarsten who suggested that, preceding fibrin formation, activation of fibrinogen by thrombin occurred by limited proteolysis. The activation mechanism was eventually clarified in the 1950s. It was shown to proceed in two discrete steps, by removal of low molecular weight activation peptides. Ferry postulated, based on physicochemical observations, that the activated molecules aligned in a half‐staggered fashion to form polymers. The rapid post‐war development of biochemical technology permitted evaluation of the primary structure of fibrinogen. With that followed identification of molecular domains in the activated fibrinogen molecules that participate in polymer formation, crosslinking of polymeric structures, and domains for cellular attachment. Crystallization of fragments and, recently, of the entire molecule has confirmed and extended this knowledge. Lately, it has also been possible to obtain detailed information on the architecture of the fiber network in the fibrin gel. The gel structure is primarily determined by the initial rate of fibrinogen activation, but without infringement of this primary rule, several factors in blood may modulate the structure. Fibrinogen and fibrin play important roles in normal hemostasis, wound healing, and pathological processes, such as thrombosis and atherosclerosis.
Contribution of the αEC Domain to the Structure and Function of Fibrinogen‐420
Authors: GRIENINGER GERD
Published: July 2010

Abstract: In addition to the conventional fibrinogen with its α, β, and γ subunit chains, there is a subclass of fibrinogen molecules, accounting for one percent of the total in human adults, in which both α chains have been replaced by extended α chains (αE) that sport a globular C‐terminal domain (αEC) comparable to βC and γC. Using nomenclature based on molecular weight, the subclass of αE‐containing molecules has been named fibrinogen‐420 to differentiate it from the better known fibrinogen, now referred to as fibrinogen‐340. Review of the events leading to the discovery of fibrinogen‐420 in the early 1990s and its subsequent characterization, culminating in the crystal structure of its unique αEC domains, highlights special aspects of its evolutionary history, outstanding features of its structure, and the perplexities of its biology. Various working hypotheses that have driven prior investigation are evaluated and practical insights are offered to spur further research into the role of fibrinogen‐420.
Synthesis of a Mouse Model of the Dysfibrinogen Vlissingen/Frankfurt IV
Authors: HOGAN KELLY A. , MAEDA NOBUYO , KLUCKMAN KIMBERLY D. , LORD SUSAN T.
Published: July 2010

Abstract: The dysfibrinogen Vlissingen/Frankfurt IV is characterized as a deletion of Asn319 and Asp320 from the C‐terminus of the γ‐chain of fibrinogen. This dysfibrinogen, which was identified in several family members that are all heterozygous for the in‐frame 6‐bp deletion, is associated with both venous and arterial thrombosis. Here, we describe the generation of a murine model of the V/F IV dysfibrinogen using gene targeting of mouse γ‐chain DNA. Preliminary analysis shows that the human and mouse variant fibrinogens are similar: analogous to the human V/F IV protein, the D1 fragment of the variant mouse fibrinogen is partially protected from digestion in the presence of calcium or Gly‐Pro‐Arg‐Pro. These heterozygous mice provide the first opportunity to examine the association of thrombophilia and dysfibrinogenemia in a controlled genetic background.
Structure and Properties of Clots from Fibrinogen Bicêtre II (γ308 Asn→Lys)
Authors: MARCHI RITA , LOYAU STÉPHANE , ANGLÉS‐CANO EDUARDO , WEISEL JOHN W.
Published: July 2010

Abstract: Fibrinogen Bicêtre II is a dysfibrinogenemia in which there is a substitution of Lys for Asn at γ308. We have studied the polymerization of this abnormal fibrinogen by measurement of turbidity and have characterized clot structure by scanning electron microscopy, permeation, and viscoelastic measurements. The results of these studies demonstrate that this amino acid substitution has substantial effects on the structure and properties of the clot, resulting in clots made up of thick fibers and large pores with greatly reduced stiffness and increased slippage of protofibrils.
Determinants of Thrombin Specificity
Authors: Di CERA ENRICO , CANTWELL ANGELENE M.
Published: July 2010

Abstract: Thrombin recognizes a number of natural substrates that are responsible for important physiologic functions. Its high specificity is controlled by residues within the active site, and by separate recognition sites located on the surface of the enzyme. A number of studies have addressed the question of how thrombin changes its specificity from fibrinogen to protein C, switching from a procoagulant to an anticoagulant enzyme. Site directed mutagenesis studies have revealed important aspects of how this switch takes place. Specifically, residues W215 and E217 have emerged as key residues in controlling the interaction with fibrinogen in that mutation of these residues compromises the procoagulant function of the enzyme up to 500‐fold. The loss of fibrinogen clotting reaches 20,000‐fold in the double mutant W215A/E217A, whereas protein C activation is compromised less than sevenfold. These findings demonstrate that thrombin specificity can be dissected at the molecular level using Ala‐scanning mutagenesis and the procoagulant function of the enzyme can be abrogated rationally and selectively. It is now possible to extend this strategy to the study of other interactions of thrombin, as well as to related serine proteases.
Conformational Changes upon Conversion of Fibrinogen into Fibrin
Authors: MEDVED LEONID , TSURUPA GALINA , YAKOVLEV SERGEI
Published: July 2010

Abstract: Conformational changes upon conversion of fibrinogen to fibrin result in the exposure of multiple binding sites that provide its interaction with various proteins and cells and, thus, its participation in a number of physiological and pathological processes. Here we focus on conformational changes in the fibrinogen D regions (domains) and αC‐domains that are directly involved in intermolecular interactions upon fibrin assembly. According to the current view, two αC‐domains that interact intramolecularly in fibrinogen undergo an intra‐ to intermolecular switch to form αC‐polymers in fibrin. The availability of recombinant fragments that correspond to the αC‐domain made it possible to further clarify this mechanism and to reveal novel cryptic sites in this domain for plasminogen and its activator tPA, whose exposure may play an important role in the regulation of fibrinolysis. To elucidate the mechanism of exposure of cryptic sites in the D regions, we tested the accessibility of their fibrin specific epitopes (Aα148–160 and γ312–324) that are also involved in binding of plasminogen and tPA, in several fragments derived from fibrinogen (fragment D), and crosslinked fibrin (fragment D‐D and its non‐covalent complex with the E1 fragment, D‐D:E1). Neither D nor D‐D bound tPA, plasminogen, or anti‐Aα148–160 and anti‐γ312–324 monoclonal antibodies. At the same time both epitopes became accessible in the D‐D:E1 complex. Melting of D and D‐D revealed that their domains have the same stability while in the D‐D:E1 complex they became more stable. These results indicate that upon fibrin assembly, driven primarily by the interaction between complementary binding sites of the E and two D regions, the latter undergo conformational changes that cause the exposure of their cryptic sites. They also suggest that the fibrin specific conformation of the D regions is preserved in the D‐D:E1 complex.
Fibrin‐Mediated Plasminogen Activation
Authors: NIEUWENHUIZEN WILLEM
Published: July 2010

Abstract: Fibrin, but not fibrinogen, enhances the rate of activation of plasminogen by tissue type plasminogen activator (t‐PA). Studies with enzymatic and chemical fragments of fibrinogen showed that several sites in fibrinogen are involved in this rate enhancement; these are, Aα148–160 (located in CNBr fragment FCB‐2), and FCB‐5 (a CNBr fragment comprising γ312–324), and recently discovered sites in the fibrinogen αC domains. All these sites are buried in fibrinogen, but exposed in fibrin and some fibrinogen fragments. For the first two of these, located in the D‐domains, this was shown by the fact that monoclonal antibodies against Aα148–160 and γ312–324 bind to fibrin and rate enhancing fibrin(ogen) fragments, but not to fibrinogen. Direct binding studies indicate that at physiological concentrations plasminogen binds to FCB‐2, and t‐PA to FCB‐5. More detailed studies have demonstrated the importance of residues Aα‐157 and Aα‐152, and that the minimum stretch with rate enhancing properties is Aα154–159. The sites in the αC domains await further identification. With the recently reported three‐dimensional structure of fragments D and D‐dimer it is now possible to explain these findings at the molecular level. Molecular calculations and experimental data show that the site Aα148–160 in fibrinogen is covered among others by a part of the Aα chain (Aα166–195) that forms an α‐helix, and by a globular domain formed by the β‐chain. On fibrin formation, the last two may move away, and give access to Aα148–160. It is conceivable that in the αC domain sites are involved in the early phases of fibrinolysis. The site Aα148–160 and that in FCB‐5 may be more important at later stages. It is also clear that fibrin polymerization is important. This polymerization has probably several effects: exposure of the rate enhancing sites; mutual positioning of the t‐PA and plasminogen binding sites; a concentrating effect of t‐PA and plasminogen on the fibrin surface; effects on the kinetic properties of t‐PA and plasminogen. These effects together explain the rate enhancement.
Factor XIII: Structure, Activation, and Interactions with Fibrinogen and Fibrin
Authors: LORAND LASZLO
Published: July 2010

Abstract: Fibrin stabilizing factor (factor XIII or FXIII) plays a critical role in the generation of a viable hemostatic plug. Following exposure to thrombin and calcium, the zymogen is activated to FXIIIa that, in turn, catalyzes the formation of Nε(γ‐glutamyl)lysine protein‐to‐protein side chain bridges within the clot network. Introduction of these covalent crosslinks greatly augments the viscoelastic storage modulus of the structure and its resistance to fibrinolytic enzymes. Analysis of the individual reaction steps and regulatory control mechanisms involved in clot stabilization enabled us to reconstruct the entire physiological process. This also serves as a guide for the differential diagnosis of the variety of molecular defects of fibrin stabilization.
Tumors and Fibrinogen
Authors: SIMPSON‐HAIDARIS P.J. , RYBARCZYK BRIAN
Published: July 2010

Abstract:The progression of a tumor from benign and localized to invasive and metastatic growth is the major cause of poor clinical outcome in cancer patients. Much like in a healing wound, the deposition of fibrin(ogen), along with other adhesive glycoproteins, into the extracellular matrix (ECM) serves as a scaffold to support binding of growth factors and to promote the cellular responses of adhesion, proliferation, and migration during angiogenesis and tumor cell growth. Inappropriate synthesis and deposition of ECM constituents is linked to altered regulation of cell proliferation, leading to tumor cell growth and malignant transformation. Fibrin deposition occurs within the stroma of a majority of tumor types. In contrast, abundant FBG, not fibrin, is present within the stroma of breast cancers. It is thought to originate from exudation of plasma FBG and subsequent deposition into the tumor stroma and not endogenous synthesis and secretion of FBG by breast tumor cells. However, we show that MCF‐7 human breast cancer cells synthesize and secrete FBG polypeptides, suggesting that the origin of FBG in the stroma of breast carcinoma may be due to endogenous synthesis and deposition. Moreover, FBG assembles into ECM as conformationally altered FBG, not as fibrin. Studies in our laboratory demonstrate that FBG alters the ability of breast cancer cells to migrate. Together, the results of studies from our laboratory, as well as the laboratories of others, indicate that the presence of fibrin(ogen) within the tumor stroma likely affects the progression of tumor cell growth and metastasis. This review focuses on FBG within tumors and its relationship with other tumor constituents, ultimately focusing on the role of FBG in breast cancer.
Attenuation of Neointima Formation Following Arterial Injury in PAI‐1 Deficient Mice
Authors: PLOPLIS VICTORIA A. , CASTELLINO FRANCIS J.
Published: July 2010

Abstract: Atherosclerosis is a chronic inflammatory disease in which the fibrinolytic system has been implicated as playing a major role. In order to directly assess the physiological impact an imbalanced fibrinolytic system has on both early and late stages of this disease, mice deficient for PAI‐1 (PAI‐1−/−) were used in a model of vascular injury/repair and compared to wildtype mice (WT). Copper‐containing cuffs were placed around the carotid arteries of these mice and the injured arteries were removed at either 7 or 21 days for histological analyses. At both times after injury, fibrin was prevalent in WT arteries, whereas only diffuse in PAI‐1−/− arteries. At 21 days after injury, a prominent, multilayered neointima was evident in WT arteries, with no evidence of a neointima in PAI‐1−/− arteries. Results from this study directly confirm the involvement of the fibrinolytic system in vascular repair processes following injury and indicate that fibrin could potentially play a role in lesion formation by stimulating smooth muscle cell proliferation, collagen synthesis, and intracellular cholesterol accumulation.
Transcriptional Control Mechanism of Fibrinogen Gene Expression
Authors: FULLER GERALD M. , ZHANG ZHIXIN
Published: July 2010

Abstract: Although fibrinogen genes are expressed constitutively in hepatocytes, their transcription can be greatly increased during inflammatory stress. Extensive studies have focused on the cytokine mediated transcriptional regulation of fibrinogen genes. It is clear that interleukin‐6 (IL‐6) and its family of cytokines are the major inducers of fibrinogen gene expression. Functional analyses of all three fibrinogen promoters for human and rat all demonstrate that the conserved CTGGGAA motifs within the proximal promoter of each fibrinogen gene are the IL‐6 responsive elements. Exploration of the rat γ fibrinogen gene demonstrated that the IL‐6 activated transcription factor, STAT3, binds to the CTGGGAA motif and is required for the IL‐6 mediated upregulation of this gene. IL‐6 mediated fibrinogen production can be significantly elevated by glucocorticoid treatment. The synergistic effect of glucocorticoids and IL‐6 relies on the functional interaction between STAT3 and glucocorticoid receptor. In addition to the upregulation signals for fibrinogen gene expression during inflammatory stress, other signaling also downregulates the expression of fibrinogen genes. For example, the proinflammatory cytokine IL‐1β exerts inhibitory function on IL‐6 mediated fibrinogen gene expression. Given the fact that elevated levels of fibrinogen in blood correlate with increased risk for cardiovascular disease, there is strong motivation to explore the molecular mechanisms that control fibrinogen expression, especially those signals that may downmodulate expression and thus provide novel approaches to controlling fibrinogen levels.
Fibrinogen Gene Mutations Accounting for Congenital Afibrinogenemia
Authors: NEERMAN‐ARBEZ MARGUERITE
Published: July 2010

Abstract: This article reviews recent progress made in understanding the molecular basis of congenital afibrinogenemia, an autosomal recessive coagulation disorder characterized by the complete absence of detectable fibrinogen. We have identified the first causative mutations for this disorder in a non‐consanguineous Swiss family; these were homozygous deletions of approximately 11 kb of the fibrinogen alpha chain (FGA) gene. Haplotype data implied that the deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. All the deletions were identical to the base pair, and probably resulted from non‐homologous (illegitimate) recombination. In a subsequent study of 13 unrelated patients with congenital afibrinogenemia we analyzed the FGA gene in order to identify the causative mutations, and to determine the prevalence of the 11‐kb FGA deletion. Although this deletion was found in an additional unrelated patient, the most common mutation was at the donor splice site of FGA intron 4 (IVS411 G>T). Three frameshift mutations, two nonsense mutations, and one other splice site mutation were also characterized. Other studies identified one further FGA nonsense mutation, two FGB missense mutations, and one FGG nonsense mutation, all in homozygosity in a single patient. In conclusion, the majority of patients have truncating mutations in the FGA gene although, intuitively, all three fibrinogen genes could be predicted to be equally implicated. These results will facilitate molecular diagnosis of the disorder, permit prenatal diagnosis for families who so desire, and pave the way for new therapeutic approaches such as gene therapy.
Effects of Diet, Drugs, and Genes on Plasma Fibrinogen Levels
Authors: DE MAAT MONIEK P.M.
Published: July 2010

Abstract: Plasma levels of fibrinogen have been identified as independent risk predictors of cardiovascular disease. This has greatly increased interest in the regulation of plasma fibrinogen levels. Many demographic and environmental factors are known to affect fibrinogen levels, such as diet, use of several drugs, age, smoking, body mass, gender, physical exercise, race, and season. Additionally, it is also known that genetic factors determine the fibrinogen levels, and also that they determine the response of fibrinogen levels to environmental factors. Estimates, based on twin studies, suggest that 30–50% of the plasma fibrinogen level is genetically determined. The effect of dietary components on plasma fibrinogen levels is modest. Several components have been identified as factors that influence fibrinogen levels. Among those are fish oil, other lipids, and fibers. Dietary components that were expected to have an effect on fibrinogen, but for which no association was observed are black and green tea. Several drugs are known to influence fibrinogen levels, the most studied of which are platelet aggregation inhibiting drugs, such as ticlopidine, and the lipid lowering fibric acid derivatives (fibrates). Both types of drugs decreased the plasma fibrinogen level by about 10%, and bezafibrate lowers fibrinogen even more in patients with diabetes. No clear effect was observed for the HMG‐CoA reductase inhibitors (statins). In the Bezalip study, fibrinogen levels decreased in patients treated with bezafibrate, but this had no clear effect on the risk of cardiovascular disease. This suggests that several mechanisms influence the fibrinogen level and that these mechanisms may contribute differently to cardiovascular disease. Several variations in the fibrinogen genes have been described and especially variations in the promoter region of the fibrinogen β‐gene are interesting, because the synthesis of the fibrinogen Bβ chain is considered to be the rate limiting step in the fibrinogen biosynthesis. In many studies the fibrinogen β‐gene polymorphisms (−455G/A, −148C/T, and BclI) are found to be associated with the plasma levels of fibrinogen. However, they are not associated with the risk of cardiovascular events, although in several studies an association with the severity and progression of atherosclerosis has been reported. It has also been observed frequently that the fibrinogen β‐gene promoter polymorphisms are associated with the response of fibrinogen levels to environmental factors, such as exercise and trauma. In conclusion, plasma fibrinogen levels are regulated by an interesting and complex interplay between environmental and genetic factors.
Modified Clotting Properties of Fibrinogen in the Presence of Acetylsalicylic Acid in a Purified System
Authors: HE SHU , BLOMBÄCK MARGARETA , YOO GINA , SINHA RAKHI , HENSCHEN ‐EDMAN AGNES H.
Published: July 2010

Abstract: To assess how treatment with acetylsalicylic acid (ASA) alters the fibrin network structure, clotting was initiated in purified fibrinogen incubated with ASA by adding thrombin. Clotting time and maximum absorbance of the fibrin aggregation curve were used to demonstrate the potential of fibrin generation. The results showed that the clotting properties of fibrinogen decreased and that the affinity of plasminogen to fibrin or thrombin inhibition by antithrombin increased if plasminogen or antithrombin, respectively, were present in the reaction system. The effect of ASA varied in a dose dependent manner. It was concluded that ASA may directly or indirectly confer positive or negative effects on the stability of the fibrin clot and that the balance between these effects may be regulated by the ASA dose.
Wound Healing
Authors: AMRANI DAVID L. , DIORIO JAMES P. , DELMOTTE YVES
Published: July 2010

Abstract: This paper focuses on the use of commercial fibrin sealant (FS) in specific wound healing applications. This review is not intended to be all inclusive, but to examine in vitro and in vivo models, as well as select clinical conditions that are representative of specific wound healing applications of FS.
Factor XIII Prevents Development of Myocardial Edema in Children Undergoing Surgery for Congenital Heart Disease
Authors: WOZNIAK GERNOLD , NOLL THOMAS , AKINTÜRK HAKAN , THUL JOSEF , MÜLLER MATTHIAS
Published: July 2010

Abstract: In a prospective investigation of perioperative cardiac edema formation requiring a delayed sternal closure, we identified thrombin increase combined with a simultaneous decrease of factor XIII as a probable cause. After experimental studies additionally revealed that factor XIII could protect endothelial barrier function, we did another prospective randomized trial in which factor XIII or placebo was preoperatively substituted. The substitution finally showed distinct effects minimizing the incidence of myocardial swelling. Therefore, the clinical application of factor XIII may have a valuable therapeutic benefit in cases of leakage syndrome during extracorporeal circulation in congenital heart surgery.
Fibrin Network Structure
Authors: MOSS S.J. , MALAN M.M. , DREYER L.I. , VORSTER H.H.
Published: July 2010

Abstract: The metabolic environment determines the characteristics of fibrin network structure (FNS) in plasma. Physical activity or changes in the diet (e.g., high and low glycemic index meals) can initiate these changes. The FNS were measured by means of mass‐length ratio, turbidity, and compaction of the plasma obtained from male subjects. Samples were taken before and after the introduction of the different diets and physical activity. The results indicate that changes in the FNS do occur, but further investigation is required to obtain conclusive results.
Modulation of the Behavioral and Neurochemical Effects of Psychostimulants by κ‐Opioid Receptor Systems
Authors: SHIPPENBERG T. S. , CHEFER V. I. , ZAPATA A. , HEIDBREDER C. A.
Published: July 2010

Abstract:The repeated, intermittent use of cocaine and other drugs of abuse produces profound and often long‐lasting alterations in behavior and brain chemistry. It has been suggested that these consequences of drug use play a critical role in drug craving and relapse to addiction. This article reviews the effects of psychostimulant administration on dopaminergic and excitatory amino acid neurotransmission in brain regions comprising the brain's motive circuit and provides evidence that the activation of endogenous κ‐opioid receptor systems in these regions opposes the behavioral and neurochemical consequences of repeated drug use. The role of this opioid system in mediating alterations in mood and affect that occur during abstinence from repeated psychostimulant use are also discussed.
Substance P Modulates Cocaine‐Evoked Dopamine Overflow in the Striatum of the Rat Brain
Authors: KRAFT MADELYNE , NOAILLES PIERRE , ANGULO JESUS A.
Published: July 2010

Abstract: To study the role of the neuropeptide substance P in modulating some of the effects of cocaine in the striatum, we administered cocaine to rats and measured preprotachykinin‐A (PPT‐A) messenger RNA and substance P peptide in the nigrostriatal pathway. We also measured the effect of a neurokinin‐1 (NK‐1) receptor antagonist on striatal cocaine‐evoked dopamine overflow by in vivo microdialysis in freely moving animals. Acute administration of cocaine to naive rats (15 mg/kg of body weight) increased preprotachykinin‐A mRNA levels in the dorsal and ventral aspects of the caudate putamen 4 hours after the intraperitoneal injection of cocaine. Concomitantly, in a separate group of animals, substance P peptide levels were decreased in the ventral caudate putamen and substantia nigra (38% below controls). In a separate experiment, infusion through the microdialysis probe of the neurokinin‐1 receptor antagonist L‐733,060 significantly decreased cocaine‐evoked striatal dopamine overflow (approximately 50% inhibition at 30 minutes after cocaine administration). Taken together, these results suggest a direct role for substance P in the modulation of some of the actions of cocaine in the striatum of the rat brain.
Endocrinological Basis of Sex Differences in Cocaine‐Induced Behavioral Responses
Authors: QUIÑONES‐JENAB VANYA , PERROTTI LINDA I. , FABIAN SOSIMO J. , CHIN JULIET , RUSSO SCOTT J. , JENAB SHIRZAD
Published: July 2010

Abstract:Currently, 1.8 million Americans use cocaine, 30% of whom are females. Sex differences in the pattern of cocaine abuse may reside in neuroendocrinological modulations that affect the use of and/or dependence on cocaine. This review discusses sex differences in cocaine‐induced behavioral and molecular alterations in the central nervous system, with emphasis on the role of endocrine responses in the neuronal modulations of this drug. Mechanisms and data supporting the role of the hypothalamic‐gonadal axis in the modulation of cocaine‐induced behavioral and molecular alterations are also provided.
Sex, Steroids, and Stimulant Sensitivity
Authors: KUHN C. M. , WALKER Q. D. , KAPLAN K. A. , LI S. T.
Published: July 2010

Abstract:The current study investigated ovarian modulation of the locomotor response to cocaine in rats. Ovariectomy in females lowered the response to cocaine (10 mg/kg ip), whereas castration did not change that of males. The locomotor responses of prepubertal males and females to cocaine were similar. However, the postpubertal sex difference resulted from a fall in cocaine‐stimulated locomotion in males rather than a rise in females. Neonatal testosterone treatment of female rat pups decreased the response to cocaine in adulthood. These findings suggest that both the activational and organizational effects of gonadal steroids contribute to the greater response of females to cocaine.
Ex Vivo Expansion and Engraftment Potential of Cord Blood‐Derived CD34+ Cells in NOD/SCID Mice
Authors: FIBBE WILLEM E. , NOORT WILLY A. , SCHIPPER FRANK , WILLEMZE ROEL
Published: July 2010

Abstract: For more than 10 years umbilical cord blood (UCB) has been used as an alternative source of hematopoietic stem cells for allogeneic transplantation. Although the clinical results are encouraging, UCB is associated with delayed engraftment. To address these issues we have used the NOD/SCID mouse model to study the engraftment potential of cord blood cells in more detail, to assess the engraftment potential of expanded megakaryocytic progenitor cells, and to study the effect of co‐transplantation of mesenchymal stem cells on engraftment.
Quantitative Assessment of the Stem Cell Self‐Renewal Capacity
Authors: NAKAUCHI HIROMITSU , SUDO KAZUHIRO , EMA HIDEO
Published: July 2010

Abstract: Little is known about the manner in which hematopoietic stem cells (HSCs) self‐renew. To address this issue, we used a serum‐free single‐cell culture, followed by transplantation of cultured cells into lethally irradiated mice. CD34‐negative or low, c‐Kit‐positive, Sca‐1‐positive, lineage marker‐negative (CD34−KSL) cells are highly enriched for murine bone marrow HSCs. Successful long‐term reconstitution with a single CD34−KSL cell enabled us to study in vitro self‐renewal of HSC at clonal level. Using this clonal cell transplantation system, we examined the effect of various cytokines on CD34−KSL cells. Among the cytokines examined, stem cell factor (SCF) and thrombopoietin (TPO) were minimum cytokines to induce cell division of CD34−KSL cells most efficiently. Similarly, multilineage repopulating activity was detected in the cells derived from a significant portion of single cells after culture in the presence of TPO and SCF. However, SCF + IL‐3, SCF + IL‐6, or SCF + IL‐11 + FL appeared to be less effective for self‐renewal of HSCs. The activity of HSCs as indicated by repopulation unit (RU) remaining after culture with SCF and TPO was not so different from that of freshly isolated HSCs. However, there was a substantial loss of HSC number in these cultured cells. Taken together, this study provides definitive proof that one HSC can generate at least one HSC in vitro.
Chemokine Regulation of Hematopoiesis and the Involvement of Pertussis Toxin‐Sensitive GαiProteins
Authors: Broxmeyer Hal E. , Youn Byung S. , Kim Chang , Hangoc Giao , Cooper Scott , Mantel Charlie
Published: July 2010

Abstract:Chemokines have been implicated in regulation of various aspects of hematopoiesis, including negative regulation of the proliferation of immature subsets of myeloid progenitor cells (MPCs), chemotaxis of MPCs, and survival enhancement of MPCs after delayed growth factor addition. Since chemokine receptors are seven‐transmembrane‐spanning G‐protein‐linked receptors and the chemotactic effectin vitroof the CXC chemokine SDF‐1 is pertussis toxin (PT)‐sensitive, implying the involvement of Gαiproteins as mediators of SDF‐1‐induced chemotaxis, we evaluated the effects of PT on other chemokine actions influencing MPCs. While thein vitrosurvival‐enhancing effects of SDF‐1 on GM‐CSF and steel factor‐dependent mouse bone marrow granulocyte macrophage progenitors (CFU‐GM) were pertussis toxin‐sensitive, the suppressive effects of the CC chemokine MIP‐1α and the CXC chemokine IL‐8 on colony formation by GM‐CSF and steel factor‐sensitive CFU‐GM were insensitive to pertussis toxin. These results suggest that not all chemokine‐mediated effects on MPCs are necessarily mediated through pertussis toxin‐sensitive Gαiproteins.
CD34 Expression by Murine Hematopoietic Stem Cells
Authors: OGAWA MAKIO , TAJIMA FUMIHITO , ITO TATSUYA , SATO TAKASHI , LAVER JOSEPH H. , DEGUCHI TAKAO
Published: July 2010

Abstract: For more than a decade it was believed that hematopoietic stem cells express CD34. However, this dogma was recently challenged by the observation that stem cells of normal adult mice are CD34−. In order to clarify the controversy, we carried out systematic examination of stem cells by using C57BL/6 mice that are congenic for Ly‐5. As reported previously, stem cells in the normal adult mice were CD34−. However, stem cells stimulated in vivo by 5‐flourouracil injection or in vitro by a combination of interleukin‐11 and steel factor were CD34+. The activated CD34+ stem cells reverted to CD34− when the recipients' marrow achieved steady state. The majority of G‐CSF‐mobilized stem cells also were CD34+ and reverted to CD34− under steady‐state conditions. Most recently, we examined the developmental changes of stem cell CD34 expression. In order to gain information on the total population of stem cells we prepared CD34+ and CD34− populations of mononuclear cells without prior enrichment and studied their engrafting potentials. All stem cells from perinatal to 5‐week‐old mice were CD34+. In 7‐week‐old mice CD34− stem cells began to emerge, and the majority of the stem cells were CD34− in the 10‐ and 20‐week‐old mice. An estimated 20% of the adult stem cells expressed CD34. These observations provide insight into the current controversy regarding CD34 expression by adult hematopoietic stem cells.
A Model for the Detection of Clonality in Marked Hematopoietic Stem Cells
Authors: SCHMIDT MANFRED , GLIMM HANNO , LEMKE NINA , MUESSIG ARNE , SPECKMANN CARSTEN , HAAS SEBASTIAN , ZICKLER PHILIPP , HOFFMANN GESA , Von KALLE CHRISTOF
Published: July 2010

Abstract: The semirandom location of retroviral integration in the target cell genome introduces a marker in the form of a fusion sequence composed of a genomic and a proviral part that is unique for each transduced cell and its clonal progeny. High‐sensitivity detection of these fusion sequences would allow the tracking of clonal contributions of individual, marked hematopoietic progenitor, and stem cells in vivo. Clone detection by Southern blot has helped to analyze models of oligoclonal repopulation but is limited in sensitivity and specificity. Inverse PCR (Nolta et al., Proc. Natl. Acad. Sci. USA 93: 2414–2419) can demonstrate the clonal identity by sequencing but does not permit simultaneous detection of multiple clones. In an efficiently transduced rhesus macaque model (Tisdale et al., Blood 92: 2681–2687; Wu et al., Mol. Ther. 1: 285–293) Kim et al. (Blood 96: 1–8) have identified more than 40 insertion sequences from marrow CFU by inverse PCR. However, no previous study has been able to directly analyze the number of clones active in vivo. Here we dem‐onstrate that the application of a recently developed PCR technology allows the simultaneous visualization of multiple integration sites from small clonal con‐tributions to hematopoietic cells. By combining solid‐phase primer extension with ligation‐mediated PCR, direct genomic sequencing of retroviral integra‐tion sites was obtained in murine bone marrow samples. Further development of this technology will allow analysis of the clonal composition of marked he‐matopoiesis in small and large animals as well as in human gene transfer.
Characterization of Multipotent Adult Progenitor Cells, a Subpopulation of Mesenchymal Stem Cells
Authors: REYES MORAYMA , VERFAILLIE CATHERINE M.
Published: July 2010

Abstract: Mesenchymal stem cells were isolated and a subpopulation of cells—multipotent adult progenitor cells—were identified that have the potential for multilineage differentiation. Their ability to engraft and differentiate in vivo is under investigation.
Lineage Commitment and Maturation Induction in Normal and Leukemic Preprogenitor Cells
Authors: METCALF D. , LAÂBI Y.
Published: July 2010

Abstract: Analysis of the critical cellular processes of self‐generation, commitment, and maturation induction ideally requires the use of clonal cultures using cells with a capacity to undergo all three processes. Preprogenitor cells from normal mouse marrow are proving useful cells for such studies. Cells of a newly established cloned leukemic cell line, the GB2, are providing a useful analogous leukemic system because GB2 cells form stratified subpopulations of clonogenic cells able to be clonally analyzed in vitro in which self‐renewal is demonstrable, but in which near‐normal maturation can be induced by a wide range of hematopoietic regulators.