bluuebunny/crossref_metadata_2025 huggingface dataset:
Flavivirus DNA Vaccines
Authors: CHANG GWONG‐JEN J. , DAVIS BRENT S. , HUNT ANN R. , HOLMES DEREK A. , KUNO GORO
Published: July 2010

Abstract: The use of DNA‐based vaccines is a novel and promising immunization approach for the development of flavivirus vaccines. This approach has been attempted in vaccine development for various virus species, including St. Louis encephalitis, Russian spring‐summer encephalitis, Central European encephalitis, dengue serotypes 1 and 2, Murray Valley encephalitis, Japanese encephalitis, and West Nile viruses. However, very little is known about the factors affecting its efficacy. Recently, we demonstrated that a single intramuscular immunization of DNA vaccine of Japanese encephalitis and West Nile viruses protected mice and horses from virus challenge. Administration of these recombinant plasmid vectors resulted in endogenous expression and secretion of extracellular virus‐like particles that correlated well with the induction of protective immunity. These results provided evidence that the virus‐like particles composed of premembrane/membrane and envelope proteins are essential for eliciting immune responses similar to those induced by live, attenuated virus vaccines. The biosynthesis and protein processing of premembrane/membrane and envelope proteins that preserve the native conformation and glycosylation profiles identical to virion proteins could be determined by the effectiveness of the transmembrane signal sequence located at the amino‐terminus of premembrane protein. The use of DNA vaccines in multivalent and/or combination vaccines designed to immunize against multiple flaviviruses is also a promising area of development.
West Nile Virus Serosurvey and Assessment of Personal Prevention Efforts in an Area with Intense Epizootic Activity: Connecticut, 2000
Authors: McCARTHY TARA A. , HADLER JAMES L. , JULIAN KATHLEEN , WALSH STEPHEN J. , BIGGERSTAFF BRAD J. , HINTEN STEVEN R. , BAISLEY CAROLINE , ITON ANTHONY , BRENNAN TIMOTHY , NELSON RANDALL S. , ACHAMBAULT GARY , MARFIN ANTHONY A. , PETERSEN LYLE R.
Published: July 2010

Abstract: West Nile virus (WNV) can cause large outbreaks of febrile illness and severe neurologic disease. This study estimates the seroprevalence of WNV infection and assesses risk perception and practices regarding potential exposures to mosquitoes of persons in an area with intense epizootics in 1999 and 2000. A serosurvey of persons aged ≥12 years was conducted in southwestern Connecticut during October 10‐15, 2000, using household‐based stratified cluster sampling. Participants completed a questionnaire regarding concern for and personal measures taken with respect to WNV and provided a blood sample for WNV testing. Seven hundred thirty persons from 645 households participated. No person tested positive for WNV (95% CI: 0‐0.5%). Overall, 44% of persons used mosquito repellent, 56% practiced ≥ two personal precautions to avoid mosquitoes, and 61% of households did ≥ two mosquito‐ source reduction activities. In multivariate analyses, using mosquito repellent was associated with age <50 years, using English as the primary language in the home, being worried about WNV, being a little worried about pesticides, and finding mosquitoes frequently in the home (P <0.05). Females (OR = 2.0; CI = 1.2‐2.9) and persons very worried about WNV (OR = 3.8; CI = 2.2‐6.5) were more likely to practice ≥ two personal precautions. Taking ≥ two mosquito source reductions was associated with persons with English as the primary language (OR = 2.0; CI = 1.1‐3.5) and finding a dead bird on the property (OR = 1.8; CI = 1.1‐2.8).

An intense epizootic can occur in an area without having a high risk for infection to humans. A better understanding of why certain people do not take personal protective measures, especially among those aged ≥50 years and those whose primary language is not English, might be needed if educational campaigns are to prevent future WNV outbreaks.
West Nile Virus Envelope Protein
Authors: WANG TIAN , ANDERSON JOHN F. , MAGNARELLI LOUIS A. , BUSHMICH SANDRA , WONG SUSAN , KOSKI RAYMOND A. , FIKRIG EROL
Published: July 2010

Abstract: The role of antibodies to the West Nile virus envelope (E) protein in serodiagnosis and protection was examined. The E protein was expressed and purified in recombinant form. Antibodies to the E protein were detected in patients with West Nile virus infection. Passive immunization with rabbit anti‐E protein sera also partially protected mice from challenge with West Nile virus. The humoral response to the West Nile virus E protein is therefore useful as an aid in the diagnosis and may also play a role in immunity to infection.
Cyclin Proteolysis as a Retinoid Cancer Prevention Mechanism
Authors: DRAGNEV KONSTANTIN H. , FREEMANTLE SARAH J. , SPINELLA MICHAEL J. , DMITROVSKY ETHAN
Published: July 2010

The retinoids, natural and synthetic derivatives of vitamin A, are active in cancer therapy and prevention. Their biological effects are mediated through ligand‐dependent interactions with retinoid receptors that associate with specific co‐regulators. A better understanding of retinoid chemopreventive mechanisms is needed. Our prior work revealed that all‐trans‐retinoic acid (RA) prevented tobacco‐specific carcinogenic transformation of cultured human bronchial epithelial cells. RA signaled G1 arrest that permitted repair of genomic DNA damage caused by these carcinogens. RA triggered G1 arrest at least partly through proteasome‐dependent degradation of cyclin D1. Proteasomal inhibitors blocked RA‐mediated cyclin D1 degradation. To confirm that a specific proteolysis pathway was induced by RA‐treatment, a degradation assay was established using in vitro translated cyclin D1 and cellular extracts from RA‐treated or untreated human bronchial epithelial cells. Incubation of RA‐treated but not the control cellular extracts with in vitro translated cyclin D1 led to cyclin degradation. This degradation depended on the PEST domain of cyclin D1, implicating ubiquitination in this retinoid degradation. Retinoid receptor selective agonists demonstrated that retinoic acid receptor (RAR)β and retinoid X receptor (RXR) but not RARα‐ or RARγ‐dependent pathways signaled this cyclin degradation. Findings were extended to the NT2/D1 human embryonal carcinoma differentiation model where a similar pathway was activated by RA‐treatment. To determine whether G1 cyclins were involved directly in bronchial preneoplasia, immunohistochemical expression profiles for cyclins D1 and E were examined. Aberrant expression of these cyclins was frequent in bronchial preneoplasia. Taken together, these findings indicate that ubiquitin‐dependent proteolysis of G1 cyclins is a retinoid chemoprevention mechanism. Whether the retinoids represent the optimal agents to activate this pathway is the subject of ongoing work. These findings provide a rationale for combining the retinoids in chemoprevention trials with other agents that do not activate this proteolysis pathway. What is now known about the retinoids as cancer prevention agents will be reviewed. Emphasis is placed on retinoid effects on cell cycle progression at G1.
Interpreting the Paradoxical in the Hispanic Paradox
Authors: PALLONI ALBERTO , MORENOFF JEFFREY D.
Published: July 2010

Abstract:This paper discusses problems that are common to both the epidemiologic risk‐factor approach and the demographic variable‐based approach to studying population health. We argue that there is a shared reluctance to move away from a narrow variable‐based thinking that pervades both disciplines, and a tendency to reify the multivariate linear procedures employed in both disciplines. In particular, we concentrate on the difficulties generated by classical variable‐based approaches that are especially striking when one neglects selection processes and the use of strategies to minimize its effects. We illustrate these difficulties in terms of the so‐called “Hispanic Paradox”, which refers to comparative health advantages that some Hispanic groups appear to have. We find that much of what is conceived by demographers and epidemiologists as a paradox may not be paradoxical at all.
The X Chromosome and the Female Survival Advantage
Authors: CHRISTENSEN KAARE , ØRSTAVIK KAREN HELENE , VAUPEL JAMES W.
Published: July 2010

Abstract: Despite differences in research traditions, the disciplines of genetics, epidemiology, and demography are becoming increasingly integrated in health‐related research. The enormous development within genetic technology, with the possibility of genotyping thousands of variants from small samples of biological material obtained by non‐invasive methods, now makes it feasible to include genetic information in epidemiologic and demographic studies. Simultaneously, new insight can be obtained from hybrids of methods and data from the three disciplines. This paper illustrates how a genetic observation combined with demographic insight and a modified genetic‐epidemiologic design (a twin study) provides evidence that part of the sex difference in survival can be attributed to the fact that females have two X chromosomes and males have only one, a result that is of potential interest for genetics, epidemiology, and demography.
Agricultural Colonization and Malaria on the Amazon Frontier
Authors: SINGER BURTON H. , DE CASTRO MARCIA CALDAS
Published: July 2010

Abstract:The purpose of this paper is to characterize the interrelationships between macropolitical, social and economic policies, human migration, agricultural development, and malaria transmission on the Amazon frontier. We focus our analysis on a recent colonization project, POLONOROESTE, in the state of Rondônia. Employing data from field surveys in 1985‐1987 and 1995, we use spatial statistical methodologies linked to a geographical information system (GIS) to describe the patterns of human settlement in the area, the ecological transformations induced by forest clearance practices, and the manner in which these factors determine gradations of malaria risk. Our findings show that land use patterns, linked to social organization of the community and the structure of the physical environment, played a key role in promoting malaria transmission. In addition, the location of each occupied area is itself an important determinant of the pattern of malaria risk. Based on lessons learned from our spatial and temporal characterization of malaria risk, we propose policies for malaria mitigation in the Brazilian Amazon.
Assessing Serial Irregularity and Its Implications for Health
Authors: PINCUS STEVEN M.
Published: July 2010

Abstract: Approximate entropy (ApEn) is a recently formulated family of parameters and statistics quantifying regularity (orderliness) in serial data, with developments within theoretical mathematics as well as numerous applications to multiple biological contexts. We discuss the motivation for ApEn development, from the study of inappropriate application of dynamical systems (complexity) algorithms to general time‐series settings. ApEn is scale invariant and model independent, evaluates both dominant and subordinant patterns in data, and discriminates series for which clear feature recognition is difficult. ApEn is applicable to systems with at least 50 data points and to broad classes of models: it can be applied to discriminate both general classes of correlated stochastic processes, as well as noisy deterministic systems. Moreover, ApEn is complementary to spectral and autocorrelation analyses, providing effective discriminatory capability in instances in which the aforementioned measures exhibit minimal distinctions. Representative ApEn applications to human aging studies, based on both heart rate and endocrinologic (hormonal secretory) time series, are featured. Heart rate (HR) studies include gender‐ and age‐related changes in HR dynamics in older subjects, and analyses of “near‐SIDS” infants. Endocrinologic applications establish clear quantitative changes in joint LH‐testosterone secretory dynamics in older versus younger men (a “partial male menopause”), via cross‐ApEn, a related two‐variable asynchrony formulation; a disruption in LH‐FSH‐NPT (penile tumescence) synchrony in older subjects; and changes in LH‐FSH secretory dynamics across menopause. The capability of ApEn to assess relatively subtle disruptions, typically found earlier in the history of a subject than mean and variance changes, holds the potential for enhanced preventative and earlier interventionist strategies.
New Data and Tools for Integrating Discrete and Continuous Population Modeling Strategies
Authors: KOOPMAN JAMES S. , JACQUEZ GEOFFREY , CHICK STEPHEN E.
Published: July 2010

Abstract:Realistic population models have interactions between individuals. Such interactions cause populations to behave as systems with nonlinear dynamics. Much population data analysis is done using linear models assuming no interactions between individuals. Such analyses miss strong influences on population behavior and can lead to serious errors—especially for infectious diseases. To promote more effective population system analyses, we present a flexible and intuitive modeling framework for infection transmission systems. This framework will help population scientists gain insight into population dynamics, develop theory about population processes, better analyze and interpret population data, design more powerful and informative studies, and better inform policy decisions. Our framework uses a hierarchy of infection transmission system models. Four levels are presented here: deterministic compartmental models using ordinary differential equations (DE); stochastic compartmental (SC) models that relax assumptions about population size and include stochastic effects; individual event history models (IEH) that relax the SC compartmental structure assumptions by allowing each individual to be unique. IEH models also track each individual's history, and thus, allow the simulation of field studies. Finally, dynamic network (DNW) models relax the assumption of the previous models that contacts between individuals are instantaneous events that do not affect subsequent contacts. Eventually it should be possible to transit between these model forms at the click of a mouse. An example is presented dealing withCryptosporidium. It illustrates how transiting model forms helps assess water contamination effects, evaluate control options, and design studies of infection transmission systems using nucleotide sequences of infectious agents.
Greater Collaboration Across the Disciplines
Authors: WEINSTEIN MAXINE , HERMALIN ALBERT I. , STOTO MICHAEL A. , EVANS V. JEFFERY , EWBANK DOUGLAS , HAAGA JOHN , IBRAHIM MICHEL , MADANS JENNIFER
Published: July 2010

Abstract:This paper reports a panel discussion—Opportunities for and Limitations to Greater Collaboration Across the Disciplines—held at the conference. It highlights the need for greater collaboration between demographers and epidemiologists and notes the institutional and disciplinary challenges to and opportunities for promoting greater cooperation.
Emotion and the Human Brain
Authors: Damasio Antonio R.
Published: July 2010

Abstract:Emotion and feeling are no more elusive than any other complex biological phenomena and can be studied objectively. They play a critical role in cognitive processes such as perception, learning, and decision‐making and are equally critical in the maintenance of health.
Language/Culture/Mind/Brain
Authors: Kuhl Patricia K. , Tsao Feng‐Ming , Liu Huei‐Mei , Zhang Yang , DE Boer Bart
Published: July 2010

Abstract:At the forefront of research on language are new data demonstrating infants' strategies in the early acquisition of language. The data show that infants perceptually “map” critical aspects of ambient language in the first year of life before they can speak. Statistical and abstract properties of speech are picked up through exposure to ambient language. Moreover, linguistic experience alters infants' perception of speech, warping perception in a way that enhances native‐language speech processing. Infants' strategies are unexpected and unpredicted by historical views. At the same time, research in three additional disciplines is contributing to our understanding of language and its acquisition by children. Cultural anthropologists are demonstrating the universality of adult speech behavior when addressing infants and children across cultures, and this is creating a new view of the role adult speakers play in bringing about language in the child. Neuroscientists, using the techniques of modern brain imaging, are revealing the temporal and structural aspects of language processing by the brain and suggesting new views of the critical period for language. Computer scientists, modeling the computational aspects of childrens' language acquisition, are meeting success using biologically inspired neural networks. Although a consilient view cannot yet be offered, the cross‐disciplinary interaction now seen among scientists pursuing one of humans' greatest achievements, language, is quite promising.
Integrated Learning
Authors: Tritton Thomas R.
Published: July 2010

Abstract: On the surface, higher education has served the nation well. An increasing percentage of adults have attended college. Information is widely and freely available to most citizens; the economy is steady; and technological developments appear to offer ever‐increasing improvements in the quality of life. Looking just beneath the surface, though, one realizes that knowledge is fragmented, access to knowledge is not universal, and there are no guarantees that past successes will sustain the future. Thus, it is worth examining how higher learning has contributed to the general prosperity and how education might evolve to address society's evident problems. This essay discusses the core approach of liberal arts in the context of the value—and obstacles—of integration across the traditional disciplines. Critical to the natural sciences is a firm grounding in the central importance of rigorous evidence, while the humanities keep us rooted in the importance of human values. Seeking linkages and connections between these realms is the lively challenge of this conference. The details of curricular design will be of less interest at this juncture than locating the critical issues and discussing how education might serve the goal of unifying knowledge and learning.
The Structure and Biological Features of Fibrinogen and Fibrin
Authors: MOSESSON MICHAEL W. , SIEBENLIST KEVIN R. , MEH DAVID A.
Published: July 2010

Abstract: Fibrinogen and fibrin play important, overlapping roles in blood clotting, fibrinolysis, cellular and matrix interactions, inflammation, wound healing, and neoplasia. These events are regulated to a large extent by fibrin formation itself and by complementary interactions between specific binding sites on fibrin(ogen) and extrinsic molecules including proenzymes, clotting factors, enzyme inhibitors, and cell receptors. Fibrinogen is comprised of two sets of three polypeptide chains termed Aα, Bβ, and γ, that are joined by disulfide bridging within the N‐terminal E domain. The molecules are elongated 45‐nm structures consisting of two outer D domains, each connected to a central E domain by a coiled‐coil segment. These domains contain constitutive binding sites that participate in fibrinogen conversion to fibrin, fibrin assembly, crosslinking, and platelet interactions (e.g., thrombin substrate, Da, Db, γXL, D:D, αC, γA chain platelet receptor) as well as sites that are available after fibrinopeptide cleavage (e.g., E domain low affinity non‐substrate thrombin binding site); or that become exposed as a consequence of the polymerization process (e.g., tPA‐dependent plasminogen activation). A constitutive plasma factor XIII binding site and a high affinity non‐substrate thrombin binding site are located on variant γ′ chains that comprise a minor proportion of the γ chain population. Initiation of fibrin assembly by thrombin‐mediated cleavage of fibrinopeptide A from Aα chains exposes two EA polymerization sites, and subsequent fibrinopeptide B cleavage exposes two EB polymerization sites that can also interact with platelets, fibroblasts, and endothelial cells. Fibrin generation leads to end‐to‐middle intermolecular Da to EA associations, resulting in linear double‐stranded fibrils and equilaterally branched trimolecular fibril junctions. Side‐to‐side fibril convergence results in bilateral network branches and multistranded thick fiber cables. Concomitantly, factor XIII or thrombin‐activated factor XIIIa introduce intermolecular covalent ε‐(γ glutamyl)lysine bonds into these polymers, first creating γ dimers between properly aligned C‐terminal γXL sites, which are positioned transversely between the two strands of each fibrin fibril. Later, crosslinks form mainly between complementary sites on γ chains (forming γ‐polymers), and even more slowly among γ dimers to create higher order crosslinked γ trimers and tetramers, to complete the mature network structure.
The Structure and Function of the αC Domains of Fibrinogen
Authors: WEISEL JOHN W. , MEDVED LEONID
Published: July 2010

Abstract: The αC domains have been localized on fibrinogen and fibrin. Several model systems have been developed to study their functions. Analysis of the amino acid sequence of the αC domains suggested that each is made up of a globular and an extended portion. Microcalorimetry confirmed this result and showed that the two αC domains interact intramolecularly. Electron microscopy of fibrinogen with a monoclonal antibody to the αC domains demonstrated that these regions normally interact with the central portion of the molecule. In the conversion from fibrinogen to fibrin there is a large scale conformational change, such that the αC domains dissociate from the central region and are available for intermolecular interaction. Experiments with highly purified and well characterized fragment X monomer, missing either one or both of the αC domains, indicate that intermolecular interactions between αC domains are important for the enhancement of lateral aggregation during fibrin polymerization. Isolated αC fragments polymerized at neutral pH and interacted with the αC domains of fibrin monomer to influence clot formation. Several dysfibrinogenemias in which there are amino acid substitutions in, or truncations of, the αC domains revealed that these changes can have dramatic effects on polymerization and clot structure. The polymerization of Aα251 recombinant fibrinogen, that contains Aα chains truncated at residue 251, was altered, as were the mechanical properties and the rate of fibrinolysis of the clots. Altogether, these results help to define the role of the αC domains in determining the structure and properties of clots.
Recognition of Fibrinogen by Leukocyte Integrins
Authors: UGAROVA TATIANA P. , YAKUBENKO VALENTIN P.
Published: July 2010

Abstract: Numerous studies have provided evidence that fibrinogen plays a multifaceted role in the immune and inflammatory response. The ability of fibrinogen to participate in the inflammatory response depends on its specific interaction with leukocyte cell surface adhesion receptors, integrins. Two leukocyte integrins, αMβ2 (CD11b/CD18, Mac‐1) and αXβ2 (CD11c/CD18, p150,95), are the main fibrinogen receptors expressed on neutrophils, monocytes, macrophages and several subsets of lymphocytes. The recognition site for αMβ2 has been previously mapped to the carboxyl‐terminal globular γC domains (γ143–411) and two sequences, γ190–202 (P1) and γ377–395 (P2), were implicated as the putative binding sites. We now demonstrate that a second leukocyte integrin, αXβ2, which is highly homologous to αMβ2, mediates adhesion of the αXβ2‐bearing cells to the D fragment and to the recombinant γ‐module, γ143–411. Within the γC domain, αXβ2 may recognize P1 and P2 sequences since synthetic peptides duplicating these sequences effectively inhibits adhesion of the αXβ2‐expressing cells to the D fragment. In addition, neutrophil inhibitory factor, NIF, a potent inhibitor of αXβ2, also inhibited αXβ2‐mediated cell adhesion. These data suggest that recognition of the γC domain of fibrinogen by αMβ2 and αXβ2 may have common structural requirements.
Interaction of Fibrin with VE‐Cadherin
Authors: MARTINEZ JOSÉ , FERBER ANDRÉS , BACH TAMI L. , YAEN CHRISTOPHER H.
Published: July 2010

Abstract: The conversion of fibrinogen into fibrin and the association of fibrin(ogen) with activated platelets play a fundamental role in hemostasis because their interaction with the injured vessel prevents blood extravasation. Platelet aggregates and fibrin also participate in the occlusion of the vascular lumen in pathological conditions. Fibrin II also promotes the formation of new blood vessels, for example, during wound healing and tumor growth. Using an in vitro assay, we have studied the mechanism by which fibrin II induces formation of capillaries. Generation of fibrin II on top of an endothelial cell monolayer rapidly rearranged the ECs into a capillary network. In contrast, neither fibrin I nor fibrin 325 induced these morphogenetic changes, indicating that exposure of the N‐terminal peptide β15–42 is involved in this process. Binding studies, using the N‐terminal fragment of fibrin (NDSK II), showed that NDSK II binds to EC with high affinity, but neither NDSK nor NDSK325 bound specifically. Binding of NDSK II to endothelial cells was blocked with an antibody to VE‐cadherin. Direct association of NDSK II and VE‐cadherin was also demonstrated in a VE‐cadherin antibody capture assay. NDSK II bound specifically with the captured VE‐cadherin but NDSK or NDSK 325 did not associate with VE‐cadherin. Moreover, fibrin II associated with EC VE‐cadherin and this interaction triggered the formation of capillary‐like structures. A better understanding of the cellular responses to fibrin, identification of the fibrin binding site within VE‐cadherin and the intracellular signaling that follows this interaction, could yield important information that may translate into better control of the angiogenic process.
A New Model for in Vitro Clot Formation that Considers the Mode of the Fibrin(ogen) Contacts to Platelets and the Arrangement of the Platelet Cytoskeleton
Authors: MORGENSTERN EBERHARD , DAUB MATTHIAS , DIERICHS ROLF
Published: July 2010

Abstract: The constitution of platelet‐fibrin(ogen) contacts, the separation of the platelets initially aggregated, and the rearrangement of the platelet cytoskeleton during clot formation (0.5 to 60 minutes after thrombin stimulation) were investigated using ultrastructural and immunocytochemical techniques. After aggregation, fibrin polymerizing within focal contacts and from degranulating secretory granules contributed to the fibers. The initially formed focal contacts with fibrin obviously persisted during clot formation. The physiological branching of the fibers enabled separation of platelets. The contact associated cytoskeleton formed a constricting and fiber internalizing sphere, but later stress fiber like bundles. As retraction progressed, the cytoskeleton changed to stress fiber connecting focal contacts with fibers. A model of clot formation in vitro is presented that reflects both the contributions of platelets (fibrin fiber internalization and retraction) and of fibers (branching) enabling the retraction.
Genetic and Immunological Characterization of Fibrinogen Inclusion Bodies in Patients with Hepatic Fibrinogen Storage and Liver Disease
Authors: MEDICINA DANIELA , FABBRETTI GIOVANNA , BRENNAN STEPHEN O. , GEORGE PETER M. , KUDRYK BO , CALLEA FRANCESCO
Published: July 2010

Abstract: Fibrinogen storage in liver cells can occur under three different morphological inclusions. Type I contain all three fibrinogen chains (Aα, Bβ, and γ) as well as D and E fragments, whereas type II and III lack Bβ as well as D and E fragments. Patients with type I inclusions carry a point mutation (γ284 Gly‐Arg). The mutation is not present in patients with type II and III inclusions. These results appear to suggest that the three various phenotypic expressions (i.e., morphological variants) reflect different genetical abnormalities of fibrinogen.
Fibrinogen Polymorphisms and Atherothrombotic Disease
Authors: GREEN F.R.
Published: July 2010

Abstract: Common polymorphisms of the fibrinogen gene cluster are associated with circulating fibrinogen level and with susceptibility to and/or severity of atherothrombotic disease. The frequencies of the polymorphisms vary among different ethnic groups but there is strong linkage disequilibrium at the β‐fibrinogen gene locus so that, in caucasian populations, there are only four common β‐fibrinogen haplotypes. One of these haplotypes, defined by the β‐fibrinogen −455A allele, is associated with elevated fibrinogen level and increased risk of atherothrombotic disease. The molecular mechanism of these associations is currently under investigation.
Fibrinogen and Its Degradation Products as Thrombotic Risk Factors
Authors: LOWE GORDON D.O. , RUMLEY ANN
Published: July 2010

Abstract: Recent meta‐analyses of prospective studies have shown that plasma levels of both fibrinogen and fibrin D‐dimer are independent predictors of ischemic heart disease. Although at present reported studies using different assays do not show heterogeneity, there is a need for prospective comparison of different assays, as well as for development of standards. Collaborative development of the clinical use of these risk predictors is also required. Finally, the causal significance of the associations of fibrinogen and D‐dimer with thrombotic events remains to be established by randomized controlled trials of reduction in their plasma levels.
Antifibrinogen IgG, Fibrinogen, and Clq Complexes Circulating in a Hypodysfibrinogenemic Proband
Authors: GALANAKIS DENNIS K. , HENSCHEN‐EDMAN AGNES , WEISEL JOHN , SPITZER SILVIA
Published: July 2010

Abstract: Circulating antifibrinogen antibodies have been reported in rare afibrinogenemic propositi, apparently occurring following fibrinogen replacement therapy, but immune complexes have not been described. In this report we describe circulating immune complexes formed by a monoclonal antifibrinogen IgG in a heterozygous hypodysfibrinogenemic (Aα 16 Arg → Cys) proband. Estimated by partial protein sequence and by other analyses, each immune complex consisted of one fibrin(ogen), one C1q, and 3–4 IgG molecules. The complexes were cryoprecipitable, a property also displayed by mixtures of proband IgG and normal fibrinogen. Indicating that both D and E domains were necessary for this behavior, cryoprecipitability was abolished by preincubation of the isolated IgG with either isolated normal fibrinogen fragment D100 or E. Consistent with the crossreactivity of the IgG with normal and mutant fibrinogen, the results suggest that the primary epitope resides on a D‐E locus on the fibrin polymer formed by normal and abnormal molecules containing the uncleaved (or mutant) peptide A.
Fibrinogen: A Vascular Risk Factor, Why?
Authors: MIRSHAHI F. , VASSE M. , VINCENT L. , TROCHON V. , POURTAU J. , VANNIER J.P. , LI H. , SORIA J. , SORIA C.
Published: July 2010

Abstract: Fibrinogen is a vascular risk factor. We suggest that it is a marker of cytokine secretion that simultaneously stimulates fibrinogen biosynthesis and vascular modifications responsible for atherothrombosis. Among these cytokines, oncostatin M (OSM) is the most potent cytokine for inducing fibrinogen biosynthesis by hepatocytes, and it could contribute to endothelial cell anomalies involved in the atherothrombotic process. Here we show that OSM acts (1) by inducing the secretion involved in invasion of the vessel wall by monocytes; (2) by inducing angiogenesis it promotes plaque destabilization, rupture, and consequently thrombosis; and (3) by decreasing fibrinolysis on macrovascular endothelial cells.
Effect of Moderate Alcohol Consumption on Fibrinogen Levels in Healthy Volunteers Is Discordant with Effects on C‐Reactive Protein
Authors: SIERKSMA AAFJE , VAN DER GAAG MARTIJN S. , KLUFT CORNELIS , HENDRIKS HENK F.J.
Published: July 2010

Abstract: In a diet‐controlled, crossover trial with 10 middle‐aged men and 9 postmenopausal women, baseline concentrations of fibrinogen influenced the magnitude of decrease of fibrinogen after moderate alcohol consumption. The mechanism of reduction is specific for fibrinogen and unrelated to a reduction in C‐reactive protein.
Drug Addictions
Authors: KREEK MARY JEANNE
Published: July 2010

Abstract:Addiction to alcohol, tobacco, and illicit drugs of abuse continues to be one of the most significant medical, social, and economic problems facing our society. Since the mid‐1960s, addictions have been recognized as diseases. We have hypothesized that three domains of factors contribute to the development and persistence of addictions: inherited or genetic differences in individual physiology, alterations in physiology induced by drugs or alcohol, and environmental or developmental factors. Neurochemical alterations in the brain caused by addictive drugs have a cellular and molecular basis and, in the setting of repeated self‐exposure, which can lead to addiction, these changes may be persistent or even permanent. Such altered molecular, cellular, and neurophysiological “set points” in the brain, in turn, contribute to alterations in behavior with implications for the specific addictive diseases.
Regulation of Opioid Receptors by Cocaine
Authors: UNTERWALD ELLEN M.
Published: July 2010

Abstract:Cocaine is a widely abused psychostimulant. Its direct actions include inhibition of dopamine, serotonin, and norepinephrine reuptake into presynaptic nerve terminals, thereby potentiating the actions of these transmitters in the synapse. A variety of studies have demonstrated that cocaine can also have profound effects on the endogenous opioid system. Compelling evidence points to the importance of mu opioid receptors in human cocaine addiction and craving. Animal studies support these findings and demonstrate that chronic cocaine administration can result in alterations in opioid receptor expression and function as measured by changes in critical signal transduction pathways. This chapter reviews studies on the regulation of opioid receptors as the result of exposure to cocaine.
Neurokinin‐1 Receptor Antagonists Block Acute Cocaine‐Induced Horizontal Locomotion
Authors: KRAFT MADELYNE , AHLUWAHLIA SONIA , ANGULO JESUS A.
Published: July 2010

Abstract: Systemic exposure to neurokinin‐1 receptor antagonists CP099994 or LY306740 prior to cocaine administration (10 mg/kg i.p.) blocks acute, cocaine‐induced horizontal locomotion. CP099994 (30 mg/kg) was delivered i.p. 30 minutes before cocaine exposure, and LY306740 (5 mg/kg) was delivered continuously by osmotic minipump for 12–14 hours before cocaine administration. These results suggest that endogenous substance P acting via neurokinin‐1 receptors is necessary for the expression of acute cocaine‐induced hyperactivity.
Ovarian Hormones Modulate Cocaine‐Induced Locomotor and Stereotypic Activity
Authors: PERROTTI LINDA I. , RUSSO SCOTT J. , FLETCHER HELEN , CHIN JULIET , WEBB TYLER , JENAB SHIRZAD , QUIÑONES‐JENAB VANYA
Published: July 2010

Abstract:Interactions between ovarian hormones and cocaine may underlie gender and estrous cycle differences in cocaine‐induced behavioral and neurochemical alterations. The aim of this study was to further understand how ovarian hormones modulate cocaine‐induced behavioral alterations. Ovariectomized rats received acute or chronic saline or cocaine (15 mg/kg i.p.) administration and were further subdivided into one of four hormone‐treatment conditions: cholesterol (vehicle‐control), estrogen, progesterone, or estrogen+progesterone. Overall, acute and chronic cocaine administration increased all locomotor measurements (total locomotor, ambulatory, and rearing counts). Estrogen administration augmented cocaine‐induced increases in ambulatory and rearing activity. After chronic cocaine administration, rats in the vehicle‐control group developed behavioral tolerance (exhibited by a decrease in activity) in rearing and ambulatory activity. Estrogen replacement not only prevented the development of tolerance in ambulatory and rearing activities, but also enhanced total locomotor activity (sensitization) in response to chronic cocaine. Progesterone treatment did not alter the behavioral responses to acute or chronic cocaine administration. Estrogen+progesterone‐treated animals had higher counts of locomotor activity in response to chronic cocaine than did vehicle‐control or progesterone‐treated rats. In stereotypic behaviors, the different hormonal treatments did not affect activity in cocaine‐ or saline‐treated rats after acute or chronic drug administration. Plasma levels of cocaine did not change after different hormonal treatments. Interestingly, animals' coadministered chronic cocaine and estrogen had higher levels of corticosterone than did nonestrogen cocaine‐treated rats. Thus, it is likely that alterations in HPA activation may underlie the observed behavioral differences. In summary, these data suggest that there are interactions between ovarian hormones and cocaine‐induced behavioral alterations in female rats, and they extend previous results by showing that estrogen and progesterone affect the development of sensitization.
Stem Cell Engraftment Strategies
Authors: QUESENBERRY P. J. , STEWART F. M. , BECKER P. , D'HONDT LIONEL , FRIMBERGER A. , LAMBERT J. F. , COLVIN G. A. , MILLER C. , HEYES C. , ABEDI MERHDAD , DOONER M. , CARLSON J. , REILLY J. , McAULIFFE C. , STENCEL K. , BALLEN K. , EMMONS R. , DOYLE P. , ZHONG S. , WANG H. , HABIBIAN H.
Published: July 2010

Abstract: The donor stem cell phenotype and host microenvironment determine the outcome of a stem cell transplant. In a series of transplant studies in syngeneic male to female or congenic Ly5.1/Ly5.2 models in which hosts have received no or minimal irradiation (100 cGy), evidence overwhelmingly supports the concept that syngeneic engraftment is determined by stem cell competition. These approaches can be extended to H‐2 mismatched allogeneic mouse combination when antigen pre‐exposure and CD40‐CD40 ligand antibody blockage are employed. A human trial in patients with resistant neoplasia infusing pheresed blood with 108 CD3 cells/kg showed that tumor responses and complete chimerism occur with very low levels of CD34+ cells/kg and that the extent of previous treatment is a critical factor in determining chimerism. A major feature of transplants is the phenotype of the donor stem cell. This phenotype shows dramatic reversible plasticity involving differentiation, adhesion protein expression, and engraftment with cytokine‐induced cell‐cycle transit. Homing is probably also plastic. Marked fluctuations in engraftment capacity are also seen at different points in marrow circadian rhythm.
Role of the Microenvironment of the Embryonic Aorta‐Gonad‐Mesonephros Region in Hematopoiesis
Authors: NISHIKAWA MITSUO , TAHARA TOMOYUKI , HINOHARA ATSUSHI , MIYAJIMA ATUSHI , NAKAHATA TATSUTOSHI , SHIMOSAKA AKIHIRO
Published: July 2010

Abstract: Although various cytokines, growth factors, and chemokines are known to regulate hematopoiesis, expansion of hematopoietic stem cells (HSCs) in vitro with the use of such agents has proved problematic. Stromal cells are major components of the microenvironment that surrounds hematopoietic cells and are thought to play an important role in hematopoiesis in vivo. Co‐culture of HSCs with stromal cells promotes hematopoiesis and self‐renewal of HSCs. Definitive hematopoietic cells first appear during mammalian embryonic development in the aorta‐gonad‐mesonephros (AGM) region, and it is therefore thought that the microenvironment of this region plays an important role in HSC ontogeny. We have adopted two approaches to studying the contribution of the AGM microenvironment to hematopoiesis. In the first approach, we have developed an in vitro culture system for mouse AGM explants. Hematopoiesis is enhanced in such cultures by the presence of the combination of stem cell factor (SCF), basic fibroblast growth factor, leukemia inhibitory factor, and oncostatin M (SFLO culture). However, transplantation assays revealed that HSCs capable of long‐term reconstitution of the hematopoietic compartment of irradiated mice (LTR‐HSCs) do not expand in AGM‐SFLO cultures; rather, these cultures appear to provide a favorable microenvironment for hematogenic angioblasts that are precursors of both endothelial and hematopoietic cells. In our second approach, we have established various stromal cell lines from the mouse AGM region. The AGM‐S3 cell line supports human and mouse primitive hematopoietic cells as well as mouse LTR‐HSCs. Maintenance of LTR‐HSCs is mediated by a mechanism other than SCF signaling through its receptor (c‐Kit). These two in vitro approaches should prove useful for further elucidation of the mechanisms that underlie hematopoiesis and HSC self‐renewal.
Hematopoietic Growth Factor Mimetics
Authors: KAUSHANSKY KENNETH
Published: July 2010

Abstract: Hematopoietic growth factors are glycoproteins of 15–70 kDa. Although much clinical success has been obtained using recombinant proteins produced in mammalian cell lines and in microbial fermentation processes, the full‐length polypeptides necessarily are expensive to produce, require parenteral administration, and in some cases have provoked detrimental immune responses. With the availability of high throughput biological function and receptor binding assays it has become possible to screen millions, if not billions, of randomly produced organic compounds and relatively short peptides to identify lead compounds for the development of small molecular mimetics of hematopoietic growth factors. Herein the strategies used to screen libraries of small molecules and peptides and the successes in finding mimetics and antagonists for/to erythropoietin, granulocyte colony‐stimulating factor, and thrombopoietin are reviewed. Finally, the structural study of mimetic‐receptor complexes has provided us with many molecular details of growth factor‐induced receptor activation and is likely to yield new insights into the molecular basis of hematopoietic signal transduction.
Implications of Mutations in Hematopoietic Growth Factor Receptor Genes in Congenital Cytopenias
Authors: GERMESHAUSEN MANUELA , BALLMAIER MATTHIAS , WELTE KARL
Published: July 2010

Abstract: Mutations in the genes of hematopoietic growth factor receptors as a cause of congenital cytopenia, such as congenital amegakaryocytic thrombocytopenia (CAMT) or severe congenital neutropenia (CN), are discussed. There are striking differences in the relevance of receptor mutations in these diseases. CAMT is a rare disease characterized by severe hypomegakaryocytic thrombocytopenia during the first years of life that develops into pancytopenia in later childhood. In patients with CAMT, we found inherited mutations in c‐mpl, the gene coding for the thrombopoietin receptor, in 8 out of 8 cases. The type of mutation seems to correlate with the clinical course seen in the patients. Functional studies demonstrated defective thrombopoietin (TPO) reactivity in hematopoietic progenitor cells and platelets in CAMT patients. CN is a group of hematopoietic disorders characterized by profound, absolute neutropenia due to a maturation arrest of myeloid progenitor cells. About 10% of all patients develop secondary MDS/leukemia. The malignant progression is associated with acquired nonsense mutations within the G‐CSF receptor gene that lead to the truncation of the carboxy‐terminal cytoplasmic domain of the receptor protein involved in maturation of myeloid progenitor cells. This seems to be one important step in leukemogenesis in CN patients. CAMT is caused by inherited mutations in c‐mpl, the gene for the thrombopoietin receptor, which lead to reduced or absent reactivity to TPO. In contrast, mutations in the G‐CSF receptor in CN are acquired and are most probably connected with progression of the neutropenia into MDS/leukemia as a result of a loss of differentiation signaling.
Nonmyeloablative Hematopoietic Cell Transplantation
Authors: FEINSTEIN LYLE , SANDMAIER BRENDA , MALONEY DAVID , McSWEENEY PETER A. , MARIS MICHAEL , FLOWERS CHRISTOPHER , RADICH JERRY , LITTLE MARIE‐TÉRÈSE , NASH RICHARD A. , CHAUNCEY THOMAS , WOOLFREY ANN , GEORGES GEORGE , KIEM HANS‐PETER , ZAUCHA JAN M. , BLUME KARL G. , SHIZURU JUDITH , NIEDERWIESER DIETGER , STORB RAINER
Published: July 2010

Abstract: Conventional allografting produces considerable regimen‐related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell‐mediated graft‐versus‐tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre‐transplant total‐body irradiation (200 cGy) followed by post‐transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)‐matched sibling donor hematopoietic cell engraftment in 82% of patients (n= 55) without prior high‐dose therapy. The addition of fludarabine (90 mg/m2) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non‐relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2–4 acute graft‐versus‐host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI. With a median follow‐up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long‐term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.
Dendritic Cell‐Based Vaccines in Patients with Hematological Malignancies
Authors: BRUGGER WOLFRAM , SCHNEIDER ANYA , SCHAMMANN THEODORA , DILL PATRICIA , GRÜNEBACH FRANK , BÜHRING HANS‐JÖRG , KANZ LOTHAR , BROSSART PETER
Published: July 2010

Abstract: The epithelial mucin MUC1 is overexpressed on many epithelial malignancies as well as on some B‐cell lymphomas and multiple myelomas. In the present study, we describe MUC1 expression also on primary AML blasts. To analyze the presentation of MUC1‐derived HLA‐A2 restricted peptides by primary AML blasts, we induced MUC1‐specific cytotoxic T‐lymphocytes (CTLs) in vitro using peptide pulsed dendritic cells from HLA‐A2+ healthy donors as antigen‐presenting cells. These CTLs efficiently lysed primary AML blasts that constitutively expressed both MUC1 and HLA‐A2. The specificity of the CTLs was confirmed in a cold target inhibition assay. Our data demonstrate that MUC1‐derived peptides are tumor antigens in AML which could potentially be used for immunotherapeutic approaches.