bluuebunny/crossref_metadata_2025 huggingface dataset:
Short Interfering RNA-Mediated Inhibition of Herpes Simplex Virus Type 1 Gene Expression and Function during Infection of Human Keratinocytes
Authors: Bhuyan Prakash K. , Karikò Katalin , Capodici John , Lubinski John , Hook Lauren M. , Friedman Harvey M. , Weissman Drew
Published: September 2004

RNA interference (RNAi) is an antiviral mechanism that is activated when double-stranded RNA is cleaved into fragments, called short interfering RNA (siRNA), that prime an inducible gene silencing enzyme complex. We applied RNAi against a herpes simplex virus type 1 (HSV-1) gene, glycoprotein E, which mediates cell-to-cell spread and immune evasion. In an in vitro model of infection, human keratinocytes were transfected with siRNA specific for glycoprotein E and then infected with wild-type HSV-1. RNAi-mediated gene silencing reproduced the small plaque phenotype of a gE-deletion mutant virus. The specificity of gene targeting was demonstrated by flow cytometry and Northern blot analyses. Exogenous siRNA can suppress HSV-1 glycoprotein E expression and function during active infection in vitro through RNAi. This work establishes RNAi as a genetic tool for the study of HSV and provides a foundation for development of RNAi as a novel antiviral therapy.
Np9 Protein of Human Endogenous Retrovirus K Interacts with Ligand of Numb Protein X
Authors: Armbruester Vivienne , Sauter Marlies , Roemer Klaus , Best Barbara , Hahn Steffen , Nty Achille , Schmid Andreas , Philipp Stephan , Mueller Anja , Mueller-Lantzsch Nikolaus
Published: September 2004

We have recently identified Np9 as a novel nuclear protein produced by the human endogenous retrovirus K and were able to document the exclusive presence of
np9
transcript in tumors and transformed cells. With the aim of studying whether Np9 has a role in tumorigenesis, a systematic search for interacting proteins was performed. Here, we identify the RING-type E3 ubiquitin ligase LNX (ligand of Numb protein X) as an Np9-interacting partner. We furthermore show that the interaction involves N- and C-terminal domains of both proteins and can affect the subcellular localization of LNX. LNX has been reported to target the cell fate determinant and Notch antagonist Numb for proteasome-dependent degradation, thereby causing an increase in transactivational activity of Notch. We document that LNX-interacting Np9, like Numb, is unstable and degraded via the proteasome pathway and that ectopic Numb can stabilize recombinant Np9. Combined, these findings point to the possibility that Np9 affects tumorigenesis through the LNX/Numb/Notch pathway.
Integration of Clinical Data, Pathology, and cDNA Microarrays in Influenza Virus-Infected Pigtailed Macaques (Macaca nemestrina)
Authors: Baskin Carole R. , García-Sastre Adolfo , Tumpey Terrence M. , Bielefeldt-Ohmann Helle , Carter Victoria S. , Nistal-Villán Estanislao , Katze Michael G.
Published: September 2004

For most severe viral pandemics such as influenza and AIDS, the exact contribution of individual viral genes to pathogenicity is still largely unknown. A necessary step toward that understanding is a systematic comparison of different influenza virus strains at the level of transcriptional regulation in the host as a whole and interpretation of these complex genetic changes in the context of multifactorial clinical outcomes and pathology. We conducted a study by infecting pigtailed macaques (Macaca nemestrina) with a genetically reconstructed strain of human influenza H1N1 A/Texas/36/91 virus and hypothesized not only that these animals would respond to the virus similarly to humans, but that gene expression patterns in the lungs and tracheobronchial lymph nodes would fit into a coherent and complete picture of the host-virus interactions during infection. The disease observed in infected macaques simulated uncomplicated influenza in humans. Clinical signs and an antibody response appeared with induction of interferon and B-cell activation pathways, respectively. Transcriptional activation of inflammatory cells and apoptotic pathways coincided with gross and histopathological signs of inflammation, with tissue damage and concurrent signs of repair. Additionally, cDNA microarrays offered new evidence of the importance of cytotoxic T cells and natural killer cells throughout infection. With this experiment, we confirmed the suitability of the nonhuman primate model in the quest for understanding the individual and joint contributions of viral genes to influenza virus pathogenesis by using cDNA microarray technology and a reverse genetics approach.
Low pH Is Required for Avian Sarcoma and Leukosis Virus Env-Dependent Viral Penetration into the Cytosol and Not for Viral Uncoating
Authors: Barnard Richard J. O. , Narayan Shakti , Dornadula Geethanjali , Miller Michael D. , Young John A. T.
Published: September 2004

A novel entry mechanism has been proposed for the avian sarcoma and leukosis virus (ASLV), whereby interaction with specific cell surface receptors activates or primes the viral envelope glycoprotein (Env), rendering it sensitive to subsequent low-pH-dependent fusion triggering in acidic intracellular organelles. However, ASLV fusion seems to proceed to a lipid mixing stage at neutral pH, leading to the suggestion that low pH might instead be required for a later stage of viral entry such as uncoating (L. J. Earp, S. E. Delos, R. C. Netter, P. Bates, and J. M. White. J. Virol. 77:3058-3066, 2003). To address this possibility, hybrid virus particles were generated with the core of human immunodeficiency virus type 1 (HIV-1), a known pH-independent virus, and with subgroups A or B ASLV Env proteins. Infection of cells by these pseudotyped virions was blocked by lysosomotropic agents, as judged by inhibition of HIV-1 DNA synthesis. Furthermore, by using HIV-1 cores that contain a Vpr-β-lactamase fusion protein (Vpr-BlaM) to monitor viral penetration into the cytosol, we demonstrated that virions bearing ASLV Env, but not HIV-1 Env, enter the cytosol in a low-pH-dependent manner. This effect was independent of the presence of the cytoplasmic tail of ASLV Env. These studies provide strong support for the model, indicating that low pH is required for ASLV Env-dependent viral penetration into the cytosol and not for viral uncoating.
Memory T-Cell-Mediated Immune Responses Specific to an Alternative Core Protein in Hepatitis C Virus Infection
Authors: Bain Christine , Parroche Peggy , Lavergne Jean Pierre , Duverger Blandine , Vieux Claude , Dubois Valérie , Komurian-Pradel Florence , Trépo Christian , Gebuhrer Lucette , Paranhos-Baccala Glaucia , Penin François , Inchauspé Geneviève
Published: September 2004

In vitro studies have described the synthesis of an alternative reading frame form of the hepatitis C virus (HCV) core protein that was named F protein or ARFP (alternative reading frame protein) and includes a domain coded by the +1 open reading frame of the RNA core coding region. The expression of this protein in HCV-infected patients remains controversial. We have analyzed peripheral blood from 47 chronically or previously HCV-infected patients for the presence of T lymphocytes and antibodies specific to the ARFP. Anti-ARFP antibodies were detected in 41.6% of the patients infected with various HCV genotypes. Using a specific ARFP 99-amino-acid polypeptide as well as four ARFP predicted class I-restricted 9-mer peptides, we show that 20% of the patients display specific lymphocytes capable of producing gamma interferon, interleukin-10, or both cytokines. Patients harboring three different viral genotypes (1a, 1b, and 3) carried T lymphocytes reactive to genotype 1b-derived peptides. In longitudinal analysis of patients receiving therapy, both core and ARFP-specific T-cell- and B-cell-mediated responses were documented. The magnitude and kinetics of the HCV antigen-specific responses differed and were not linked with viremia or therapy outcome. These observations provide strong and new arguments in favor of the synthesis, during natural HCV infection, of an ARFP derived from the core sequence. Moreover, the present data provide the first demonstration of the presence of T-cell-mediated immune responses directed to this novel HCV antigen.
Immediate-Early Expression of the Herpes Simplex Virus Type 1 ICP27 Transcript Is Not Critical for Efficient Replication In Vitro or In Vivo
Authors: Sun Aixu , Devi-Rao G. V. , Rice M. K. , Gary L. W. , Bloom D. C. , Sandri-Goldin R. M. , Ghazal P. , Wagner E. K.
Published: September 2004

We constructed a promoter mutation altering the immediate-early expression of the herpes simplex virus type 1 (HSV-1) ICP27 transcript and its cognate wild-type rescue viruses in order to assess the role of the ICP27 protein in the earliest stages of viral infection by global transcriptional analysis with a DNA microarray. This mutant, ICP27/VP16, replaces the whole ICP27 promoter/enhancer with the VP16 promoter. It demonstrates loss of immediate-early expression of ICP27 according to the criteria expression in the absence of de novo protein synthesis and earliest expression in the kinetic cascade. Significant differences in relative transcript abundances between the mutant and wild-type rescue viruses were limited at the earliest times measured and not evident at all by 4 h after infection. Consistent with this observation, levels of some critical proteins were reduced in the mutant as compared to rescue virus infections at the earliest times tested, but were equivalent by 8 h postinfection. Further, both single and multistep levels of virus replication were equivalent with both mutant and rescue viruses. Thus, altering the immediate-early kinetics of ICP27 leads to a suboptimal quantitative lag phase in gene expression but without consequence for replication fitness in vitro. Infections in vivo also revealed equivalent ability of mutant and rescue viruses to invade the central nervous system of mice following footpad injections. Limitations to an immediate-early role of ICP27 in the biology of HSV are discussed in light of these observations.
Protective Immunoglobulin A and G Antibodies Bind to Overlapping Intersubunit Epitopes in the Head Domain of Type 1 Reovirus Adhesin σ1
Authors: Helander Anna , Miller Cathy L. , Myers Kimberly S. , Neutra Marian R. , Nibert Max L.
Published: September 2004

Nonfusogenic mammalian orthoreovirus (reovirus) is an enteric pathogen of mice and a useful model for studies of how an enteric virus crosses the mucosal barrier of its host and is subject to control by the mucosal immune system. We recently generated and characterized a new murine immunoglobulin A (IgA)-class monoclonal antibody (MAb), 1E1, that binds to the adhesin fiber, σ1, of reovirus type 1 Lang (T1L) and thereby neutralizes the infectivity of that strain in cell culture. 1E1 is produced in hybridoma cultures as a mixture of monomers, dimers, and higher polymers and is protective against peroral challenges with T1L either when the MAb is passively administered or when it is secreted into the intestines of mice bearing subcutaneous hybridoma tumors. In the present study, selection and analysis of mutants resistant to neutralization by 1E1 identified the region of T1L σ1 to which the MAb binds. The region bound by a previously characterized type 1 σ1-specific neutralizing IgG MAb, 5C6, was identified in the same way. Each of the 15 mutants isolated and analyzed was found to be much less sensitive to neutralization by either 1E1 or 5C6, suggesting the two MAbs bind to largely overlapping regions of σ1. The tested mutants retained the capacity to recognize specific glycoconjugate receptors on rabbit M cells and cultured epithelial cells, even though viral binding to epithelial cells was inhibited by both MAbs. S1 sequence determinations for 12 of the mutants identified σ1 mutations at four positions between residues 415 and 447, which contribute to forming the receptor-binding head domain. When aligned with the σ1 sequence of reovirus type 3 Dearing (T3D) and mapped onto the previously reported crystal structure of the T3D σ1 trimer, the four positions cluster on the side of the σ1 head, across the interface between two subunits. Three such interface-spanning epitopes are thus present per σ1 trimer and require the intact quaternary structure of the head domain for MAb binding. Identification of these intersubunit epitopes on σ1 opens the way for further studies of the mechanisms of antibody-based neutralization and protection with type 1 reoviruses.
Entry and Transcription as Key Determinants of Differences in CD4 T-Cell Permissiveness to Human Immunodeficiency Virus Type 1 Infection
Authors: Ciuffi Angela , Bleiber Gabriela , Muñoz Miguel , Martinez Raquel , Loeuillet Corinne , Rehr Manuela , Fischer Marek , Günthard Huldrych F. , Oxenius Annette , Meylan Pascal , Bonhoeffer Sebastian , Trono Didier , Telenti Amalio
Published: September 2004

Isolated primary human cells from different donors vary in their permissiveness—the ability of cells to be infected and sustain the replication of human immunodeficiency virus type 1 (HIV-1). We used replicating HIV-1 and single-cycle lentivirus vectors in a population approach to identify polymorphic steps during viral replication. We found that phytohemagglutinin-stimulated CD4+CD45RO+CD57−T cells from healthy blood donors (n= 128) exhibited a 5.2-log-unit range in virus production. For 20 selected donors representing the spectrum of CD4 T-cell permissiveness, we could attribute up to 42% of the total variance in virus production to entry factors and 48% to postentry steps. Efficacy at key intracellular steps of the replicative cycle (reverse transcription, integration, transcription and splicing, translation, and budding and release) varied from 0.71 to 1.45 log units among donors. However, interindividual differences in transcription efficiency alone accounted for 64 to 83% of the total variance in virus production that was attributable to postentry factors. While vesicular stomatitis virus G protein-mediated fusion was more efficacious than CCR5/CD4 entry, the latter resulted in greater transcriptional activity per proviral copy. The phenotype of provirus transcription was stable over time, indicating that it represents a genetic trait.
Construction and Characterization of a Fluorescently Labeled Infectious Human Immunodeficiency Virus Type 1 Derivative
Authors: Müller Barbara , Daecke Jessica , Fackler Oliver T. , Dittmar Matthias T. , Zentgraf Hanswalter , Kräusslich Hans-Georg
Published: September 2004

The introduction of a label which can be detected in living cells opens new possibilities for the direct analysis of dynamic processes in virus replication, such as the transport and assembly of structural proteins. Our aim was to generate a tool for the analysis of the trafficking of the main structural protein of human immunodeficiency virus type 1 (HIV-1), Gag, as well as for the analysis of virus-host cell interactions in an authentic setting. We describe here the construction and characterization of infectious HIV derivatives carrying a label within the Gag polyprotein. Based on our initial finding that a short epitope tag could be inserted near the C terminus of the matrix domain of Gag without affecting viral replication, we constructed HIV derivatives carrying the
egfp
gene at the analogous position, resulting in the expression of a Gag-EGFP fusion protein in the authentic viral context. Particles displaying normal viral protein compositions were released from transfected cells, and Gag-EGFP was efficiently processed by the viral protease, yielding the expected products. Furthermore, particles with mature morphology were observed by thin-section electron microscopy. The modified virus was even found to be infectious, albeit with reduced relative infectivity. By preparing mixed particles containing equimolar amounts of Gag-EGFP and Gag, we were able to obtain highly fluorescently labeled virion preparations which displayed normal morphology and full wild-type infectivity, demonstrating that the process of HIV particle assembly displays a remarkable flexibility. The fluorescent virus derivative is a useful tool for investigating the interaction of HIV with live cells.
African Swine Fever Virus Inhibits Induction of the Stress-Induced Proapoptotic Transcription Factor CHOP/GADD153
Authors: Netherton Christopher L. , Parsley James C. , Wileman Thomas
Published: September 2004

Stress signaling from mitochondria and the endoplasmic reticulum (ER) leads to the induction of the proapoptotic transcription factor CHOP/GADD153. Many viruses use the ER as a site of replication and/or envelopment, and this activity can lead to the activation of ER stress and apoptosis. African swine fever virus (ASFV) is assembled on the cytoplasmic face of the ER and ultimately enveloped by ER membrane cisternae. The virus also recruits mitochondria to sites of viral replication and induces the mitochondrial stress protein hsp60. Here we studied the effects of ASFV on the induction of CHOP/GADD153 in infected cells. Interestingly, unlike other ER-tropic viruses, ASFV did not activate CHOP and was able to inhibit the induction of CHOP/GADD153 by a number of exogenous stimuli.
T-Cell Responses to the M3 Immune Evasion Protein of Murid Gammaherpesvirus 68 Are Partially Protective and Induced with Lytic Antigen Kinetics
Authors: Obar Joshua J. , Donovan Douglas C. , Crist Sarah G. , Silvia Ondine , Stewart James P. , Usherwood Edward J.
Published: September 2004

DNA vaccination with theM3gene, encoding an immune evasion molecule expressed during both the acute lytic and persistent phases of murid gammaherpesvirus 68 infection, yielded a significantly lower titer of virus in the lung than controls. The protection seen was dependent on T cells, and we mapped an epitope recognized by CD8 T cells. The immune response to this epitope follows the same kinetics as lytic cycle antigens, despite the fact that this gene is expressed in both lytic and persistent stages of infection. This has important implications for our understanding of T-cell responses to putative latency-associated gammaherpesvirus proteins and how vaccination may improve control of these viruses.
Quantitative 3-Dimensional Echocardiography for Accurate and Rapid Cardiac Phenotype Characterization in Mice
Authors: Dawson Dana , Lygate Craig A. , Saunders James , Schneider Jürgen E. , Ye Xujiong , Hulbert Karen , Noble J. Alison , Neubauer Stefan
Published: September 2004

Background—

Insufficient techniques exist for rapid and reliable phenotype characterization of genetically manipulated mouse models of cardiac dysfunction. We developed a new, robust, 3-dimensional echocardiography (3D-echo) technique and hypothesized that this 3D-echo technique is as accurate as magnetic resonance imaging (MRI) and histology for assessment of left ventricular (LV) volume, ejection fraction, mass, and infarct size in normal and chronically infarcted mice.

Methods and Results—

Using a high-frequency, 7/15-MHz, linear-array ultrasound transducer, we acquired ECG and respiratory-gated, 500-μm consecutive short-axis slices of the murine heart within 4 minutes. The short-axis movies were reassembled off-line in a 3D matrix by using the measured platform locations to position each slice in 3D. Epicardial and endocardial heart contours were manually traced, and a B-spline surface was fitted to the delineated image curves to reconstruct the heart volumes. Excellent correlations were obtained between 3D-echo and MRI for LV end-systolic volumes (
r
=0.99,
P
<0.0001), LV end-diastolic volumes (
r
=0.99,
P
<0.0001), ejection fraction (
r
=0.99,
P
<0.0001), LV mass (
r
=0.94,
P
<0.0019), and infarct size (
r
=0.98,
P
<0.0001). Also, excellent correlations were found between the 3D-echo–derived LV mass and necropsy LV mass in normal mice (
r
=0.99,
P
<0.0001), as well as for 3D-echo–derived infarct size and histologically determined infarct size (
r
=0.99,
P
<0.0001) in mice with chronic heart failure. Bland-Altman analysis showed excellent limits of agreement between techniques for all measured parameters.

Conclusion—

This new, fast, and highly reproducible 3D-echo technique should be of widespread applicability for high-throughput murine cardiac phenotyping studies.
Akt/Protein Kinase B and Endothelial Nitric Oxide Synthase Mediate Muscular Neovascularization Induced by Tissue Kallikrein Gene Transfer
Authors: Emanueli Costanza , Salis Maria B. , Van Linthout Sophie , Meloni Marco , Desortes Elisa , Silvestre Jean-Sebastien , Clergue Michel , Figueroa Carlos D. , Gadau Sergio , Condorelli Gianluigi , Madeddu Paolo
Published: September 2004

Background—

Angiogenesis gene therapy with human tissue kallikrein (hTK) has shown promise for ischemic disease. The present study was undertaken to (1) assess an optimal gene transfer modality, (2) clarify hTK angiogenic pathways, and (3) discount possible side effects.

Methods and Results—

The hTK gene was transferred to murine adductors by increasing doses of an adenovirus (Ad.hTK). Heterologous protein production was evaluated by ELISA and immunohistochemistry. Structural and functional characteristics of hTK-induced neovascularization were assessed. Muscular endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF)-A mRNA and protein content were evaluated by real-time polymerase chain reaction and Western blotting. The ability of hTK to phosphorylate-activate Akt/protein kinase B (Akt-B) and VEGF receptor 2 (VEGF-R2) was also determined. Implication of the aforementioned mechanisms in Ad.hTK-induced neovascularization was challenged by blocking Akt-B with a dominant-negative Akt construct; NOS with
N
G
-nitro-
l
-arginine methyl ester; and VEGF-A with neutralizing antibody, VEGF-R2 antagonist, or Ad carrying soluble VEGF-R1 gene. We found that 10
7
PFU Ad.hTK led to peak increases in capillary and arteriole density. Newly developed arterioles persisted for up to 8 weeks. Ad.hTK did not change microvascular permeability. Ad.hTK upregulated eNOS mRNA and protein and activated Akt-B through Ser-473 phosphorylation. Inhibitory studies documented that these biochemical events were instrumental to Ad.hTK-induced neovascularization. In contrast, Ad.hTK neither affected VEGF-A and VEGF-R2 levels nor increased VEGF-R2 phosphorylation. Consistently, Ad.hTK-induced neovascularization was not disturbed by any of the different approaches used to block VEGF-A.

Conclusions—

Our findings provide new information on the pathway involved in hTK-induced neoangiogenesis and represent an advancement toward clinical applications with Ad.hTK.
Different Quantitative Apoptotic Traits in Coronary Atherosclerotic Plaques From Patients With Stable Angina Pectoris and Acute Coronary Syndromes
Authors: Rossi Marco L. , Marziliano Nicola , Merlini Piera Angelica , Bramucci Ezio , Canosi Umberto , Belli Guido , Parenti Dennis Zavalloni , Mannucci Pier Mannuccio , Ardissino Diego
Published: September 2004

Background—

Apoptosis in human atherosclerotic coronary plaques possibly causes plaque destabilization by contributing to the weakening and breaking down of the fibrous cap. We tested the hypothesis that apoptosis is quantitatively increased in unstable atherosclerotic plaques.

Methods and Results—

We analyzed the expression of apoptotic genes such as
BAX
,
CASP1
,
FAS
,
FAS L
,
FOS
,
MDM2
,
NFkB2
,
P53
,
PCNA
,
TERT
, and
XRCC1
in coronary plaques collected with directional coronary atherectomy from 15 patients with stable angina and 15 with acute coronary syndromes without ST elevation (ACS). Total RNA was extracted and cDNA was amplified with a specific set of primers and TaqMan probes. Apoptosis was also revealed by DNA laddering. To clarify the source of mRNAs, we performed in situ reverse transcriptase-polymerase chain reaction coupled with immunocytochemistry and found a substantial overlap between the mRNAs of the above genes and vascular smooth muscle cells. Gene expression analysis showed that the proapoptotic genes (ie,
BAX
,
CASP1
,
FAS
,
FAS L
,
FOS
,
NFkB2
,
P53
,
PCNA
) were significantly more expressed (
P
<0.001) in ACS plaques, whereas the antiapoptotic genes (ie,
MDM2
,
TERT
,
XRCC1
) were more transcribed (
P
<0.001) in stable angina plaques. Total gDNA gel electrophoresis identified a laddering pattern in the ACS plaques as evidence of end-point apoptosis. Western blotting substantially confirmed the above data.

Conclusions—

Our findings support the idea that ACS plaques are committed to apoptosis through an established meshwork of gene activation and inactivation, whereas stable angina plaques retain active cell homeostasis and repair mechanisms.
“Early” Class III Drugs for the Treatment of Atrial Fibrillation
Authors: Blaauw Y. , Gögelein H. , Tieleman R.G. , van Hunnik A. , Schotten U. , Allessie M.A.
Published: September 2004

Background—

Currently available antiarrhythmic drugs are only moderately effective against atrial fibrillation (AF) and may cause ventricular proarrhythmia. AVE0118 is a blocker of atrium-specific early K
+
currents (
I
Kur
/
I
to
).

Methods and Results—

Effects of intravenous AVE0118 and dofetilide on atrial effective refractory period (AERP) and inducibility of AF were measured before and after 48-hours of AF-induced electrical remodeling in the goat. During persistent AF (53±19 days), the cardioversion efficacy and effects on atrial wavelength of AVE0118, dofetilide, and ibutilide were evaluated. QT durations were measured during atrial pacing and persistent AF. After 48 hours of AF, the effect of dofetilide on AERP was reduced, and induction of AF was not prevented. In contrast, the class III action of AVE0118 was enhanced, and AF inducibility decreased from 100% to 32% (
P
<0.001). At 1, 3, and 10 mg · kg
−1
· h
−1
, AVE0118 terminated persistent AF in 1 of 8, 3 of 8, and 5 of 8 goats, respectively. Dofetilide and ibutilide terminated AF in 1 of 5 and 2 of 7 goats. AVE0118 0.5, 1.5, and 5 mg/kg prolonged the AERP during AF and increased the fibrillation wavelength from 6.7±0.6 to 8.5±0.5, 9.7±0.5, and 11.2±0.9 cm (
P
<0.01). Whereas dofetilide and ibutilide prolonged QT duration, AVE0118 had no appreciable effect.

Conclusions—

AVE0118 markedly prolongs the AERP during AF without affecting QT duration. Cardioversion of AF was due to an ≈2-fold increase in fibrillation wavelength. Atrium-selective class III drugs like AVE0118 may be a promising new option for safe and effective cardioversion of AF.
Suppression of Acute and Chronic Rejection by Hepatocyte Growth Factor in a Murine Model of Cardiac Transplantation
Authors: Yamaura Kazuhiro , Ito Ken-ichi , Tsukioka Katsuaki , Wada Yuko , Makiuchi Akiko , Sakaguchi Masayuki , Akashima Tomohiro , Fujimori Minoru , Sawa Yoshiki , Morishita Ryuichi , Matsumoto Kunio , Nakamura Toshikazu , Suzuki Jun-ichi , Amano Jun , Isobe Mitsuaki
Published: September 2004

Background—

Although treatment with immunosuppressive agents has contributed to overcoming acute rejection and improving the midterm survival of transplanted hearts, cardiac allograft vasculopathy (CAV) has remained the main cause of primary graft failure. Recent approaches have shown that hepatocyte growth factor (HGF) exhibits cardiotrophic functions. We therefore addressed whether HGF would regulate acute and chronic rejection in cardiac transplantation.

Methods and Results—

We used a murine heterotopic cardiac transplantation model between fully incompatible strains and administered 500 μg · kg
−1
· d
−1
HGF during the initial 14 days after transplantation. The HGF-treated allografts showed significantly prolonged survival (42.3±4.1 days,
P
<0.001) compared with the controls (11.1±0.6 days), with tolerance induction in 47.4%. Histopathologically, the number of infiltrating cells was significantly decreased and myocardial necrosis was less prominent with a reduction of apoptosis in the allografts by HGF treatment during acute rejection. In the long-term surviving allografts, HGF significantly inhibited the development of CAV and interstitial fibrosis. With respect to intragraft cytokine mRNA expression, HGF treatment reduced the early expression of interferon-γ and enhanced the expression of transforming growth factor-β1 during the acute phase and of interleukin-10 continuously through the acute phase to the chronic phase.

Conclusions—

Our findings demonstrate that HGF can prolong the survival of allografts by its cardioprotective and immunomodulative potencies. Thus, HGF administration may constitute a new therapeutic approach to preventing cardiac graft failure that has not been overcome by conventional immunosuppressive agents.
Endothelial Dysfunction and Damage in Congestive Heart Failure
Authors: Chong Aun Yeong , Blann Andrew D. , Patel Jeetesh , Freestone Bethan , Hughes Elizabeth , Lip Gregory Y.H.
Published: September 2004

Background—Congestive heart failure (CHF) is associated with endothelial perturbation (as defined by flow-mediated endothelial-dependent vasodilation [FMD, an index of endothelial dysfunction], circulating endothelial cells [CECs, an index of endothelial damage], or plasma indexes of endothelial damage/dysfunction [eg, von Willebrand factor (vWf) and soluble thrombomodulin (sTM)]) and raised plasma levels of brain natriuretic peptide (BNP, a peptide hormone associated with left ventricular systolic dysfunction and prognosis). However, the relations between these parameters are unclear.

Methods and Results—To test the hypothesis that there is a relation between endothelial perturbation (defined by FMD, CECs, vWf, and sTM) and BNP in CHF, we studied these indexes in 30 patients with CHF who were compared with 20 age-matched control subjects. FMD, CECs, plasma vWf, and BNP levels (but not sTM) were all abnormal in patients with CHF. There were significant inverse correlations between FMD and vWf (P=0.001), CECs (P=0.002) and BNP (P=0.006) as well as a positive correlation between CECs and vWf (P=0.032). In multivariate analysis, BNP (P<0.001) and FMD (P<0.001) were both independently associated with CHF.

Conclusions—Ample evidence of endothelial cell damage/dysfunction in CHF cannot be fully explained by the variance in plasma BNP per se. Therefore, the routes by which these indexes influence the pathophysiology of CHF as well as predict adverse outcomes may be independent.
Sensitivity and Specificity of Prenatal Features of Physiological Shunts to Predict Neonatal Clinical Status in Transposition of the Great Arteries
Authors: Jouannic Jean-Marie , Gavard Laurent , Fermont Laurent , Le Bidois Jérôme , Parat Sophie , Vouhé Pascal R. , Dumez Yves , Sidi Daniel , Bonnet Damien
Published: September 2004

Background—

Although prenatal diagnosis of transposition of the great arteries (TGA) reduces neonatal mortality, the preoperative course can be complicated in infants with a restrictive foramen ovale (FO) or a ductus arteriosus (DA) constriction. We sought to determine the specificity and sensitivity of prenatal features of physiological shunts in predicting postnatal clinical status in prenatally diagnosed TGA in babies delivered in a tertiary care center providing all facilities for neonatal urgent care.

Methods and Results—

The outcomes of 130 fetuses with TGA were reviewed over a period of 5.5 years. Restriction of the FO and/or constriction of the DA could be analyzed in 119/130 fetuses at 36±2.7 weeks of gestation. Twenty-four out of 119 had at least 1 abnormal shunt (23 FO, 5 DA, and 4 both). Thirteen of 130 neonates had profound hypoxemia (PaO
2
<25 mm Hg) and metabolic acidosis (pH <7.15) in the first 30 minutes and required immediate balloon atrioseptostomy. Two who had abnormal FO and DA died despite aggressive resuscitation. The specificity and sensitivity of the fetal echo in predicting neonatal emergency were 84% and 54%, respectively. The specificity and sensitivity of a combination of restrictive FO and DA constriction were 100% and 31%, respectively.

Conclusions—

Restriction of the FO and/or of the DA has a high specificity to predict the need for emergency neonatal care in fetuses with TGA, but the sensitivity is too low to detect all high-risk fetuses. Exceptional procedures should be considered for fetuses that have a combination of restrictive FO and DA constriction.
Endothelial NO Synthase Genotype and Risk of Preeclampsia
Authors: Serrano Norma C. , Casas Juan P. , Díaz Luis A. , Páez Carolina , Mesa Clara M. , Cifuentes Rodrigo , Monterrosa Alvaro , Bautista Alejandro , Hawe Emma , Hingorani Aroon D. , Vallance Patrick , López-Jaramillo Patricio
Published: September 2004

Polymorphisms in the endothelial NO synthase (eNOS) gene have been evaluated as risk factors for preeclampsia. However, data from small studies are conflicting. We assessed whether eNOS genotypes alter the risk of preeclampsia in a population in which the incidence of this disorder is high. A total of 844 young pregnant women (322 preeclamptic and 522 controls) were recruited from 5 cities. Genotyping for the Glu298Asp, intron-4 and –786T→C polymorphisms in the eNOS gene was conducted. Multivariate odds ratios (ORs) were obtained to estimate the association of individual polymorphisms and haplotypes with preeclampsia risk. No increase in the risk of preeclampsia for the intron-4 or –786T→C polymorphisms was observed under any model of inheritance. In contrast, in women homozygous for the Asp298 allele, the adjusted OR for preeclampsia was 4.60 (95% confidence interval [CI], 1.73 to 12.22) compared with carriers of the Glu298 allele. After a multivariate analysis, carriage of the “Asp298–786C-4b” haplotype was also associated with increased risk of preeclampsia (OR, 2.11 [95% CI, 1.33 to 3.34]) compared with carriers of the “Glu298–786T-4b” haplotype. The eNOS Glu298Asp polymorphism and the Asp298–786C-4b haplotype are risk factors for preeclampsia.
When Sexual and Religious Orientation Collide:
Authors: Haldeman Douglas C.
Published: September 2004

The debate among scholars and gay activists and religious/political activists about the appropriateness and efficacy of conversion therapy has left out a number of individuals for whom neither gay-affirmative nor conversion therapy may be indicated. The present discussion, through the use of case material, offers considerations for the practitioner who seeks to assist same-sex attracted male clients in the integration of their conflicting religious and sexual selves. Issues of attachment, social and family considerations, religious and spiritual factors, and developing familiarity with the gay community are considered. Ethical considerations of treatment are discussed.
Learning about ‘good enough’ through ‘bad enough’: A story of a planned dialogue between israeli jews and palestinians
Authors: Maoz Ifat , Bar-On Dan , Bekerman Zvi , Jaber-Massarwa Summer
Published: September 2004

This study analyzes a dialogue process aimed at building relationships between Jews and Palestinians in Israel using an innovative research approach of following the story of the encounter. It attempts to explore whether such dialogue groups are able, in practice, to actually get away from the unbalanced political–structural conditions of the conflict between them. Usually we try to learn about such processes through successful ‘good enough’ encounters. This study takes the opposite position of looking at what we can learn from an unsuccessful encounter: A ‘bad enough’ one. Analysis of the dynamics that evolved in this dialogue shows the different tactics that were used by two Jewish-Israeli students to control the dialogue and emphasize themes of ‘togetherness’, ‘we want quiet’ and ‘we are all human beings’. We follow the futile attempts made by both other Jewish and Palestinian participants to counter these control attempts and to center the discussion on national identity and conflict. Finally, we discuss ways in which such a dialogue process could have been improved and could have served as a learning experience for its participants.
National Cultural Values and the Evolution of Process and Outcome Discrepancies in International Strategic Alliances
Authors: Kumar Rajesh , Nti Kofi O.
Published: September 2004

The article assesses the role played by national cultural values in shaping the evolution of international strategic alliances. The authors build on a systems dynamic model of alliance evolution in which the developmental path of an alliance depends on how the partners manage process and outcome discrepancies that may emerge during the course of an alliance. They argue that national culture affects alliance evolution by influencing partners’ sensitivity to discrepancy detection, shaping the nature of attributions they make, and by affecting the partners’ reactions to discrepancies. They focus on differences in three value orientations among cultures. Activity orientation, mastery over nature, and assumptions about human nature are the value orientations that affect alliance functioning. The authors argue that alliances are prone to interpretational, attributional, and behavioral conflicts originating from differences in value orientation among partners. The three value orientations are shown to be the most useful in explaining the dynamics of alliances.
Oliver C. Cox and the Chicago School of Sociology
Authors: Johnson Yolanda Y.
Published: September 2004

Oliver C. Cox did a study on the marital trends of Negroes (African Americans) in 1938 and found that the sex ratio and male employment status of a given area could predict the marriage rates for said area. His findings are very similar to present sociological literature on African American marital trends. He is not, however, credited for his foundational role in the genesis of the theory of the marriageable male. He was a student in the Chicago School of Sociology during the tenure of many of the school’s most prominent faculty. Many of these leading faculty members were also his instructors in addition to presiding as president of the American Sociological Association at some point in their careers. Despite his connection to these powerful sociologists, Cox was relegated to the margins of his discipline. He has been successfully hidden from the cannon of marriageable male research.
Analytical Calculation of the Transient Thermoelastic Stresses in Thick Walled Composite Pipes
Authors: Jacquemin F. , Vautrin A.
Published: September 2004

This article aims at assessing the internal stresses in thick laminated pipes, composed of orthotropic plies, subjected to transient thermal fields. The original contribution of the work is to provide novel analytical solutions, based on well-founded assumptions, to compute the internal stresses due to transient thermal fields throughout the pipe thickness, within the framework of thermoelasticity. The structures considered here are thick, laminated and anisotropic pipes of infinite length. They are subjected to heat flux conditions on their inner and outer surfaces due to the environmental conditions. The transient thermal field is determined and the thermoelastic stresses are derived by using the classical equations of solid mechanics and assuming a thermoelastic orthotropic ply behavior. Finally, particular attention is paid to wall thickness effect.
The Cult of the Spanish Civil War in east Germany
Authors: Krammer Arnold
Published: September 2004

The Spanish Civil War of 1936–39, particularly the role of the International Brigades, was of enormous importance in the literature, history and lore of communist East Germany. Despite the loss of the leftist Popular Front republic to Franco’s repressive fascist dictatorship, the war in distant Spain waselevated to near-mythic proportions in the GDR.

In the early days of its postwar existence the communist government found itself without historical roots beyond the Soviet occupation of Eastern Europe — the only point of political and ideological origin to which East Germany could point. The Peasant Uprising and Thomas Münzer were considered, and discarded, as were the revolutions of 1848, Luxemburg and Liebknecht, and the leftist parties of the Weimar years. The Spanish Civil War, however, was perfect. Guns had been raised in communist hands against fascists, while the capitalist West stood helplessly by. The International Brigades became the first armed opposition to Hitler and were seen as the embryo of the invading Red Army.

From government officials to authors, schoolbooks to popular history, the importance of the myth of the Spanish Civil War was surpassed in importance only by that of the October Revolution. High-ranking leaders in the Politburo, military, media, education and literature had all fought in Spain. The problem was that the myth never changed, despite the opening of western archives and the periodic publication of memoirs which disclosed communist errors and ideological murder. The East German public grew bored and confused with their model of socialist obedience and sacrifice at a time when the very foundations of the artificial state were beginning fatally to erode. In the end, the GDR went to its grave clinging to an ossified myth which had become as much a burden as it once had been an inspiration.
The Role of Culture in Interpersonal Relationships
Authors: Lalonde Richard N. , Hynie Michaela , Pannu Manjit , Tatla Sandeep
Published: September 2004

Two studies examined the influence of Eastern cultural heritage on relationship preferences among second generation immigrants to the West, and explicitly tested the mediating roles of interdependence and familial cultural influence in mate preferences. The first used a between-subjects approach to compare the preferred mate attributes of South Asian Canadians (n= 97) to those of Euro-Canadians (n= 89). The second study used a within-subject approach by using the strength of cultural identity of South Asian Canadians (n= 92) as a predictor of preferred attributes. Both studies found a culture influence on “traditional” mate attribute preferences. Moreover, familial cultural influence (e.g., family allocentrism) was a better mediator of the culture-traditional attribute preference relationship than the more generic measure of interdependent self-construal. The results further suggest that a cross-cultural approach, rather than a strength-of-culturalidentity approach, is better suited to tap into non-conscious influences of culture on behavior.
Culture-Level Dimensions of Social Axioms and Their Correlates across 41 Cultures
Authors: Bond Michael Harris , Leung Kwok , Au Al , Tong Kwok-Kit , de Carrasquel Sharon Reimel , Murakami Fumio , Yamaguchi Susumu , Bierbrauer Günter , Singelis Theodore M. , Broer Markus , Boen Filip , Lambert Sophie M. , Ferreira Maria Cristina , Noels Kimberly A. , van Bavel Jay , Safdar Saba , Zhang Jianxin , Chen Lina , Solcova Iva , Stetovska Iva , Niit Toomas , Niit Kaisa-Kitri , Hurme Helena , Böling Mia , Franchi Vijé , Magradze Guguli , Javakhishvili Nino , Boehnke Klaus , Klinger Edgar , Huang Xu , Fulop Marta , Berkics Mihaly , Panagiotopoulou Penny , Sriram Sujata , Chaudhary Nandita , Ghosh Anjali , Vohra Neharika , Iqbal Dien Fakhri , Kurman Jenny , Thein Ram David , Comunian Anna Laura , Ae Son, Kyung , Austers Ivars , Harb Charles , Odusanya Joseph O. T. , Ahmed Zainal A. , Ismail Rosnah , van deVijver Fons , Ward Colleen , Mogaji Andrew , Sam David Lackland , Khan Muhammad Jahan Zeb , Cabanillas William E. , Sycip Ly , Neto Félix , Cabecinhas Rosa , Xavier Paulo , Dinca Margareta , Lebedeva Nadezhda , Viskochil Andrianna , Ponomareva Oksana , Burgess Steven Michael , Oceja Luis , Campo Silvia , Hwang Kwang-Kuo , D’souza June Bernadette , Ataca Bilge , Furnham Adrian , Lewis J. Rees
Published: September 2004

Leung and colleagues have revealed a five-dimensional structure of social axioms across individuals from five cultural groups. The present research was designed to reveal the culture level factor structure of social axioms and its correlates across 41 nations. An ecological factor analysis on the 60 items of the Social Axioms Survey extracted two factors: Dynamic Externality correlates with value measures tapping collectivism, hierarchy, and conservatism and with national indices indicative of lower social development. Societal Cynicism is less strongly and broadly correlated with previous values measures or other national indices and seems to define a novel cultural syndrome. Its national correlates suggest that it taps the cognitive component of a cultural constellation labeled maleficence, a cultural syndrome associated with a general mistrust of social systems and other people. Discussion focused on the meaning of these national level factors of beliefs and on their relationships with individual level factors of belief derived from the same data set.
Identifying National Types: A Cluster Analysis of Politics, Economics, and Conflict
Authors: Wolfson Murray , Madjd-Sadjadi Zagros , James Patrick
Published: September 2004

This article is founded on the assumption that cluster analysis can be used to complement regressionbased techniques to obtain further improvement in systematic understanding of the nexus of politics, economics, and conflict. It assumes such variables form part of a yet to be understood, non-linear, timedependent interactive system. Cluster analysis is used to classify entities into groups and aims toward explanations based on characteristics cutting across the objects in which they are embedded; thus, the analysis seeks a more compelling account of the complex linkages between and among economic, political, and conflict-related variables. Cross-sectional data for 1967, 1974, 1981, 1988, and 1995 from the Dataset on National Attributes is used in the cluster analysis. The data analysis identifies clusters of states based on a range of characteristics. As expected within a time-dependent system, there is evidence of consistent clustering of countries within and across years, along with evidence of change. Several clusters, such as the advanced states, are very stable and indicate patterns that should be explored further with regression analysis.
Accountability, Autonomy, and Academic Freedom in Educator Preparation Programs
Authors: Pullin Diana
Published: September 2004

As external pressures on teacher education programs mount, including recent federal critiques and requirements, institutions and their faculty must consider how they will respond to calls for increased accountability. This article discusses the legal and policy issues associated with the academic freedom claims that might arise in the current atmosphere of increased accountability and diminished autonomy for teacher education programs. It assesses the institutional academic freedom interests of both public and private institutions. It also addresses the potential outcome of academic freedom claims by individual faculty.
An Assessment of Bank of England and National Institute Inflation Forecast Uncertainties
Authors: Wallis Kenneth F.
Published: September 2004

In February 1996 the Bank of England and the National Institute of Economic and Social Research significantly increased the amount of information they published about the uncertainty surrounding their central projections of inflation. In effect, and in different ways, they each began to publish a density forecast of inflation, that is, an estimate of the probability distribution of possible outcomes for future inflation. The Bank represented this graphically, as a set of forecast intervals covering 10, 20, 30, …, 90 per cent of the probability distribution, coloured red, of lighter shades for the outer bands. This was done for inflation forecasts up to eight quarters ahead, and since the distribution becomes increasingly dispersed and the intervals ‘fan out’ as the forecast horizon increases, the chart became known as the ‘fan chart’ (or, rather more informally, and noting its red colour, the ‘rivers of blood’). The National Institute represented the distribution as a histogram, in the form of a table reporting the probabilities of inflation falling in various ranges. These intervals, or ‘bins’ of the histogram, have changed from time to time; those used currently are: less than 1.5 per cent, 1.5 to 2.0 per cent, 2.0 to 2.5 per cent, and so on. The forecasts refer to the fourth quarters of the current and following years, and from the beginning have included not only inflation but also real GDP growth. Fan charts for real GDP growth first appeared in the Bank's Inflation Report in November 1997.