bluuebunny/crossref_metadata_2025 huggingface dataset:
Parvovirus Infection Suppresses Long-Term Repopulating Hematopoietic Stem Cells
Authors: Segovia José C. , Guenechea Guillermo , Gallego Jesús M. , Almendral José M. , Bueren Juan A.
Published: July 2003

The functional disturbance of self-renewing and multipotent hematopoietic stem cells (HSCs) in viral diseases is poorly understood. In this report, we have assessed the susceptibility of mouse HSCs to strain i of the autonomous parvovirus minute virus of mice (MVMi) in vitro and during persistent infection of an immunodeficient host. Purified 5FU
r
Lin
−
Sca-1
+
primitive hematopoietic precursors were permissive for MVMi genome replication and the expression of viral gene products. The lymphoid and myeloid repopulating capacity of bone marrow (BM) cells was significantly impaired after in vitro infection, although the degree of functional effect proportionally decreased with the posttransplantation time. This indicated that MVMi targets the heterogeneous compartment of repopulating cells with differential affinity and suggests that the virus may persist in some primitive HSCs in the quiescent stage, killing those eventually recruited for proliferative activity. Immunodeficient SCID mice oronasally infected with MVMi were cured of the characteristic virus-induced lethal leukopenia by transplantation of immunocompetent BM grafts. However, two double-stranded viral DNA species, probably uncommon replicative intermediates, remained in the marrow of every transplanted mouse months after infectious virus clearance. Genetic analysis of the rescued mice showed that the infection ensured a stable engraftment of donor hematopoiesis by markedly depleting the pool of endogenous HSCs. The MVMi-induced suppression of HSC functions illustrates the accessibility of this compartment to infection during a natural viral hematological disease. These results may provide clues to understanding delayed hematopoietic syndromes associated with persistent viral infections and to prospective gene delivery to HSCs in vivo.
A Cellular Receptor of Human Rhinovirus Type 2, the Very-Low-Density Lipoprotein Receptor, Binds to Two Neighboring Proteins of the Viral Capsid
Authors: Neumann Emmanuelle , Moser Rosita , Snyers Luc , Blaas Dieter , Hewat Elizabeth A.
Published: July 2003

The very-low-density lipoprotein receptor (VLDL-R) is a receptor for the minor-group human rhinoviruses (HRVs). Only two of the eight binding repeats of the VLDL-R bind to HRV2, and their footprints describe an annulus on the dome at each fivefold axis. By studying the complex formed between a selection of soluble fragments of the VLDL-R and HRV2, we demonstrate that it is the second and third repeats that bind. We also show that artificial concatemers of the same repeat can bind to HRV2 with the same footprint as that for the native receptor. In a 16-Å-resolution cryoelectron microscopy map of HRV2 in complex with the VLDL-R, the individual repeats are defined. The third repeat is strongly bound to charged and polar residues of the HI and BC loops of viral protein 1 (VP1), while the second repeat is more weakly bound to the neighboring VP1. The footprint of the strongly bound third repeat extends down the north side of the canyon. Since the receptor molecule can bind to two adjacent copies of VP1, we suggest that the bound receptor “staples” the VP1s together and must be detached before release of the RNA can occur. When the receptor is bound to neighboring sites on HRV2, steric hindrance prevents binding of the second repeat.
Replication Complex of Human Parechovirus 1
Authors: Krogerus Camilla , Egger Denise , Samuilova Olga , Hyypiä Timo , Bienz Kurt
Published: July 2003

The parechoviruses differ in many biological properties from other picornaviruses, and their replication strategy is largely unknown. In order to identify the viral RNA replication complex in human parechovirus type 1 (HPEV-1)-infected cells, we located viral protein and RNA in correlation to virus-induced membrane alterations. Structural changes in the infected cells included a disintegrated Golgi apparatus and disorganized, dilated endoplasmic reticulum (ER) which had lost its ribosomes. Viral plus-strand RNA, located by electron microscopic (EM) in situ hybridization, and the viral protein 2C, located by EM immunocytochemistry were found on clusters of small vesicles. Nascent viral RNA, visualized by 5-bromo-UTP incorporation, localized to compartments which were immunocytochemically found to contain the viral protein 2C and the
trans
-Golgi marker 1,4-galactosyltransferase. Protein 2C was immunodetected additionally on altered ER membranes which displayed a complex network-like structure devoid of cytoskeletal elements and with no apparent involvement in viral RNA replication. This protein also exhibited membrane binding properties in an in vitro assay. Our data suggest that the HPEV-1 replication complex is built up from vesicles carrying a Golgi marker and forming a structure different from that of replication complexes induced by other picornaviruses.
Human Cellular Nucleic Acid-Binding Protein Zn2+Fingers Support Replication of Human Immunodeficiency Virus Type 1 When They Are Substituted in the Nucleocapsid Protein
Authors: McGrath Connor F. , Buckman James S. , Gagliardi Tracy D. , Bosche William J. , Coren Lori V. , Gorelick Robert J.
Published: July 2003

A family of cellular nucleic acid binding proteins (CNBPs) contains seven Zn2+fingers that have many of the structural characteristics found in retroviral nucleocapsid (NC) Zn2+fingers. The sequence of the NH2-terminal NC Zn2+finger of the pNL4-3 clone of human immunodeficiency virus type 1 (HIV-1) was replaced individually with sequences from each of the seven fingers from human CNBP. Six of the mutants were normal with respect to protein composition and processing, full-length genomic RNA content, and infectivity. One of the mutants, containing the fifth CNBP Zn2+finger (CNBP-5) packaged reduced levels of genomic RNA and was defective in infectivity. There appear to be defects in reverse transcription in the CNBP-5 infections. Models of Zn2+fingers were constructed by using computational methods based on available structural data, and atom-atom interactions were determined by the hydropathic orthogonal dynamic analysis of the protein method. Defects in the CNBP-5 mutant could possibly be explained, in part, by restrictions of a set of required atom-atom interactions in the CNBP-5 Zn2+finger compared to mutant and wild-type Zn2+fingers in NC that support replication. The present study shows that six of seven of the Zn2+fingers from the CNBP protein can be used as substitutes for the Zn2+finger in the NH2-terminal position of HIV-1 NC. This has obvious implications in antiviral therapeutics and DNA vaccines employing NC Zn2+finger mutants.
Microtubule Network Facilitates Nuclear Targeting of Human Cytomegalovirus Capsid
Authors: Ogawa-Goto K. , Tanaka K. , Gibson W. , Moriishi E. , Miura Y. , Kurata T. , Irie S. , Sata T.
Published: July 2003

We assessed the requirement of the host cytoskeleton for the intracytosolic transport of incoming human cytomegalovirus (HCMV) capsids. Treatments with microtubule (MT)-depolymerizing drugs nocodazole and colchicine led to a drastic decrease in levels of IE1 antigen, whereas cytochalasin B had no effect on the level of IE1 as determined by Western blot analyses. Sequential treatment including nocodazole washout and removal of cell surface virion revealed that HCMV entry into the cells occurred normally in the absence of the MT network. This finding was also supported by data obtained by monitoring pUL83 signals with an immunofluorescent assay (IFA). Furthermore, we demonstrated a close association of incoming HCMV capsids with MTs by IFA and ultrastructural analyses. In the absence of the MT network, the capsids which had entered the cytoplasm did not move to close proximity of the nucleus. These data suggest that HCMV capsids associate with the MT network to facilitate their own movement to the nucleus before the onset of immediate-early (IE) gene expression and that this association is required to start efficient IE gene expression.
Mutation of Amino Acids in the Connection Domain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase That Contact the Template-Primer Affects RNase H Activity
Authors: Julias John G. , McWilliams Mary Jane , Sarafianos Stefan G. , Alvord W. Gregory , Arnold Edward , Hughes Stephen H.
Published: July 2003

The crystal structure of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a complex with an RNA-DNA template-primer identified amino acids in the connection domain that make specific contacts with the nucleic acid. We analyzed the effects of mutations in these amino acids by using a one-round HIV-1 vector. Mutations in amino acids in the connection domain generally had small effects on virus titers. To determine whether the mutations affected the level of RNase H activity or the specificity of RNase H cleavage, we used the two-long-terminal-repeat circle junction as a surrogate for the ends of linear viral DNA; specific RNase H cleavages determine the ends of the viral DNA. Several of the mutations in the connection domain affected the frequency of the generation of viral DNAs with aberrant ends. The mutation H361A had the largest effect on the titer and on the generation of DNAs with aberrant ends. H361 contacts the phosphate backbone of the nucleic acid in the same location as amino acid Y501 in the RNase H primer grip. Mutations at Y501 have been shown to decrease the virus titer and affect the specificity of RNase H cleavage. H361A affected the frequency of the generation of linear viral DNAs with aberrant ends, but in general the connection domain mutations had subtle effects on the efficiency of RNase H cleavage. The results of this study suggest that, in addition to its primary role in linking the polymerase and RNase H domains, the connection subdomain has a modest role in binding and positioning the nucleic acid.
Length of Epstein-Barr Virus Termini as a Determinant of Epithelial Cell Clonal Emergence
Authors: Moody Cary A. , Scott Rona S. , Su Tao , Sixbey John W.
Published: July 2003

Reiterated terminal sequences of Epstein-Barr virus (EBV) DNA are numerically heterogeneous among infectious virions, providing a viral measure of clonality in infected cells. After in vitro infection, carcinoma cells bearing EBV episomes with fewer terminal repeats (TRs) proliferated faster. In single-cell clones, TR number varied inversely to the quantity of latent membrane protein 2A (LMP2A) transcripts whose unspliced precursors cross joined TRs. Thus, EBV clonality may reflect selection for a TR number that optimizes LMP2A-enhanced tumor progression, with infection occurring after epithelial cell transformation.
Development of a Novel Surrogate Virus for Human T-Cell Leukemia Virus Type 1: Inhibition of Infection by Osteoprotegerin
Authors: Okuma Kazu , Dalton Kevin P. , Buonocore Linda , Ramsburg Elizabeth , Rose John K.
Published: July 2003

To develop a high-titer surrogate virus for human T-cell leukemia virus type 1 (HTLV-1), we generated recombinant vesicular stomatitis viruses (VSVs) in which the gene encoding the single transmembrane glycoprotein (G) was deleted. Genes encoding HTLV-1 envelope glycoproteins (HTEnv) or HTEnvG hybrid proteins were then inserted into either of two different sites in the VSV genome. The viruses also encoded a green fluorescent protein. With this surrogate virus, we found that a soluble protein, osteoprotegerin (OPG), or an OPG/Fc chimeric protein inhibited the infection of various cell lines. Our experiments indicate that this inhibition resulted from binding of heparan sulfate by OPG.
Human Immunodeficiency Virus Type 1 Primary Isolate Neutralization Resistance Is Associated with the Syncytium-Inducing Phenotype and Lower CD4 Cell Counts in Subtype CRF01_AE-Infected Patients
Authors: Polonis Victoria R. , Souza Mark S. de , Darden Janice M. , Chantakulkij Somsak , Chuenchitra Thippawan , Nitayaphan Sorachai , Brown Arthur E. , Robb Merlin L. , Birx Deborah L.
Published: July 2003

A number of human immunodeficiency virus type 1 (HIV-1) non-B-subtype products have been developed for present or future vaccine trials; in Thailand, several studies using subtype B and/or CRF01_AE vaccines have been conducted. To better characterize the biologic properties of these subtypes, 70 HIV-1 subtype B and E isolates were phenotyped as syncytium-inducing (SI) or non-syncytium-inducing (NSI) isolates and assessed for sensitivity to neutralizing antibody (NAb). A significantly higher number of NSI subtype E viruses were neutralization sensitive than SI subtype E viruses (
P
= 0.009), while no association between viral phenotype and sensitivity to NAb was observed for subtype B (
P
= 0.856), suggesting a difference in the neutralization patterns of subtypes B and E. Strikingly, concurrent CD4 T-cell numbers were significantly lower for subtype E-infected patients whose isolates were more resistant to NAb, both for the overall study group (
P
< 0.001) as well as for the 22 patients with NSI isolates (
P
= 0.013). Characterization of the evolution of biologic properties of both B and non-B HIV-1 subtypes will provide a clearer understanding of the repertoire of antibodies that must be elicited for a vaccine to be effective against all phenotypes and subtypes.
Dissection of Cauliflower Mosaic Virus Transactivator/Viroplasmin Reveals Distinct Essential Functions in Basic Virus Replication
Authors: Kobayashi Kappei , Hohn Thomas
Published: July 2003

Cauliflower mosaic virus (CaMV) transactivator/viroplasmin (Tav) is an essential multifunctional viral protein. Dissection of Tav by deletion mutagenesis revealed that the central region is essential for CaMV replication in single cells but that the N- and C-terminal parts are not. Strains with mutations in the central region were defective in the translational transactivator function and could be complemented by coexpressing Gag (capsid protein precursor) and Pol (polyprotein with protease, reverse transcriptase, and RNase H activity) from separate monocistronic plasmids. In contrast, total omission of Tav was only partially complemented by Gag and Pol overexpression from separate plasmids. These results indicate that CaMV basic replication requires both Tav-activated polycistronic translation and some posttranslational function(s) of Tav that is not affected by the deletions in the central region of Tav.
Structural and Evolutionary Analysis of an Orangutan Foamy Virus
Authors: Verschoor Ernst J. , Langenhuijzen Susan , van den Engel Saskia , Niphuis Henk , Warren Kristin S. , Heeney Jonathan L.
Published: July 2003

The full-length proviral genome of a foamy virus infecting a Bornean orangutan was amplified, and its sequence was analyzed. Although the genome showed a clear resemblance to other published foamy virus genomes from apes and monkeys, phylogenetic analysis revealed that simian foamy virus SFVora was evolutionarily equidistant from foamy viruses from other hominoids and from those from Old World monkeys. This finding suggests an independent evolution within its host over a long period of time.
Identification of a Critical Basic Residue on the Ecotropic Murine Leukemia Virus Receptor
Authors: Qian Zhaohui , Donald Robin , Wang Hongzhe , Chen Qianmin , Albritton Lorraine M.
Published: July 2003

Susceptibility to ecotropic murine leukemia viruses (MLV) is restricted to mice and rats at the level of virus binding to the host cell receptor. Asparagine 232, valine 233, tyrosine 235, and glutamic acid 237 in the third extracellular domain (EL3) of the receptor are critical determinants of the host range difference between mice and humans. However, placing these residues in the human homolog confers only partial binding, indicating that other divergent sequences are involved. We sought to determine if the other sequences lie within or outside EL3. Here we report the identification of lysine 234 as another critical residue that influences virus binding and infection, as well as evidence that the unidentified sequences lie outside EL3. Each of the four basic residues in the third extracellular domain were changed to an acidic residue and initially examined in combination with a change at position 235 or position 237. Substitution of lysine 211, 215, or 222 combined with substitution of the critical tyrosine 235 or glutamic acid 237 did not affect virus infection. However, combined substitution of lysine 234, a conserved residue between mice and humans, and tyrosine 235 resulted in a marked decrease in virus infection and binding. A lysine 234 change alone reduced virus binding, contrary to previous observations that at least two of the other four residues must be changed before binding is reduced. Interestingly, there was no decrease in infection when lysine 234 was replaced in combination with glutamic acid 237. This result suggests that residue 234 may act by influencing the local structure of residues 233 to 235, whereas the presence of a glycine at position 236 may prevent this influence from extending to residue 237. With this report, the involvement of all the residues divergent between mice and humans in the third extracellular domain has been ruled out, suggesting that as yet unidentified determinants lie in other extracellular domains.
A Naturally Occurring Substitution in Human Immunodeficiency Virus Tat Increases Expression of the Viral Genome
Authors: Reza Syed M. , Shen Lin-Ming , Mukhopadhyay Rupa , Rosetti Mihaela , Pe'ery Tsafi , Mathews Michael B.
Published: July 2003

A natural amino acid substitution in the human immunodeficiency virus type 1 (HIV-1) transcriptional activator Tat increases its activity and compensates for deleterious mutations elsewhere in the Tat protein. Substitution of asparagine for threonine 23 increases Tat transactivation of the HIV-1 promoter and the binding of Tat to the cellular kinase positive transcription elongation factor b (P-TEFb). Of nine other position 23 mutations tested, only the serine substitution retained wild-type activity. Correspondingly, asparagine is the most frequent amino acid at this position in HIV-1 isolates, followed by threonine and serine. Asparagine is prevalent in Tat proteins of viruses in clades A, C, and D, which are major etiologic agents of AIDS. We suggest that selection for asparagine in position 23 confers an advantage to the virus, since it can compensate for deleterious mutations in Tat. It may also support the replication of otherwise less fit drug-resistant viruses and permit the emergence of virulent strains.
SURFACE GROWTH WITH TEMPORALLY CORRELATED NOISE
Authors: LAM CHI-HANG , SANDER LEONARD M. , WOLF DIETRICH E.
Published: July 2003

We simulate ballistic deposition with long range temporally correlated noise of bounded amplitude in 1 + 1 dimension. Good agreement with the dynamical renormalization group calculation of Medina et al. is obtained for the scaling exponents when the noise is generated by a version of Mandelbrot's fast fractional Gaussian noise (ffGn) generator. However, using either the original ffGn or a chaotic map generator, other exponents are obtained. We suggest that this difference is due to an extraordinarily slow crossover caused by the existence of an anomalous growth mode incompatible with the KPZ equation. This may have implications on similar model dependent results for recent simulations on growth with power-law noise and spatially correlated noise.
CHAOS, NOISE AND COMPLEX FRACTAL DIMENSIONS
Authors: WEST BRUCE J. , FAN X.
Published: July 2003

Herein we propose a measure to distinguish a chaotic time series from one which is colored noise. We apply rescaled range analysis to the chaotic time series generated by a two-degree-of-freedom, nonintegrable Hamiltonian system, and find a modulated power-law for R/S. The combination of the power-law index and the period of modulation suggests a complex fractal dimension, which may be the signature of chaos. Some residual questions are collected.
THE BEHAVIOR OF A THRESHOLD MODEL OF MARKET PRICE IN STOCK EXCHANGE
Authors: HIRABAYASHI TADASHI , TAKAYASU HIDEKI , MIURA HITOSHI , HAMADA KOICHI
Published: July 2003

We analyze the behavior of deterministic threshold dynamics in a model of stock market. We observe global trends in the virtual market prices and find a kind of phase transition. At the critical region, the macroscopic variable of stock market price shows seemingly stochastic fluctuation with f-2 power spectrum consistent with real economic fluctuations. The maximum Lyapunov exponent is estimated to be slightly positive in short time steps (5 or 10 steps) and, as the observation time becomes longer, it converges to zero. This result indicates that the system is at the edge of chaos.
FIXED SCALE TRANSFORMATION APPROACH TO CLUSTER-CLUSTER AGGREGATION
Authors: PIETRONERO L. , SIDORETTI S. , VESPIGNANI A.
Published: July 2003

The new theoretical framework for fractal growth named Fixed Scale Transformation allows the first analytical study of the process of Cluster-Cluster Aggregation. Detailed results are presented for two dimensions and the value of the fractal dimension computed analytically is in good agreement with the values of the simulations. It is interesting to note that this problem cannot even be formulated from the point of view of the Renormalization Group methods.
LONG RANGE CORRELATION IN HUMAN WRITINGS
Authors: SCHENKEL ALAIN , ZHANG JUN , ZHANG YI-CHENG
Published: July 2003

We study long range correlation in various human writings by mapping them into a simple 1d random walk model. This approach allows us to obtain better quality scaling data than the traditional power spectrum methods. Optimally written computer programs seem to have the highest scaling exponent, i.e., close to that of ideal 1/f noise. Literature, on the other hand, leads to smaller exponents. The Bible, however, has the strongest correlation among the Roman letter writings examined.
MORPHOLOGY OF COBALT ELECTRODEPOSITS
Authors: IMRE ATTILA , VÉRTESY ZOFIA , PAJKOSSY TAMÁS , NYIKOS LAJOS
Published: July 2003

Three-dimensional cobalt deposits with good mechanical properties and stability were grown by electrocrystallization from acidic aqueous solution. The deposits exhibited a rich variety of morphology. Pattern features illustrated with sample pictures are summarized in a morphology diagram giving qualitative morphological properties as a function of solution concentration and deposition time. Gas evolution was seen to play a crucial role in the formation of rounded rather than crystal-like deposits.
CONNECTED LENGTH OF FRACTALS (WHY ARE NUCLEATION AND CRITICAL RELAXATION STEPWISE, WHY POLYMERS DESCRIBE n = 0 SPINS)
Authors: ALEXANDROWICZ Z.
Published: July 2003

A stepwise "growth" process, which divides a fractal cluster into branches of sequentially connected particles, helps us to show the following: A reversible growth of a cluster is dominated by an addition of subunits to (or subtraction from) the branches' ends. Main contribution is due to the smallest subunits, viz. single particles. Two consequences follow. First, large scale aggregation and fragmentation may be safely ignored, which supports the classical nucleation theory. Second, relaxation of a cluster is described by the number of back and forth steps needed to traverse the branches' typical length, which supports a recent theory of critical slowing-down. The growth process also helps us to show that bifurcation is due to a fluctuation, modified by a mutual screening, of the branches' ends. For thermal critical clusters, the screening is determined by two opposing effects: Repulsion due to excluded volume, and attraction due to an "induced-growth" of ends by ends. The resultant determines the clusters' deviation from ideality. However, in the case of the uniformly oriented n = 0 vector spins (with no up-or-down option), there can be no fluctuation and clusters grow without bifurcation. This "explains" why linear real polymers describe critical clusters of n = 0 spins.
FRACTAL SURFACES: MEASUREMENT AND APPLICATIONS IN THE EARTH SCIENCES
Authors: COX B. LEA , WANG J. S. Y.
Published: July 2003

Earth scientists have measured fractal dimensions of surfaces by different techniques, including the divider, box, triangle, slit-island, power spectral, variogram and distribution methods. We review these seven measurement techniques, finding that fractal dimensions may vary systematically with measurement method. We discuss possible reasons for these differences, and point to common problems shared by all of the methods, including the remainder problem, curve-fitting, orientation of the measurement plane, size and direction of the sample. Fractal measurements have been applied to many problems in the earth sciences, at a wide range of spatial scales. These include map data of topography; fault traces and fracture networks; fracture surfaces of natural rocks, both in the field and at laboratory scales; metal surfaces; porous aggregate geometry; flow and transport through heterogeneous systems; and various microscopic surface phenomena associated with adsorption, aggregation, erosion and chemical dissolution. We review these applications and discuss the usefulness and limitations of fractal analysis to these types of problems in the earth sciences.
Liver X Receptor Agonists as Potential Therapeutic Agents for Dyslipidemia and Atherosclerosis
Authors: Lund Erik G. , Menke John G. , Sparrow Carl P.
Published: July 2003

The recent identification of liver X receptors (LXR) as regulators of the cholesterol and phospholipid export pump ABCA1 has raised the possibility that LXR agonists could be developed as HDL-raising agents, possibly also acting on the artery wall to stimulate cholesterol efflux from lipid-laden macrophages. Presently several pharmaceutical companies are working to develop such compounds, which will require finding a path for separating these beneficial effects from the detrimental stimulation of triglyceride synthesis also inherent to LXR agonists. Other challenges to the drug development process include species differences, which makes prediction of in vivo effects of LXR agonists in humans difficult. This review summarizes the present state of knowledge on LXR as a drug target and discusses possible solutions for dissociating the favorable effects of LXR agonists from their unwanted effects.
Quantitative Research and Theory Building: Dubin’s Method
Authors: Lynham Susan A.
Published: July 2003

The problem and the solution. There are a number of strategies and methods that the theory builder can use to develop applied theory. Each strategy and method is informed by assumptions about what makes for knowledge and in turn good theory—and each is a way of seeing and understanding the phenomenon central to the theory. Dubin, a recognized scholar in applied theory building, advocates a theory-then-research strategy and quantitative hypothetico-deductive approach to applied theory building. This chapter focuses on Dubin’s quantitative method of theory building for applied disciplines, a two-part, eight-steptheory-building method as a specific variation of the general method of theory-building research in applied disciplines presented in chapter 1.
Selective enhancement of multipotential hematopoietic progenitors in vitro and in vivo by IL-20
Authors: Liu Ling , Ding Chunjin , Zeng Wei , Heuer Josef G. , Tetreault Jonathan W. , Noblitt Timothy W. , Hangoc Giao , Cooper Scott , Brune Kellie A. , Sharma Ganesh , Fox Niles , Rowlinson Scott W. , Rogers Danise P. , Witcher Derrick R. , Lambooy Peter K. , Wroblewski Victor J. , Miller James R. , Broxmeyer Hal E.
Published: July 2003

In a search for novel growth factors, we discovered that human interleukin-20 (IL-20) enhanced colony formation by CD34+ multipotential progenitors. IL-20 had no effect on erythroid, granulocyte-macrophage, or megakaryocyte progenitors. IL-20 transgenic mice increased the numbers and cell cycling of multipotential but not other progenitors. IL-20 administration to normal mice significantly increased only multipotential progenitor cells, demonstrating that IL-20 significantly influences hematopoiesis, with specificity toward multipotential progenitors. This is the first cytokine with such specificity identified.
Prophylaxis of the antiphospholipid syndrome: a consensus report
Authors: Alarcón-Segovia D , Boffa M C , Branch W , Cervera R , Gharavi A , Khamashta M , Shoenfeld Y , Wilson W , Roubey R
Published: July 2003

Hypothetical circumstances that may require prophylaxis for a potential antiphospholipid syndrome (primary prophylaxis), or in some instances when there already had been some manifestations of the syndrome (secondary prophylaxis), were presented to a panel of experts for their consideration on potential prophylactic intervention. These were subsequently presented to the participants in the First InternationalConsensuson Treatment of the AntiphospholipidSyndrome. In most instances there was consensus in adding low dose aspirin, an exception being aspirin allergy when other antiaggregants could be used in nonpregnant subjects. General measures to prevent thrombosis and other vaso-protective actions should also be provided. Higher risk of fetal loss or thrombosis called for anticoagulation with coumadin in nonpregnant subjects or subcutaneous low molecular weight heparin in pregnant ones. When indicated, prophylaxis of the antiphospholipid syndrome should be provided in systemic lupus erythematosus patients who are being treated for their disease. In no instanceshould corticosteroidsor immunosuppresantsbe given as prophylacticof an antiphospholipid syndrome.
Venous thromboembolism in the antiphospholipid syndrome: management guidelines for secondary prophylaxis
Authors: Meroni P L , Moia M , Derksen R HWM , Tincani A , McIntyre J A , Arnout J MMC , Koike T , Piette J-C , Khamashta M A , Shoenfeld Y
Published: July 2003

Venous thromboembolism(VTE) in patients suffering from the antiphospholipidsyndrome (APS) has been reported in almost any location of the vessel tree and the risk of recurrences has been found in several studies to be more closely associated with the presence of lupus anticoagulant than with the positivity for anti-cardiolipin antibodies. The thrombophilic state of APS raises the problem of the secondary prophylaxis to avoid VTE recurrences. For APS patients with VTE, published data appear to support a longer warfarin treatment if compared with the standard management of anti-phospholipid (aPL)-negative patients with VTE. The question of how long oral anticoagulant treatment should be continued for APS patients, however, remains unanswered. Concerning the intensity of anticoagulation, several authors recommend a target international normalized ratio (INR) between 3.0 and 4.0 to efficiently protect from VTE recurrences.A recentdecisionanalysisstudy does support such a suggestion. On the contrary, in a few prospective studies regimens with lower target INRs appear to be effective, and some authors therefore recommend a target INR of between 2.0 and 3.0. Specific large and prospective trials are needed to address this question. Until such information becomes available, individualized treatment according to the patient’s individual risk factors for both bleeding and thrombosis is the general practice.
Stroke and the antiphospholipid syndrome: consensus meeting Taormina 2002
Authors: Brey R L , Chapman J , Levine S R , Ruiz-Irastorza G , Derksen R HWM , Khamashta M , Shoenfeld Y
Published: July 2003

Ischaemic stroke is the only neurological manifestation accepted as a clinical diagnostic criterion for the antiphospholipidsyndrome (APS). This association is reasonably well established in patients first diagnosed with APS but is less clear in randomly selected stroke patients who test positive on one occasion for antiphospholipid antibodies and who have no other evidence of systemic autoimmune disease. We propose a grading system that posits stroke to be definitely, likely or possibly associated with antiphospholipid antibodies (aPL). Further, there are limited prospective data to determine appropriatetreatment. There is controversy as to whether the presence of aPL even increases risk of a recurrent stroke or other thromboembolic event, although data point to persistent medium-high titre aCL and/or LA as risk factors for recurrence. In the absence of data to guide clinicians on the best treatment, we cannot make strong recommendations as to optimal therapy, nor can we propose clear consensus treatment guidelines.
Cardiac disease in the antiphospholipid syndrome: recommendations for treatment. Committee consensus report
Authors: Lockshin M , Tenedios F , Petri M , McCarty G , Forastiero R , Krilis S , Tincani A , Erkan D , Khamashta M A , Shoenfeld Y
Published: July 2003

The Committee reviewed cardiac involvement in the antiphospholipid antibody syndrome. The Committee’s recommendations are:

Valve abnormalities: anticoagulation is recommended for symptomatic patients with valvulopathy. Prophylactic antiplatelet therapy may be appropriate for asymptomatic patients (recommended by 13/17 experts in an independent review). Committee members disagreed whether corticosteroid therapy is helpful, but agree that distinguishing among presumptive valvulitis (valve thickening on echocardiogram), valve deformity and vegetations is important, as treatment implications may differ.

Occlusive arterial disease (angina, myocardial infarction): the Committee recommends aggressive treatment of all risk factors for atherosclerosis (hypertension, hypercholesterolaemia, smoking) and liberal use of folic acid, B vitamins and cholesterol-lowering drugs (preferably statins). Hydroxychloroquine for cardiac protection in APS patients may be considered. The Committee also recommends warfarin anticoagulationfor those who have suffered thrombosis in the absence of atherosclerosis, but recognizesthat developingdata may support the use of antiplateletagents instead.

Intracardiac thrombi: the Committee recommends intensive warfarin anticoagulation, and consultation with cardiac surgeons when appropriate.

Ventricular dysfunction: the Committee has no recommendations on this aspect of cardiac disease. Pulmonary hypertension: the Committee recommends intensive anticoagulationwith warfarin and clinical trials of bosentan, epoprostenol and other new agents.
Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies
Authors: Chapman J , Rand J H , Brey R L , Levine S R , Blatt I , Khamashta M A , Shoenfeld Y
Published: July 2003

Although many types of neurological disorders and events have been described in association with antiphospholipidantibodies(aPL) and the antiphospholipidsyndrome (APS), only ischaemic stroke is reasonably well established and accepted as a diagnostic criterion for the syndrome. We propose to evaluate, classify and rank the association of other neurological manifestations as possible, probable, or definite according to the data available from clinical studies and animal models. By these criteria, none of the neurologicaldisordersor events such as epilepsy, psychiatricdisease, dementia, transverse myelitis, multiple sclerosis-like disease, chorea, migraine, Guillian-Barrèsyndrome, and sensory-neural hearing loss, can be definitely associated with aPL or APS.
Treatment of pregnant patients with antiphospholipid syndrome
Authors: Tincani A , Branch W , Levy R A , Piette J C , Carp H , Rai R S , Khamashta M , Shoenfeld Y
Published: July 2003

Antiphospholipid Syndrome (APS) has been widely recognized as a risk factor for the recurrence of both thrombosis and pregnancy losses; however the optimal treatment of patients is debatable. The aim of this paper was to establish a consensus among experts on the treatment of APS in pregnancy. A questionnaire that described possible different clinical situations was sent to the International Advisory Board of the 10th International Congress on AntiphospholipidAntibodies. Sixteen experts from different medical branches and different geographic areas sent their replies. The consensus was that treatment for APS pregnant patients should be low molecular weight heparin (LMWH) and low dose aspirin (LDA). The dosage, and frequency of LMWH depends on different situations, including the body weight and past history. Patients with previous thromboses usually receive two injections per day. Warfarin can also be used from 14 to 34 weeks, for patients with previousstroke or severe arterial thromboses. The use of intravenous immunoglobulin (IVIG) seems to be restricted to patients with pregnancy losses despite conventional treatment. The experts usually advised barrier methods of contraception, intrauterine device (if the patient is not taking corticosteroids) or progestins. Oral contraception with oestrogens was usually avoided.
Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines
Authors: Asherson R A , Cervera R , de Groot P G , Erkan D , Boffa M-C , Piette J-C , Khamashta M A , Shoenfeld Y ,   Catastrophic Antiphospholipid Syndrome Registry Project Group
Published: July 2003

The term ‘catastrophic’ antiphospholipid syndrome (APS) is used to define an accelerated form of APS resulting in multiorgan failure. Although catastrophicAPS patients represent less than 1% of all patients with APS, they are usually in a life-threatening medical situation that requires high clinical awareness. The careful and open discussion of several proposals by all participants in the pre-symposium workshop on APS consensus, held in Taormina on occasion of the 10th International Congress on aPL and chaired by Munther A Khamashta and Yehuda Shoenfeld (29 September 2002), has allowed the acceptation of a preliminary set of classification criteria. On the other hand, the optimal management of catastrophicAPS must have three clear aims: to treat any precipitating factors (prompt use of antibioticsif infection is suspected, amputation for any necrotic organ, high awareness in patients with APS who undergo an operation or an invasive procedure), to prevent and to treat the ongoing thrombotic events and to suppress the excessive cytokine ‘storm’. Anticoagulation (usually intravenous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous gammaglobulins and, if associated with lupus flare, cyclophosphamide, are the most commonly used treatments for catastrophic APS patients.
Systemic antiphospholipid syndrome
Authors: Shoenfeld Y
Published: July 2003

The antiphospholipid syndrome (APS) was reported in the early 1980s as a triad of manifestations. Since than it became one of the most systemic conditions. Almost any organ and tissue may be involved in the disease, including the brain, the heart, the placenta, the endocrine system, the blood, the kidneys and many more. In the article it is suggested to add to the syndrome the word systemic in analogy to its sister condition, systemic lupus erythematosus.
Activation of complement mediates antiphospholipid antibody-induced pregnancy loss
Authors: Salmon J E , Girardi G , Holers V M
Published: July 2003

Although it is clear that the specific antigenic reactivityof antiphospholipid(aPL) antibodiesis critical to their effect, the pathogenicmechanisms that resultin injury in vivo are incompletelyunderstood.We hyphothesized that aPL antibodies targeted to the placenta activate complement locally, generating split products that mediate placental injury and lead to foetal loss and growth retardation. To test this hypothesis, we used a murine model of APS in which pregnant mice are injected with human IgG containing aPL antibodies. Mice treated with inhibitors of complement activation and mice deficient in complement components were protected from aPL antibody-inducedfoetal damage. Although the cause of tissue injury in this disease is probably multifactoral, we have shown that complement activation is an absolute requirement for foetal loss and growth restriction and, therefore, that this pathway acts upstream of other important effector mechanisms. Identification of complement activation as a mechanism that is necessary for aPL-induced tissue damage and definition of the complement components necessary to trigger such injury is likely to lead to a better understandingof the pathogenesis of vascular and tissue injury in SLE and to new and improved treatments.
TNF αDNA vaccination prevents clinical manifestations of experimental antiphospholipid syndrome
Authors: Blank M , Krause I , Wildbaum G , Karin N , Shoenfeld Y
Published: July 2003

Naked DNA encoding TNFa was introduced to BALB/c mice with experimental antiphospholipid syndrome (APS) induced by b2GPI. Administration of naked DNA encoding TNFa resulted in the generation of immunological memory to its gene product, associated with elevated circulating anti-TNFa antibodies. Enriched IgG fraction of the mouse anti-TNFa was biologically active since it prevented endothelial cell activation by TNFa, e.g., inhibition of monocyte adhesion to activated endothelial cells (HUVEC). Mice immunized with b2GPI, vaccinated with TNFa DNA at an early stage of disease development, showed decreased titres of circulating anti-b2GPI antibodies as compared to the group of mice vaccinated with a control naked DNA. The reduction of anti-phospholipid antibody production was followed by amelioration of the foetal loss, increased platelet count to normal values as well as normalization of the prolonged aPTT. APS mice which were introduced to the TNFa DNA vector at a later stage of the disease development, showed less improvement in their clinical manifestations. The current study suggests a way in which a DNA vaccine can be employed for induction of a protective immunity in experimental APS.
Oxidized low-density lipoprotein as a risk factor of thrombosis in antiphospholipid syndrome
Authors: Matsuura E , Kobayashi K , Koike T , Shoenfeld Y , Khamashta M A , Hughes G RV
Published: July 2003

β2-Glycoprotein I (β2-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipidsyndrome (APS). We recently reported that oxidized LDL (oxLDL) is subsequently targeted by β2-GPI and anti-β2-GPI auto-Abs and that -carboxyl variants of 7-ketocholesteryl esters, such as 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and 7-ketocholesteryl-12-carboxy (keto) octadodecanoate (oxLig-2), are ligands for β2-GPI ( J Lipid Res 2001; 42: 697; J Lipid Res 2002; 43: 1486). These β2-GPI ligands provide an electrostatic interaction between oxLDL and β2-GPI followed by forming stable complexes (such as Schiff base adducts). The -carboxyl function in these ligands is responsible for β2-GPI binding to oxLDL and the oxLDL-β2-GPI complexes are anti-β2-GPI auto-Ab-dependentlytaken up by macrophages (i.e., by phagocytosis). Our recent observations are consistent with the evidence that β2-GPI co-localizes with lymphocytes and mononuclear cells in human athero-plaques. Thus, autoimmune thrombogenesis (atherogenesis) is linked to interaction of anti-β2-GPI Abs with the β2-GPI-oxLDL complexes. We propose an alternative idea, that an immune response against the β2-GPI-oxLDL complexes may be involved in mechanisms in the development of atherosclerosis, which has been explained by the theory of ‘the response to injury’.
Antiphospholipid antibodies and renal transplantation: a risk assessment
Authors: McIntyre J A , Wagenknecht D R
Published: July 2003

Data from 110 transplanted patients show that the presence of antiphospholipid antibodies (aPL) at the time of transplantation is an important risk factor for early renal allograft failure. Sera were tested for IgG, IgM and IgA to CL, PS, PE and PC. Haemodialysis patients had a significantly higher incidence of aPL compared to patients who did not receive haemodialysis (P 0.0171). aPL-positive ESRD patients on peritoneal dialysis (CAPD) or who had never received haemodialysis were at maximal risk; 100% failure (P 0.0022). aPL-positive patients receiving haemodialysis were not at such risk. Biopsy findings from the failed kidneys show abundant fibrin deposition in the microvasculature. Serial blood samples from transplanted patients showed aPL titres to decrease immediately after transplant and increase after removal of the failed graft, indicating that aPL specifically target the allografts. To confirm this, we were able to isolate aPL from a failed graft after transplant nephrectomy. Ninety-seven per cent of the aPL-positive patients’ historic pre-transplant serum samples demonstrated the presence of the same aPL specificity detected in the final crossmatch sera. The exposure to heparin during haemodialysis suggested to us that heparin reduces the risk of clotting in aPL positive transplant candidates. To lessen the risk of graft loss in aPL positive kidney transplant patients (including CAPD), subcutaneous heparin was administered peri- and post-operatively. To date, none of the heparin-treated aPL-positive transplanted patients suffered an early graft loss. Further, they experienced fewer rejection episodes requiring biopsy and thus are prescribed less steroid therapy than patients not treated with heparin.
HLA-DPB1 alleles association of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus
Authors: Sebastiani G D , Galeazzi M , Tincani A , Scorza R , Mathieu A , Passiu G , Morozzi G , Piette J C , Cervera R , Houssiau F , Smolen J , Nebro A Fernandez , De Ramon E , Goral A Jedryka , Papasteriades C , Ferrara G B , Carcassi C , Bellisai F , Marcolongo R ,   European Concerted Action on Immunogenetics of SLE
Published: July 2003

Our objective was to determine the HLA-DPB1 allele associations of anticardiolipin (aCL) and anti-beta2 GPI (aβ2 GPI) antibodies, and of clinical manifestations of the antiphospholipid syndrome (APS), in systemic lupus erythematosus(SLE). We studied 577 European patients with SLE. aCL and aβ2 GPI antibodies were measured by ELISA. Molecular typing of HLA-DPB1 locus was performed by polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. aCL showed positive association with -DPB1*1501 (P 0.005, OR 7.4), and -DPB1*2301 (P 0.009, OR 3.3). aβ2 GPI showed positive association with -DPB1*0301 (P 0.01, OR 1.9), and -DPB1*1901 (P 0.004, OR 8.1). In addition, livedo reticularis was associated with -DPB1*1401, and Raynaud’s phenomenon with -DPB1*2001. In conclusion, HLA-DPB1 locus may contribute to the genetic predisposition to develop antiphospholipid antibodies and clinical manifestations of the APS in patients with SLE.
Primary anetoderma: a cutaneous sign of antiphospholipid antibodies
Authors: Hodak E , Feuerman H , Molad Y , Monselise Y , David M
Published: July 2003

Although a few reports in recent years have suggested that patients with antiphospholipid antibodies (aPL) are proneto developingprimaryanetoderma(PA), it is still unclearhowoften aPL are detectedin unselected PA patients. We studied nine consecutive PA patients for the presence of autoimmune antibodies and disorders in general and the presence of aPL in particular. Six of the nine patients had clinical evidence of associated autoimmune disorders (Graves’disease and autoimmune haemolysis in one, systemic scleroderma in one, Hashimoto’s thyroiditisin one, alopecia areata in one) and/or signs of hypercoagulability (recurrent fetal loss in two, recurrent strokes in one, recurrent deep vein thrombosis in one). In four of these six patients the onset of PA preceded these signs. Positive aPL was foundin all: anticardiolipin(aCL) in six, anti-β2-glycoprotein-I(aβ2 GPI) in six and lupusanticoagulant (LAC) in four. The most frequent isotype was IgA. Among other autoantibodies found the most frequentlywas antinuclearantibodies.Four of theninepatientsfulfilled thecriteriaforantiphospholipid syndrome (APS). It is concluded that PA is an important cutaneous sign for autoimmune disorders in general and the presence of aPL in particular. Hence, the work-up of these patients should include testingfor LAC as well as forall differentisotypesof aCL andaβ2 GPI. We recommendthat PA be added to the list of the cutaneous manifestations of APS.