bluuebunny/crossref_metadata_2025 huggingface dataset:
REVIEW OF LISA STERNLIEB, THE FEMALE NARRATOR IN THE BRITISH NOVEL
Authors: FRAWLEY M.
Published: March 2004

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REVIEW OF ANN ARDIS,MODERNISM AND CULTURALCONFLICT, 1880-1922
Authors: FELDMAN J. R.
Published: March 2004

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Americanism Musically: Nation, Evolution, and Public Education at the Columbian Exposition, 1893
Authors: Miller Kiri
Published: March 2004

The Columbian Exposition (the World's Fair in Chicago, 1893) was intended to represent the entire progress of human history, with American civilization as its culminating triumph. The Exposition celebrated the four-hundredth anniversary of Columbus's discovery of the New World; it restaged that discovery in myriad ways: from the display of “savage races” on the Midway to the construction of an emergent American middle class as civilization's newest noble savages, hungry for education. Music was an integral part of the Exposition. America's musical elite took an active role in the fair's promotion and design. The Exposition also stimulated a flood of writing on the nature and future of “truly American” music. This article examines American musical culture at the Exposition, with attention to music as art, science, and commerce three categories at the heart of the Exposition's formal definition of music. The network of mutual reinforcements, contradictions and the related concepts of nation, race, and evolution has powerful implications for the ensuing history of music in America. Analysis of the educational agenda of music at the Exposition suggests it taught its visitors--5 to 10 percent of the American population--a great deal about race, class, nationhood, and their identity as consumers. Reading the musical criticism, speculative philosophy, and patriotic grandstanding that accompanied the fair shows how musical thought of the day relied on evolutionary theory.
THE LIMITS OF STATE SUFFRAGE FOR CALIFORNIA WOMEN CANDIDATES IN THE PROGRESSIVE ERA
Authors: INGEN L.V.
Published: March 2004

California women gained the right to run for the state legislature and Congress when they won the vote in 1911. Coming nine years before the Nineteenth Amendment enfranchised women nationally in 1920, this era of state enfranchisement appeared ripe for women's electoral success. The ongoing national suffrage movement, the California Progressive Party, and the extensive network of California women's clubs could all have worked to advance women's candidacies. Instead, these factors created conditions that undermined women's political ambitions. Not until 1918, when passage of a national suffrage amendment seemed imminent and the power of the Progressive Party in California faded, did women �nd success as candidates. Their delayed victories reveal the limits of state enfranchisement for women's political power.
Mast cells degranulation affects angiogenesis in the rat uterine cervix during pregnancy
Authors: Varayoud J , Ramos J G , Bosquiazzo V L , Muñoz-de-Toro M , Luque E H
Published: March 2004

During pregnancy, it is essential that sufficient nutrients are supplied by the vascular system to support the dramatic modifications of the rat uterine cervix. Angiogenesis refers to the growth of new blood vessels from pre-existing microcirculation and mast cells have been associated with this process. This study examined the modifications of the vascular compartment and the distribution of mast cells on cervical tissue during pregnancy. Using disodium cromoglycate as a mast cell stabilizer, we determined the effects of the mast cell degranulation on cervical angiogenesis. Mast cell distribution and their degranulation status were evaluated by immunohistochemistry. Endothelial cell proliferation was measured by bromodeoxyuridine incorporation. Vascular areas (absolute and relative) and maturation indices were assessed by quantitative immunohistochemistry of von Willebrand factor and α-smooth muscle actin respectively. Mast cells were predominantly observed during the first half of pregnancy in the perivascular zones. The values of bromodeoxyuridine incorporation, absolute vascular area and vascular maturation index exhibited a significant increase throughout pregnancy. All animals that received mast cell stabilizer showed more than 40% of non-degranulated mast cells. Treated rats exhibited a decrease in endothelial proliferation and in relative vascular area; in addition, a large proportion of mature blood vessels was observed, suggesting a diminished level of new vessel formation. The effects of the mast cell stabilizer were sustained beyond the end of treatment. This is the first report that brings evidence that mast cell degranulation could be a necessary process to contribute to the normal angiogenesis of the rat cervix during pregnancy. Further investigations are needed to elucidate the possible implications of abnormal vascular development of the uterine cervix on the physiological process of ripening and parturition.
Sequential development of flagellar defects in spermatids and epididymal spermatozoa of selenium-deficient rats
Authors: Olson Gary E , Winfrey Virginia P , Hill Kristina E , Burk Raymond F
Published: March 2004

In this study cauda epididymal spermatozoa of rats maintained on a selenium-deficient diet for 5 and 7 months exhibited an array of flagellar defects. Spermatids and spermatozoa were analyzed by light and electron microscopy to define the appearance of flagellar abnormalities during spermiogenesis and post-testicular sperm development. Late spermatids of selenium-deficient rats displayed normal structural organization of the flagellar plasma membrane, axoneme, outer dense fibers, fibrous sheath and annulus, but they exhibited a premature termination of the mitochondrial sheath. A comparison of late spermatids and caput epididymal spermatozoa revealed that a late step in flagellar differentiation was the structural remodeling of the annulus and its accompanying fusion with both the fibrous sheath and the mitochondrial sheath. In selenium-deficient animals, however, the annulus failed to fuse with the mitochondrial sheath, generating an apparent weak point in the flagellum. After epididymal passage, cauda epididymal spermatozoa of selenium-deficient animals also exhibited extensive flagellar disorganization resulting from the apparent sliding and extrusion of specific outer dense fiber–doublet microtubule complexes from the proximal and the distal ends of the mitochondrial sheath and the accompanying loss of the midpiece plasma membrane. Only fiber complex number 4 was extruded proximally, whereas fibers 4, 5, 6 and 7 were extruded from the mitochondrial sheath-deficient posterior midpiece. Axonemal fibers 8, 9, 1, 2 and 3 retained their normal geometric relationships. These data suggest that the known loss of male fertility in selenium deficiency results from the sequential development of sperm defects expressed during both spermiogenesis and maturation in the epididymis.
Partial characterization, sperm association and significance of N- and O-linked glycoproteins in epididymal fluid of rhesus monkeys (Macaca mulatta)
Authors: Srivastav Archana , Singh Balvir , Chandra Abhishek , Jamal Farrukh , Khan Mohammad Y , Chowdhury Sunil R
Published: March 2004

The present study investigated regional modifications of glycosylation status, sperm association and functional significance of N- and O-linked glycoproteins in epididymal luminal fluid of the rhesus monkey (Macaca mulatta). The predominant glycoproteins of the epididymal luminal fluid that increase in the extent of glycosylation or unmasking of exposed epitopes in a region-specific, maturation-dependent manner, included those of 150, 116, 68, 64, 58 (N- and O-linked) and 170 kDa (O-linked). The higher expression of 40 (N-linked), 38 (N- and O-linked) and 60, 56 and 33 kDa (O-linked) glycoproteins in the proximal caput epididymal fluid was followed by alteration or reorganization of 60, 38 and 33 kDa (O-linked) glycoproteins in the distal segments of the epididymis. The association of epididymal fluid glycoproteins with maturing spermatozoa was identified by generating polyclonal antiserum against monkey caudal sperm membrane in female albino rabbits. The antiserum crossreacted strongly with 58 and 33 kDa epididymal fluid glycoproteins of monkeys and also reacted with 116, 68, 58, 56 and 33 kDa glycoproteins from Triton X-100 extracts of human spermatozoa, indicating the presence of antigenically related components in both species. The functional significance of epididymal fluid glycoproteins in sperm functions was investigated by raising antiserum against a heavily glycosylated 58 kDa glycoprotein (MEF1) of caudal epididymal fluid, which crossreacted with the Triton X-100 extracts of epididymal spermatozoa of monkey and ejaculated human spermatozoa on immunoblots. In an in vitro micro-sperm agglutination assay, anti-MEF1 serum agglutinated both rat caudal epididymal spermatozoa and human spermatozoa. MEF1 seemed to be involved in fertilization as demonstrated by inhibition of fertility (100%) in female albino rabbits and rats immunized with this protein. A sperm-agglutinating 58 kDa glycoprotein of rhesus monkey epididymis with functional significance in fertility was identified, thus indicating that it is a potential candidate for contraceptive vaccine development.
Minor involvement of somatic growth in the onset of puberty of Hatano high- and low-avoidance rats
Authors: Shirota M , Sato M , Kojima K , Ohta R
Published: March 2004

The present study was planned to examine the effects of somatic growth on the determination of timing of puberty using Hatano high- and low-avoidance rats (HAAs and LAAs); the rats were genetically selected from Sprague–Dawley (SD) rats for good or poor performance in a two-way active avoidance-learning test. Since these two lines were found to have different characteristics, such as body weight at birth, maternal care and timing of male puberty, the present study characterized female puberty in Hatano rats and then compared postnatal growth and timing of puberty between the two lines of rats when they were nursed by foster SD dams. When nursed under biological dams, HAAs became heavier, exhibited vaginal opening at a younger age and first ovulation was accompanied by more oocytes than LAAs. In all of the HAAs, but none of the LAAs, ovulation was induced by a single s.c. injection of 5 IU equine chorionic gonadotropin (eCG) on day 22 after birth. An additional treatment with 10 IU human CG revealed that, in the ovaries of LAAs, a small number of follicles had developed to an ovulable stage as a result of the treatment. The fostering improved somatic growth, and weights of LAAs were sustained at a heavier level than those of fostered HAAs. The fostering, however, did not eliminate the line difference in the timing of puberty of both sexes; it did accelerate the vaginal opening of LAAs but not the balanopreputial separation. Thus, there is a phenotypic difference in the timing of female puberty in Hatano rats exhibiting a different timing of ovarian development in response to gonadotropin. The present study indicates that postnatal somatic growth is not the predominant determinant in the onset of puberty in Hatano rats.
The effect of endotoxin on functional parameters of mammary CID-9 cells
Authors: Safieh-Garabedian B , Mouneimne G M , El-Jouni W , Khattar M , Talhouk R
Published: March 2004

The effect of endotoxin on mammary CID-9 cells, which differentiate in culture and express β-casein, was investigated. Cells in culture supplemented with lactogenic hormones and dripped with EMS-Matrix (EMS-drip), were treated daily with endotoxin (0.5–500 μg/ml). Endotoxin at concentrations of less or equal to 10 μg/ml did not affect cell growth and viability up to 5 days post endotoxin treatment. Endotoxin (0.01–10 μg/ml) was added to the culture medium, upon confluence, and functional parameters were examined within 48 h post endotoxin treatment. Nuclear factor-κB (NF-κB) (p52) increased in nuclear extracts from endotoxin-stimulated cells within 1 h of treatment, while β-casein mRNA and protein expression decreased in a concentration-dependent manner at 24 and 48 h post treatment. Zymography showed that the 72 and 92 kDa gelatinase activity increased in cells at 24 and 48 h post endotoxin treatment at 10 and 50 μg/ml. At the latter concentration, the active form of 72 kDa gelatinase was induced at 48 h. Interleukin-6 and tumor necrosis factor-α levels increased at 1–3 h post endotoxin treatment and peaked at 6 h in cells on plastic and EHS-drip. Nerve growth factor (NGF) levels increased in control and endotoxin-treated cells in a time-dependent manner, and endotoxin increased NGF levels in culture at 6 and 9 h post endotoxin treatment. This study shows that endotoxin activated NF-κB, suppressed β-casein expression and upregulated gelatinases, cytokines and NGF. This model could be used to investigate the role of mammary cells in initiating and propagating inflammation and to test candidate molecules for potential anti-inflammatory properties.
Magnetic Fields as an Investigation Technique and Manipulation Tool for Phthalocyanine Molecular Aggregates
Authors: Boamfa M. I. , Christianen P. C. M. , Engelkamp H. , Nolte R. J. M. , Maan J. C.
Published: March 2004

A polarized absorption spectroscopy (PAS) study of molecular aggregate solutions of phthalocyanine molecules in high magnetic fields is presented. We show that a magnetic field can induce macroscopic ordering of molecular aggregates (MAs), in a clean, non‐contact method, which is well suited for MA manipulation. We also demonstrate that magnetic‐field‐induced alignment in combination with PAS can be used to determine the MA size and the precise position of the absorption lines in concentrated solutions, as well as probe interaggregate interactions.
Nanohomojunction (GaN) and Nanoheterojunction (InN) Nanorods on One‐Dimensional GaN Nanowire Substrates
Authors: Lan Z. H. , Liang C. H. , Hsu C. W. , Wu C. T. , Lin H. M. , Dhara S. , Chen K. H. , Chen L. C. , Chen C. C.
Published: March 2004

The formation of homojunctions and heterojunctions on two‐dimensional (2D) substrates plays a key role in the device performance of thin films. Accelerating the progress of device fabrication in nanowires (NWs) also necessitates a similar understanding in the one‐dimensional (1D) system. Nanohomojunction (GaN on GaN) and nanoheterojunction (InN on GaN) nanorods (NRs) were formed in a two‐step growth process by a vapor–liquid–solid (VLS) mechanism. Ga2O3 nanoribbons were formed using Ni as catalyst in a chemical vapor deposition (CVD) technique and then completely converted to GaN NWs with NH3 as reactant gas. An Au catalyst is used in the second step of the VLS process to grow GaN and InN NRs on GaN NWs using CVD techniques. A morphological study showed the formation of nanobrushes with different structural symmetries and sub‐symmetries in both homogeneous and heterogeneous systems. Structural characterizations showed nearly defect‐free growth of nanohomojunction (GaN) and nanoheterojunction (InN) NRs on 1D GaN NW substrates.
Panchromatic Chromophore Mixtures in an AlPO4‐5 Molecular Sieve: Spatial Separation Effects and Energy Transfer Cascades
Authors: Ganschow M. , Hellriegel C. , Kneuper E. , Wark M. , Thiel C. , Schulz‐Ekloff G. , Bräuchle C. , Wöhrle D.
Published: March 2004

Dye‐loaded AlPO4‐5 single crystals were prepared by microwave‐assisted hydrothermal synthesis from a batch, containing a mixture of three chromophores (Coumarin 40, Rhodamine BE50, and Oxazine 1) differing in their absorption range, molecular dimensions, and solubilities. Confocal fluorescence images reveal a spatial separation effect of the dye molecules, where the slimmer, more‐soluble dye molecule (Coumarin 40) is uniformly distributed in the body of the single crystal, and the bulky and/or less‐soluble ones (Rhodamine BE50, Oxazine 1) are situated in distinct domains. Visible spectra show good panchromatic absorption of visible light. Fluorescence lifetime measurements indicate the presence of an energy transfer cascade of the entirely fixed dye molecules from Coumarin 40 to Oxazine 1. The transfer mechanism is predominantly radiative.
Charge‐Transport Behavior in Aligned Carbon Nanotubes: A Quantum‐Chemical Investigation
Authors: Yang X. , Chen L.‐P. , Shuai Z.‐G. , Liu Y.‐Q. , Zhu D.‐B.
Published: March 2004

Correlated quantum‐chemical calculations are applied to analyze the amplitude of the electronic‐transfer integrals that describe charge transport in interacting carbon nanotubes (CNTs) by investigating the influences of: i) the relative positions of the CNTs, ii) the size of the CNTs, and iii) their chemical impurities. Our results indicate that the mobility of the charge carrier is extremely sensitive to the molecular packing and the presence of chemical impurities. The largest splitting for the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) levels is in the case of perfectly cofacial conformations where hexagons face hexagons in the dimer structure. We found that the diameter of the CNT determines the type of transporting carrier: for CNTs with large diameters hole transport dominates, while for thin CNTs electron transport dominates. In general, the carrier mobility for the perfect CNTs (n ≥ 3) is less pronounced than that of C60 due to their relatively small strain. B‐ and N‐doped CNTs exhibit considerably larger mobilities owing to the possibility of metallic behavior. These results provide a plausible explanation for the high mobility found experimentally in a field‐effect transistor (FET) made from a large‐area, well‐aligned CNT array. In addition, these hole‐rich and electron‐rich dopants imply potential applications in nanoelectronics.
Photogeneration of High Pretilt Angles of Nematic Liquid Crystals by Non‐Polarized Light Irradiation of Azobenzene‐Containing Polymer Films
Authors: Furumi S. , Ichimura K.
Published: March 2004

A vertical‐alignment (VA) cell of nematic liquid crystals (LCs) was prepared using photoirradiated thin films of a poly(methacrylate) with mesogenic moieties of 4‐trifluoromethoxyazobenzene as the side chains. Optical anisotropy was generated by oblique irradiation of the azobenzene‐containing polymer films with non‐polarized UV light, followed by annealing treatment to enhance the photodichroism, which displayed thermal stability. The combination of oblique exposure to non‐polarized UV light and subsequent annealing treatment brought about high pretilt angles of nematic LCs so that a photoaligned VA LC cell was fabricated. The photopatterned LC cell exhibited electro‐optical properties with excellent optical quality when a voltage was applied even after heating at 100 °C for several hours.
High‐Contrast Electrochromism and Controllable Dissolution of Assembled Prussian Blue/Polymer Nanocomposites
Authors: DeLongchamp D. M. , Hammond P. T.
Published: March 2004

To maintain the momentum and impact of the field, assembled materials systems must increasingly incorporate broad functionality to meet real‐world applications. Here we describe nanocomposite films of specially synthesized inorganic Prussian blue (PB) nanoparticles and linear poly(ethylene imine) (LPEI) that possess the unusual functional combination of high‐performance electrochromism for displays and controllable dissolution for drug delivery. Fabrication using layer‐by‐layer (LBL) assembly was followed by spectroelectrochemical characterization, allowing a full composition determination rarely achieved for LBL films. The electrochromic performance of thick LPEI/PB nanocomposites most relevant to applications surpassed that of inorganic PB films with competitive switching speed and superior contrast. Oxidation beyond the primary electrochromic transition removes nanoparticle ionization and can controllably dissolve the films. Because PB is non‐toxic we suggest this mechanism for controlled in‐vivo drug delivery. The performance and multifunctional quality of these nanocomposites promise a strong impact on flexible displays, electrochromic windows, and even biomedical devices.
Molecules with Linear π‐Conjugated Pathways between All Substituents: Omniconjugation
Authors: van der Veen M. H. , Rispens M. T. , Jonkman H. T. , Hummelen J. C.
Published: March 2004

In this paper, omniconjugation is introduced as a topological phenomenon in π‐conjugated systems. Omniconjugated molecules are defined by the fact that they provide direct and fully π‐conjugated pathways between all substituents attached to them. Surprisingly, until now such topologies have never been explicitly recognized or investigated from this point of view. A topological design scheme is presented as a tool, which enables for the systematic construction of this novel class of π‐electron molecular structures. Molecular building blocks with three or more connection points to the external moieties are proposed, which for the first time allows for the interconnection of many functional entities in a fully conjugated manner. In being truly conjugated, these pathways are expected to provide high transmission probabilities for holes and/or electrons. Omniconjugated structures may play an important role in the design of complex electronic circuitry based on organic molecules. On a larger scale, they may also give rise to special material properties. Although omniconjugation is based on a valence‐bond description of the system, it is shown that our concept is in good agreement with results obtained from a molecular‐orbital description of the electron probability distribution in the frontier orbitals.
Morphological Control of Nanoporous Films by the Use of Functionalized Cyclodextrins as Porogens
Authors: Yim J‐H. , Seon J‐B. , Jeong H‐D. , Pu L. S. , Baklanov M. R. , Gidley D. W.
Published: March 2004

Porous cyclic silsesquioxane (CSSQ) thin films containing nanopores (∼ 2 nm) with low dielectric constant (k < 2.2), have been prepared by using various kinds of cyclodextrin (CD) derivatives as porogenic materials. The pore structure, including average pore size and interconnectivity, can be controlled by changing the functional groups of the cyclodextrin derivatives. The pore structure is found to be strongly related to the affinity of the functional groups between CD molecules. The electrical and mechanical properties of the porous thin films were monitored in order to determine the relationship between the pore structure and film properties. The mechanical properties of porous low‐k thin films (total porosity ∼ 30 %) prepared with CD derivatives are found to be correlated with the pore interconnection length. The longer the deduced interconnection length in the thin film, the worse the mechanical properties (such as hardness and modulus) of the thin film, even though the porogen‐induced pore diameters are very small (∼ 2 nm).
Synthesis and Room‐Temperature Ultraviolet Photoluminescence Properties of Zirconia Nanowires
Authors: Cao H. Q. , Qiu X. Q. , Luo B. , Liang Y. , Zhang Y. H. , Tan R. Q. , Zhao M. J. , Zhu Q. M.
Published: March 2004

This paper reports the synthesis of tetragonal zirconia nanowires using template method. An as‐prepared sample was characterized by scanning and transmission electron microscopy. It was found that the as‐prepared materials were tetragonal zirconia nanowires with average diameters of ca. 80 nm and length of over 10 μm. The Raman spectrum showed peaks at 120, 461, and 629 cm–1, which are attributed to the Eg, Eg, and B1g phonon modes of the tetragonal zirconia structure, respectively. The UV‐vis absorption spectrum showed an absorption peak at 232.5 nm (5.33 eV in photon energy). Photoluminescence (PL) spectra of zirconia nanowires showed a strong emission peak at ca. 388 nm at room temperature, which is attributed to the ionized oxygen vacancy in the zirconia nanowires system.
Morphology‐Controlled Growth of Large‐Area Two‐Dimensional Ordered Pore Arrays
Authors: Sun F. , Cai W. , Li Y. , Cao B. , Lei Y. , Zhang L.
Published: March 2004

A solution‐dipping template strategy for large‐area synthesis of morphology‐controlled, ordered pore arrays is reported. The morphology of the pore array can easily be controlled by concentration of the precursor solution and treatment conditions. With decrease of the concentration from a high level to a very low level nanostructured complex (pore–hole, and pore–particle) arrays, through‐pore arrays, and even ring arrays can, in turn, be obtained. The pore size is adjustable over a large range by changing the diameter of the template's latex spheres. This synthesis route is universal and can be used for various metals, semiconductors and compounds on any substrate. Such structures may be useful in applications such as energy storage or conversion, especially in integrated next‐generation nanophotonics devices, and biomolecular labeling and identification.
Mechanical and Structural Properties of BaCrO4 Nanorod Films under Confinement and Shear
Authors: Gourdon D. , Yasa M. , Godfrey Alig A. R. , Li Y. , Safinya C. R. , Israelachvili J. N.
Published: March 2004

Using an X‐ray surface forces apparatus (X‐SFA) we have investigated the effects of normal load (stress) and shear on the ordering and tribological properties of 10 nm × 30 nm surfactant‐coated BaCrO4 nanorods in isooctane, confined within submicrometer films. The film structure and corresponding friction forces were monitored as a function of time and shearing distance at different gap sizes and loads. The X‐ray diffraction patterns indicate a cubic phase of nanorods coexisting with a surfactant phase that depends on the load, film thickness, shear rate, and shearing time. Atomic force microscopy and birefringence measurements performed on each surface after a shearing experiment showed ordered domains of nanorods over length scales of several tens of micrometers.
Step‐by‐Step Construction of the Electronic Structure of Molecular Conductors: Conceptual Aspects and Applications
Authors: Rousseau R. , Gener M. , Canadell E.
Published: March 2004

A qualitative scheme that leads to the step‐by‐step construction of the band structure and Fermi surface of molecular conductors is developed based on a simple analytical treatment as well as some fundamental symmetry and overlap ideas and the concept of folding. This treatment is valuable in that it provides a detailed understanding of how the crystal and electronic structures of molecular conductors are related. Specifically, the proposed perspective clarifies how relatively weak structural changes can result in significant differences in the transport properties of these materials. Molecular conductors with donor layers of the β″‐type are used in order to illustrate the approach.
Investigation of susceptibility loci identified in the UK rheumatoid arthritis whole‐genome scan in a further series of 217 UK affected sibling pairs
Authors: Eyre Stephen , Barton Anne , Shephard Neil , Hinks Anne , Brintnell William , MacKay Kirsten , Silman Alan , Ollier William , Wordsworth Paul , John Sally , Worthington Jane
Published: March 2004

Objective

A previous whole‐genome scan (WGS) of 182 UK rheumatoid arthritis (RA) affected sibling pair (ASP) families suggested linkage to HLA and 11 other chromosome regions. Replication of such findings in an independent cohort can help to distinguish true linkages from false‐positive linkages. Since RA is a heterogeneous disease, some loci may be linked only in subsets of patients. Thus, the aim of this study was to investigate in an additional set of RA ASP families linkage to regions showing deviation in expected allele‐sharing ratios in the UK WGS and to perform subset analysis on the combined cohort.

Methods

Twenty loci were investigated for linkage in 217 Caucasian UK RA ASPs. Stratification analysis was performed on the combined cohort of 377 RA ASP families to account for sex, RA severity, and the shared epitope (SE).

Results

None of the regions of linkage identified in the initial WGS achieved statistical significance in the second cohort. In contrast, after stratification analysis, 14 regions showed nominal evidence of linkage (logarithm of odds score >0.8) in one or more subgroups. In particular, the strength of evidence for linkage to chromosome 16p was increased in subsets of ASPs with younger age at disease onset (LOD score 2.38) and for linkage to chromosome 6q in female–female ASPs (LOD score 2.31) and in ASPs in which both siblings had 2 copies of the SE (LOD score 3.03).

Conclusion

These results support the evidence for heterogeneity of RA. This information will inform the future design of association‐based investigations as the search for disease genes in the linked regions begins.
Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus
Authors: Lin Shih‐Chang , Yen Jeng‐Hsien , Tsai Jaw‐Ji , Tsai Wen‐Chen , Ou Tsan‐Teng , Liu Hong‐Wen , Chen Chung‐Jen
Published: March 2004

Objective.

The expression of autoimmunity in mice deficient in programmed death 1 (PD‐1) suggests that PD‐1 is a candidate gene involved in the development of human autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We therefore tested the potential association between PD‐1 and the development of SLE and RA by conducting case–control genetic‐association studies.

Methods.

Ninety‐eight SLE patients, 84 RA patients, and sex‐matched control subjects for each disease group were recruited and genotyped for a single‐nucleotide polymorphism, C+872T, in the human PD‐1 gene. The significance of the association of the PD‐1 gene with SLE or with RA was analyzed by statistical tests for the difference in genotype distribution between disease and control groups.

Results.

The human PD‐1 gene was found to be significantly associated with disease development in RA patients, but not SLE patients. The risk of RA development appeared to be significantly increased by carriage of the T allele (odds ratio 3.32, P < 0.0001) or the C/T genotype (odds ratio 3.52, P < 0.00005).

Conclusion.

The PD‐1 gene is significantly associated with RA susceptibility, suggesting the possibility that PD‐1 may contribute to the pathogenesis of RA.
Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1 locus
Authors: Kilding Rachael , Iles Mark M. , Timms Janine M. , Worthington Jane , Wilson Anthony G.
Published: March 2004

Objective

Rheumatoid arthritis (RA) has an estimated genetic contribution of 30–50%, approximately one‐third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a shared epitope. However, several recent studies have suggested that additional telomeric genetic influences may exist. In this study, we sought to investigate whether a separate non‐DRB1 effect could be detected and to determine its likely location.

Methods

We typed 13 single‐nucleotide polymorphisms, located mainly in the telomeric class III region of the major histocompatibility complex, in 164 British Caucasian families with RA that had at least 1 affected offspring and used unconditioned and DRB1‐conditioned transmission disequilibrium tests (TDTs).

Results

Unconditioned TDTs revealed overtransmission of shared epitope alleles (P = 2.12 × 10−5) and an allele of the HLA–B–associated transcript 1 (BAT1) gene in the telomeric class III region (P = 0.009). Using a DRB1‐conditioned TDT to assess whether an independent effect existed, we detected unequal transmission of alleles of lymphocyte‐specific transcript 1 (P = 0.004), BAT1 (P = 0.003), and PG8 (P = 0.003).

Conclusion

At least 1 additional non‐DRB1 susceptibility locus for RA exists in an interval that encompasses the junction of the class III and I regions. This is a genomic segment of high linkage disequilibrium containing a large number of poorly characterized immunomodulatory genes.
Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: A prospective cohort study
Authors: van Gaalen F. A. , Linn‐Rasker S. P. , van Venrooij W. J. , de Jong B. A. , Breedveld F. C. , Verweij C. L. , Toes R. E. M. , Huizinga T. W. J.
Published: March 2004

Objective

Rheumatoid arthritis (RA) is a common, severe, chronic inflammatory joint disease. Since the disease may initially be indistinguishable from other forms of arthritis, early diagnosis can be difficult. Autoantibodies seen in RA can be detected years before clinical symptoms develop. In an inception cohort of patients with recent‐onset arthritis, we undertook this study to assess the predictive value of RA‐specific autoantibodies to cyclic citrullinated peptides (CCPs) in patients with undifferentiated arthritis (UA).

Methods

Anti‐CCP2 antibody tests were performed at baseline in 936 consecutive, newly referred patients with recent‐onset arthritis. Patients who could not be properly classified 2 weeks after inclusion were categorized as having UA. Patients with UA were followed up for 3 years and evaluated for progression of their disease to RA as defined by the American College of Rheumatology (ACR) 1987 revised criteria.

Results

Three hundred eighteen of 936 patients with recent‐onset arthritis were classified as having UA and were available for analysis. After 3 years of followup, 127 of 318 UA patients (40%) had been classified as having RA. RA had developed in 63 of 249 patients (25%) with a negative anti‐CCP test and in 64 of 69 patients (93%) with a positive anti‐CCP test (odds ratio 37.8 [95% confidence interval 13.8–111.9]). Multivariate analysis of the presence of anti‐CCP antibodies and parameters from the ACR criteria identified polyarthritis, symmetric arthritis, erosions on radiographs, and anti‐CCP antibodies as significant predictors of RA.

Conclusion

Testing for anti‐CCP antibodies in UA allows accurate prediction of a substantial number of patients who will fulfill the ACR criteria for RA.
Normative values for the Health Assessment Questionnaire Disability Index: Benchmarking disability in the general population
Authors: Krishnan Eswar , Sokka Tuulikki , Häkkinen Arja , Hubert Helen , Hannonen Pekka
Published: March 2004

Objective

The Health Assessment Questionnaire (HAQ) disability index (DI) has been commonly used in rheumatology to quantify functional disability in patient groups, but current general population values of this index are not available. This study was undertaken to establish normative values for the HAQ DI in a general population and to analyze its correlates.

Methods

The HAQ DI (range of scores 0–3) was measured in a random sample of 1,530 adults in the Central Finland District. Prevalence rates of disability by strata of age, sex, education level, body mass index (BMI), and health behaviors (including smoking and exercise habits) were calculated. Pearson's product‐moment correlation coefficient and ordinary least squares regression were used to analyze the data.

Results

The estimated population mean HAQ DI was 0.25 (95% confidence interval 0.22–0.28), and 32% of respondents had at least some disability. Both for men and for women, functional disability increased exponentially with age. The HAQ DI was correlated with pain (r = 0.58) and global self assessment (r = 0.61). The prevalence of disability decreased with increasing number of years of education, lower BMI, and increasing frequency of physical exercise.

Conclusion

Almost one‐third of the general population has some functional disability. Functional disability is associated in part with lifestyle choices and increases with age in a nonlinear manner. The normative values of the HAQ DI that we have presented could be used as a reference benchmark for clinical and epidemiologic studies using this measure of disability.
A novel synthetic, nonpsychoactive cannabinoid acid (HU‐320) with antiinflammatory properties in murine collagen‐induced arthritis
Authors: Sumariwalla Percy F. , Gallily Ruth , Tchilibon Susanna , Fride Ester , Mechoulam Raphael , Feldmann Marc
Published: March 2004

Objective

To explore the antiarthritic potential of a novel synthetic cannabinoid acid, Hebrew University–320 (HU‐320), in the DBA/1 mouse model of arthritis, and to investigate in vitro antiinflammatory and immunosuppressive effects of HU‐320 on macrophages and lymphocytes.

Methods

DBA/1 mice were immunized with bovine type II collagen (CII) to induce arthritis and then injected intraperitoneally daily with HU‐320. The effects of treatment on arthritic changes in hind feet were assessed clinically and histologically, and draining lymph node responses to CII were assayed. Murine splenic and human blood lymphocytes were cultured to study the effect of HU‐320 on polyclonal mitogenic stimulation. Macrophage cultures were set up to evaluate in vitro effects of HU‐320 on production of tumor necrosis factor α (TNFα) and reactive oxygen intermediates (ROIs). The effect of HU‐320 administration on lipopolysaccharide‐induced serum TNF levels was assayed using C57BL/6 mice. Bioactive TNF production was measured using BALB/c clone 7 target cells. Evaluation of HU‐320 psychoactivity was performed using established laboratory tests on Sabra mice.

Results

Systemic daily administration of 1 and 2 mg/kg HU‐320 ameliorated established CII‐induced arthritis. Hind foot joints of treated mice were protected from pathologic damage. CII‐specific and polyclonal responses of murine and human lymphocytes were down‐modulated. HU‐320 inhibited production of TNF from mouse macrophages and of ROIs from RAW 264.7 cells and suppressed the rise in serum TNF level following endotoxin challenge. HU‐320 administration yielded no adverse psychotropic effects in mice.

Conclusion

Our studies show that the novel synthetic cannabinoid acid HU‐320 has strong antiinflammatory and immunosuppressive properties while demonstrating no psychoactive effects. The profound suppressive effects on cellular immune responses and on the production of proinflammatory mediators all indicate its usefulness as a novel nonpsychoactive, synthetic antiinflammatory product.
Mutant fibrillin 1 from tight skin mice increases extracellular matrix incorporation of microfibril‐associated glycoprotein 2 and type I collagen
Authors: Lemaire Raphael , Farina Guiseppina , Kissin Eugene , Shipley J. Michael , Bona Constantine , Korn Joseph H. , Lafyatis Robert
Published: March 2004

Objective

Skin fibrosis in the TSK mouse, a model of skin fibrosis seen in systemic sclerosis (SSc), is caused by a large in‐frame duplication in the Fbn1 gene, tsk‐Fbn1. We investigated whether tsk‐Fbn1 might cause dermal fibrosis by affecting Fbn1 and associated extracellular matrices. We also studied whether deposition of microfibril‐associated glycoprotein 2 (MAGP‐2), a protein that is associated with fibrillin 1, was altered in the skin of patients with SSc.

Methods

An in vitro model of the TSK mouse was created by conditionally expressing tsk‐Fbn1 in mouse embryonic fibroblasts (MEFs). Cell cultures were examined by immunofluorescence and Western and Northern blotting to determine the effect of tsk‐Fbn1 on the structure, expression, and deposition of fibrillin 1 (Fbn‐1), type I collagen, and MAGP‐2. The skin of TSK mice and SSc patients was analyzed by immunohistochemistry for MAGP‐2 expression.

Results

Expression of tsk‐Fbn1 in cultured MEF cells altered the morphology of Fbn‐1 fibers and increased the deposition of type I collagen into the extracellular matrix (ECM) without concomitantly changing messenger RNA expression, secretion, or processing of type I procollagen. Moreover, MEF cells expressing tsk‐Fbn1 showed increased MAGP‐2 matrix. MAGP‐2 was increased in the dermis of TSK mice. Fibrotic SSc skin also showed higher levels of MAGP‐2 in the dermis than nonfibrotic SSc skin and normal skin.

Conclusion

Tsk‐Fbn1 altered ECM organization and caused fibrosis by affecting the deposition of MAGP‐2 or other Fbn‐1–associated proteins. Alterations in microfibril structure or deposition might contribute to fibrosis in SSc.
MEK/ERK and signal transducer and activator of transcription signaling pathways modulate oncostatin M–stimulated CCL2 expression in human osteoblasts through a common transcription factor
Authors: Lin Sze‐Kwan , Kok Sang‐Heng , Yeh Flora Tzu‐Chin , Kuo Mark Yen‐Ping , Lin Ching‐Chuan , Wang Chih‐Chiang , Goldring Steven R. , Hong Chi‐Yuan
Published: March 2004

Objective

To analyze the effects of oncostatin M (OSM), a gp130‐type cytokine, on CCL2 expression in MG‐63 cells, a human osteosarcoma cell line with a characteristic osteoblastic phenotype, and to investigate the signaling pathway involved.

Methods

The expression of messenger RNA (mRNA) for CCL2 and c‐Fos was analyzed by Northern blotting. Amounts of CCL2 released into the supernatant were measured by enzyme‐linked immunosorbent assay. Western blotting was used to examine the activation of MAPK signaling pathways. Interactions between activator protein 1 (AP‐1) and DNA were evaluated by electrophoretic mobility shift assay.

Results

OSM stimulated CCL2 expression at both the mRNA and the protein levels. Cyclooxygenase 2 (COX‐2) was also induced by OSM. However, the up‐regulation of CCL2 mRNA was COX‐2–independent but required tyrosine kinase and protein kinase C (PKC). OSM stimulated the phosphorylation of MEK‐1/2 and ERK‐1/2 but not p38 and JNK. A transient elevation of c‐Fos mRNA was induced by OSM, but PD 98059 (MEK inhibitor), fludarabine (signal transducer and activator of transcription 1 [STAT‐1] inhibitor), and piceatannol (STAT‐3 and STAT‐5 inhibitor) abolished this effect. Electrophoretic mobility shift assay revealed that OSM stimulated AP‐1–DNA binding, which was also abolished by PD 98059, fludarabine, and piceatannol. Supershift study further confirmed the role of c‐Fos in the above interaction. PD 98059, fludarabine, piceatannol, and curcumin (AP‐1 inhibitor) inhibited the OSM‐induced expression of CCL2.

Conclusion

OSM induces CCL‐2 expression in osteoblasts. Activation of the MEK/ERK and STAT pathways, which leads to c‐Fos expression and AP‐1–DNA binding, is involved in the process. The signaling requires tyrosine kinase and PKC but not COX‐2.
Magnetic resonance imaging evaluation of the effects of juvenile rheumatoid arthritis on distal femoral weight‐bearing cartilage
Authors: Kight Amanda C. , Dardzinski Bernard J. , Laor Tal , Graham T. Brent
Published: March 2004

Objective

To examine magnetic resonance imaging–derived T2 relaxation times in the weight‐bearing cartilage of the distal femur in healthy children and in children with juvenile rheumatoid arthritis (JRA).

Methods

T2 relaxation time maps were created for 39 girls (ages 4.9–10.9 years), 21 of whom were considered healthy and 18 of whom had JRA. The spatial distribution of T2 relaxation times for the distal femoral weight‐bearing cartilage (including epiphyseal and articular cartilage) was mapped for each group as a whole. Average data sets for each group were then compared using paired t‐tests to detect differences between the 2 populations.

Results

The spatial distribution of T2 relaxation time values was nearly identical in the 2 groups, with a concave curve that was highest near the subchondral bone and articular surfaces. The average T2 relaxation times were significantly higher in the girls with JRA than in the group of healthy girls (P < 0.05).

Conclusion

The finding of an increased average T2 relaxation time in the children with JRA suggests that T2 relaxation time maps may reflect cartilage microstructure differences that occur in JRA. T2 relaxation time mapping may allow for early detection of cartilage changes and provide an objective, quantitative method of monitoring disease progression, with the long‐term potential to guide therapy.
Clustering of disease features within 512 multicase rheumatoid arthritis families
Authors: Jawaheer Damini , Lum Raymond F. , Amos Christopher I. , Gregersen Peter K. , Criswell Lindsey A.
Published: March 2004

Objective

To determine whether specific rheumatoid arthritis (RA) disease features demonstrate the presence of significant familial clustering.

Methods

We studied 1,097 individuals with RA from 512 multicase families enrolled in the North American Rheumatoid Arthritis Consortium. All patients were interviewed and examined to collect standardized information about demographic and clinical characteristics. Affected individuals also underwent radiography of the hands and wrists and were genotyped for the HLA–DRB1 shared epitope. Familial clustering of disease features was assessed using contingency table analysis and Pearson correlation coefficients. Multivariate logistic and linear regression analyses were used to account for other characteristics that might influence familial clustering, such as disease duration, sex, and age at diagnosis.

Results

Several disease characteristics exhibited significant familial clustering, including seropositivity (multivariate odds ratio [OR] 4.3, P < 0.0001), nodules (OR 2.3, P < 0.0001), and age at RA diagnosis (multivariate regression coefficient [β] 0.44, P < 0.0001). Other characteristics demonstrated statistically significant but modest degrees of familial clustering (Joint Alignment and Motion score, Health Assessment Questionnaire score, and year of RA diagnosis) or modest but nonsignificant familial clustering (other extraarticular manifestations, other autoimmune diseases).

Conclusion

The clustering of certain disease characteristics implicates specific genetic or nongenetic causes. These results highlight the importance of considering disease phenotype in future genetic and epidemiologic studies of RA.
Anti‐DFS70 antibodies in 597 healthy hospital workers
Authors: Watanabe Akihiro , Kodera Masanari , Sugiura Kazumitsu , Usuda Toshikazu , Tan Eng M. , Takasaki Yoshinari , Tomita Yasushi , Muro Yoshinao
Published: March 2004

Objective

Autoantibodies against DFS70 (dense fine speckles 70) antigen (also known as lens epithelium–derived growth factor) have been recently identified among the antinuclear antibodies (ANAs) in patients with atopic disorders. We undertook this study to examine the frequency of anti‐DFS70 antibodies in a large number of healthy people.

Methods

Sera of 597 healthy individuals working in a hospital (142 men, 455 women) were analyzed for ANAs and for anti‐DFS70 antibodies by indirect immunofluorescence (IIF) with HEp‐2 cells as a substrate and by immunoblotting using DFS70 recombinant protein and whole HeLa cell extract.

Results

ANAs were present in 20% of all individuals by IIF. Nine percent of subjects were ANA positive at a serum dilution of 1:40, 4.0% at 1:80, 5.5% at 1:160, 1.0% at 1:320, and 0.3% at 1:640. There were 64 anti‐DFS70 antibody–positive individuals. Surprisingly, this was 11% of the whole population and 54% of the ANA‐positive population. The percentage of female anti‐DFS70 antibody–positive subjects (86%; 55 of 64 subjects) was higher than the percentage of female anti‐DFS70 antibody–negative subjects (75%; 398 of 533 subjects) (P < 0.05). The prevalence of anti‐DFS70 antibody–positive sera decreased with increasing age (P = 0.0017).

Conclusion

Considering that anti‐DFS70 antibody positivity is rare in patients with systemic autoimmune diseases, introducing the anti‐DFS70 antibody examination as a screening test for ANA‐positive persons could be used to rule out systemic autoimmune diseases, resulting in considerable cost‐saving potential. In addition, this test defines a subpopulation of healthy people in whom long‐term followup might reveal health‐related implications of this finding, since anti‐DFS70 antibodies have been shown to be associated with some illnesses.