bluuebunny/crossref_metadata_2025 huggingface dataset:
Disruption of a synaptotagmin (SYT14) associated with neurodevelopmental abnormalities
Authors: Quintero‐Rivera Fabiola , Chan Alicia , Donovan Diana J. , Gusella James F. , Ligon Azra H.
Published: February 2007

We report cytogenetic and molecular studies of a de novo, apparently balanced t(1;3)(q32.1;q25.1) identified in a 12‐year‐old female (designated DGAP128) with cerebral atrophy, macrocephaly seizures, and developmental delay. A combination of fluorescence in situ hybridization (FISH) and Southern blot analysis demonstrated disruption of a synaptotagmin gene (SYT14) at the 1q32 breakpoint. Expression of SYT14 in human brain was confirmed using Northern analysis. Because members of the synaptotagmin family of proteins function as sensors that link changes in calcium levels with a variety of biological processes, including neurotransmission and hormone‐responsiveness, SYT14 is an intriguing candidate gene for the abnormal development in this child. This is the first known constitutional rearrangement of SYT14, and further systematic genetic analysis and clinical studies of DGAP128 may offer unique insights into the role of SYT14 in neurodevelopment. © 2007 Wiley‐Liss, Inc.
Plasma obestatin and ghrelin levels in subjects with Prader–Willi syndrome
Authors: Butler Merlin G. , Bittel Douglas C.
Published: February 2007

Prader–Willi syndrome (PWS) is an obesity syndrome characterized by rapid weight gain and excessive food intake. Food intake is regulated by the hypothalamus but directly influenced by gastrointestinal peptides responding to the nutritional status and body composition of an individual. Ghrelin, derived from preproghrelin, is secreted by the stomach and increases appetite while obestatin, a recently identified peptide derived post‐translationally from preproghrelin, works in opposition to ghrelin by decreasing appetite. The objective of this study was to measure fasting obestatin and ghrelin levels in peripheral blood of subjects with PWS and compare to age and gender matched control subjects. Plasma obestatin and ghrelin levels were measured in subjects with PWS (n = 16, mean age = 16.0 ± 13.3 years; age range 1–44 years) and age and gender matched control subjects (n = 16). Significantly higher obestatin levels were seen in the 16 PWS subjects (398 ± 102 pg/ml) compared with 16 controls (325 ± 109 pg/ml; matched t‐test, P = 0.04), particularly in 5 young (≤3 years old) PWS subjects (460 ± 49 pg/ml) compared with 5 young controls (369 ± 96 pg/ml; matched t‐test, P = 0.03). No significant difference in ghrelin levels was seen between the PWS and comparison groups. No significant correlation was observed for either peptide when compared with body mass index but a significant negative correlation was seen for ghrelin and age in PWS subjects. Our observations suggest that obestatin may be higher in infants with PWS compared to comparison infants. The possibility that obestatin may contribute to the failure to thrive which is common in infants with PWS warrants further investigation. © 2007 Wiley‐Liss, Inc.
The second trimester genetic sonogram
Authors: Breathnach Fionnuala M. , Fleming Ann , Malone Fergal D.
Published: February 2007

The genetic sonogram, a fetal anatomic survey targeted at identifying features associated with aneuploidy, is carried out between 15 and 20 weeks' gestation. It has evolved as an adjunctive screening tool capable of further refining the individualized risk‐calculation for trisomy that is based on maternal age or serum screening markers. The significance of a range of major structural anomalies and so‐called “soft‐markers” for trisomy, detected both in isolation and in combination, has been widely investigated. This review serves to describe the key components of the second trimester genetic sonogram and to illustrate how these markers are integrated into risk assessment for aneuploidy. © 2007 Wiley‐Liss, Inc.
Prenatal diagnosis of structural cardiac defects
Authors: Allan Lindsey
Published: February 2007

Prenatal diagnosis of congenital heart defects has been possible now for over 25 years. This ability has extended from a few specialists to being within the scope of any sonographer engaged in routine obstetric evaluation of the low‐risk patient. However, the detection rate is widely varied. The recognition of major structural heart disease in fetal life has important implications for the child's future, so further efforts should be made to improve the success in diagnosis. © 2007 Wiley‐Liss, Inc.
Neuropeptides and inflammation. A somatostatin analog as a selective antagonist of neutrophil activation by substance P
Authors: Kolasinski Sharon L. , Haines Kathleen A. , Siegel Evan L. , Cronstein Bruce N. , Abramson Steven B.
Published: February 2007

Objective. Substance P and somatostatin are neuropeptides found in peripheral sensory nerves. In vitro, these have opposing effects on inflammatory cells. We compared the effects of these peptides on the activation of neutrophils.

Methods. Neutrophils were isolated from healthy volunteers, and chemotaxis, superoxide anion generation, aggregation, and changes in cytosolic calcium and GTPase activity were measured in the presence of substance P, somatostatin, and the chemoattractant FMLP.

Results. Substance P was an effective chemoattractant, 20% as potent as FMLP at equimolar concentrations. Substance P also stimulated GTPase activity in neutrophil plasma membranes. Somatostatin did not activate neutrophils; however, it effectively inhibited neutrophil chemotaxis and GTPase activity provoked substance P, but not by FMLP.

Conclusions. These studies demonstrate that substance P can effectively stimulate chemotaxis, possible via effects on a GTP‐binding protein distinct from that triggered by FMLP, and that somatostatin is a selective antagonist of substance P. The biochemical specificities of these peptides on cells may modulate neurogenic inflammation at the local level.
Acute and chronic suppression of leukotriene B4 synthesis EX vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate
Authors: Sperling Richard I. , Benincaso Anthony I. , Anderson Ronald J. , Coblyn Jonathan S. , Austen K. Frank , Weinblatt Michael E.
Published: February 2007

Objective. To compare the cumulative effects of oral methotrexate (MTX) therapy (after 6–8 weeks) with the acute effects (24 hours after a dose) on arachidonic acid metabolism by the 5‐lipoxygenase (5‐LO) pathway in neutrophils from patients with active rheumatoid arthritis (RA) who were beginning therapy with MTX.

Methods. Neutrophils and monocytes were isolated from whole blood from 7 patients with RA, immediately before and 24 hours after their first weekly dose of 7.5 mg of MTX, and again after their dose at 6–8 weeks.

Results. Total immunoreactive leukotriene B4 (LTB4) formation in neutrophils activated ex vivo with calcium ionophore A23187 was significantly suppressed (by 33%) before the 6–8‐week dose, compared with the level before the first dose (mean ± SEM 8.29 ± 1.24 ng/106 cells at predose 6–8 weeks versus 12.29 ± 2.13 ng/106 cells at predose 1; P = 0.03). Reductions were also observed after the first dose (27%; P = 0.07) and after the 6–8‐week dose (43%; P = 0.05) compared with the respective predose levels. MTX treatment produced significant reductions in the total generation of 5‐LO pathway products (5‐hydroxyeicosatetraenoic acid + 6‐trans‐LTB4 + LTB4 + ω‐oxidation products of LTB4) by calcium ionophore‐activated neutrophils, as quantitated by integrated optical density after resolution on reverse‐phase high‐performance liquid chromatography. Decreases were observed after the first dose (26%; P = 0.025), immediately before the 6–8‐week dose (23%; P = 0.05), and after the 6–8‐week dose (47%; P = 0.0033) compared with levels before the first dose, and after the 6–8‐week dose compared with the level before it (32%; P = 0.04). The generation of LTB4 by calcium ionophore‐activated monocytes was not significantly affected by MTX therapy.

Conclusion. The significant decreases in the formation of ω‐oxidation products of LTB4 and in the total generation of neutrophil 5‐LO pathway products in the absence of a significant change in the release of 3H‐arachidonic acid or the generation of platelet‐activating factor suggest that the activity of the 5‐LO enzyme in neutrophils is inhibited. We conclude that weekly oral MTX therapy in patients with active RA inhibits neutrophil 5‐LO pathway product generation in a pattern consistent with inhibition of the activity of the 5‐LO enzyme; an effect is observed after the first dose. The inhibition of 5‐LO is cell‐selective and cumulative, with a superimposed incremental inhibition observed after the weekly MTX dose.
Synovial fluid analysis of two groups of proteoglycan epitopes distinguishes early and late cartilage lesions
Authors: Saxne Tore , Heinegård Dick
Published: February 2007

Objective. To investigate whether fragmentation of proteoglycans in arthritis results in domains that have different levels of release from cartilage at different stages of the disease.

Methods. Two regions of the proteoglycan, the hyaluronan‐binding region and the glycosaminoglycanrich region of the core protein, were measured, by immunoassay, in knee joint synovial fluids of patients with rheumatoid arthritis or reactive arthritis.

Results. Synovial fluid concentrations of the glycosaminoglycan‐rich region were highest in rheumatoid arthritis patients who had little cartilage damage as determined by radiography, whereas release of the hyaluronan‐binding region predominated in patients with advanced cartilage destruction. In reactive arthritis, release of the glycosaminoglycan‐rich region predominated.

Conclusion. These findings indicate that the hyaluronan‐binding region is initially retained in the tissue during the development of cartilage destruction. The combined analysis of these markers offers a new avenue for assessment of the degree of cartilage damage in arthritis.
Isolation and culture of synovial microvascular endothelial cells. Characterization and assessment of adhesion molecule expression
Authors: Abbot S. E. , Kaul A. , Stevens C. R. , Blake D. R.
Published: February 2007

Objective. In vitro studies investigating the role of the synovial endothelium in the pathogenesis of rheumatoid arthritis (RA) have, until recently, been performed using cultured endothelial cells of nonsynovial macrovascular origin. In an attempt to more correctly model in vivo conditions, a method for the isolation and culture of synovial microvascular endothelial cells (SMEC) has been developed.

Methods. SMEC were isolated, primarily, by the use of lectin‐coated (Ulex europaeus agglutinin type I), magnetizable polystyrene beads.

Results. Isolated cells exhibit classic endothelial ‘cobblestone’ morphology, express von Willebrand factor, metabolize acetylated low‐density lipoprotein, and exhibit a cytokine (interleukin‐1)–mediated expression of endothelial leukocyte adhesion molecule type 1 (ELAM‐1) and intercellular adhesion molecule type 1 (ICAM‐1). ELAM‐1 levels were significantly elevated in SMEC, compared with human umbilical vein endothelial cells, over a range of interleukin‐1 concentrations.

Conclusion. This increased expression of ELAM‐1 by SMEC may be a potentiating step in pathogenesis of RA.
Psychiatric disorder and cognitive impairment in systemic lupus erythematosus
Authors: Hay Elaine M. , Black Dawn , Huddy Alice , Creed Francis , Tomenson Barbara , Bernstein Robert M. , Holt P. J. Lennox
Published: February 2007

Objectives. To determine the point prevalence of psychiatric disorder in patients with systemic lupus erythematosus (SLE). To investigate associations between psychiatric disorder and social stress, cognitive impairment, systemic disease activity, and corticosteroid therapy.

Methods. A cross‐sectional study of 73 consecutive patients with SLE assessed using standardized psychiatric and clinical research methods.

Results. Current psychiatric disorder was present in 15 patients (20.5%) and was significantly associated with social stress, lack of social support, and impairment on 2 tests of cognitive function (Verbal Fluency Test and Benton Visual Retention Test, Part A, number of errors). There was no association with systemic disease activity or corticosteroid therapy. Cognitive impairment on 2 or more tests was found in 26% and was associated with clinical evidence of central nervous system (CNS) disease, but not systemic disease activity or corticosteroid therapy.

Conclusions. The point prevalence of psychiatric disorder in this cohort of patients with SLE was found to be similar to that observed in patients with rheumatoid arthritis. It was independently associated with social stress and 2 indicators of cognitive impairment, but not with systemic disease activity or corticosteroid therapy. Marked cognitive impairment was present in a significant percentage of patients even when there was no overt evidence of CNS involvement.
Interferon‐alpha in lupus psychosis
Authors: Shiozawa Shunichi , Kuroki Yasuo , Kim Mitsunori , Hirohata Shunsei , Ogino Tetsuya
Published: February 2007

Objective. Since the level of interferon‐α (IFNα) is increased in the sera of patients with active systemic lupus erythematosus (SLE) and is detectable in the cerebrospinal fluid (CSF) of some SLE patients with neuropsychiatric manifestations, we investigated the contribution of IFNα to the pathogenesis of the neuropsychiatric manifestations of SLE.

Methods. IFNα levels were quantitated by radioimmunoassay in CSF and serum samples from 17 SLE patients with neuropsychiatric manifestations and 28 patients with SLE alone or SLE and other neurologic disorders.

Results. Levels of IFNα were increased in the CSF of 5 of 6 patients with lupus psychosis, and in 4 of these 5 patients, the levels in CSF were higher than those in serum. IFNα levels decreased when the manifestation of lupus psychosis subsided. In contrast, IFNα levels in CSF samples from patients with seizures alone were not increased. One patient with lupus psychosis died of complications of generalized seizures resulting from the SLE. At autopsy, we investigated whether IFNα protein or messenger RNA was detectable in the subject's brain. IFNα protein was immunohistochemically demonstrated in the neurons and in the microglia (focal accumulation), features not present in the brain tissues of subjects who died of other diseases.

Conclusion. These findings support the hypothesis that IFNα, possibly synthesized in the brain, is the cause of the manifestation of psychosis in patients with SLE.
Ureaplasma urealyticum and mycoplasma hominis in women with systemic lupus erythematosus
Authors: Ginsburg Katherine S. , Kundsin Ruth B. , Walter Carl W. , Schur Peter H.
Published: February 2007

Objective. To determine the prevalence of genitourinary mycoplasma infection in women with systemic lupus erythematosus (SLE).

Methods. Urine specimens from 49 patients with SLE and 22 patients with chronic fatigue syndrome (CFS) were cultured for mycoplasma. Patient records were reviewed for medical history and SLE disease activity.

Results. Sixty‐three percent of the SLE patients were culture positive, compared with 4.5% of the CFS patients (P < 0.001). Neither corticosteroid treatment, SLE activity, nor age accounted for this difference.

Conclusion. Genitourinary mycoplasma colonization occurs significantly more frequently in SLE than in CFS.
Mycoplasma arthritidis mitogen. Vβ engaged in mice, rats, and humans, and requirement of HLA‐DRα for presentation
Authors: Baccala Roberto , Smith Lawrence R. , Vestberg Mikael , Peterson Per A. , Cole Barry C. , Theofilopoulos Argyrios N.
Published: February 2007

Objective. Mycoplasma arthritidis mitogen (MAM) is mitogenic for mouse, rat, and human T cells, and behaves as a superantigen in mice through its capacity to bind to the α chain of I‐E molecules and engage entire sets of T cells expressing specific Vβ. Here, we have attempted to fully characterize the Vβ‐engaging activities of MAM in mice, and define similar activities in rats and humans.

Methods. Multiprobe RNase‐protection assays and mice transgenic for human DRα, DRβ, and DRαβ were utilized for this purpose.

Results. MAM‐reactive Vβ in the mouse included not only the previously reported Vβ6, Vβ8.1, Vβ8.2, and Vβ8.3, but also Vβ5.1. In the rat, engagement of Vβ5.1, Vβ6, Vβ8.1, and Vβ8.2, but not Vβ8.3, was documented, whereas in humans, the engaged Vβ included primarily Vβ19.1 (alternatively termed Vβ17.1) and, to a lesser extent, Vβ3.1, Vβ11.1, Vβ12.1, and Vβ13.1. In DR transgenic Eα‐Eβ‐ mice, presentation of MAM and engagement of specific Vβ was effected by DRα.

Conclusions. Homologous Vβ are engaged by MAM in mice, rats, and humans, presumably through a binding site similar to that proposed previously for other superantigens. MAM presentation primarily via the nonpolymorphic DRα makes it unlikely that there is involvement of such a superantigen in the pathogenesis of autoimmune diseases known to be associated with certain DR haplotypes. The possibility cannot be excluded, however, that superantigen‐activated T cells may lead to disease by cross‐reactions with self‐antigens presented by particular DR haplotypes.
Molecular diagnosis of ureaplasma urealyticum septic arthritis in a patient with hypogammaglobulinemia
Authors: Lee Albert H. , Ramanujam Thaila , Ware Paul , Edelstein Paul H. , Brooks John J. , Freundlich Bruce , Schumacher H. Ralph , Zurier Robert B. , Weiner David B. , Williams William V.
Published: February 2007

Objective. We report a hypogammaglobulinemic patient with a destructive oligoarticular arthritis, whose synovial fluid cultures were repeatedly sterile.

Methods and Results. We identified a Ureaplasma urealyticum infection in his affected joints, using a polymerase chain reaction (PCR) assay.

Conclusion. The PCR technique promises to be extremely valuable in the rapid and specific diagnosis of infectious arthritis.
Autoantibodies to small nuclear and cytoplasmic ribonucleoproteins in japanese patients with inflammatory muscle disease
Authors: Hirakata Michito , Mimori Tsuneyo , Akizuki Masashi , Craft Joe , Hardin John A. , Homma Mitsuo
Published: February 2007

Objective. To elucidate the profile and clinical significance of autoantibodies to small nuclear and small cytoplasmic ribonucleoproteins in Japanese patients with polymyositis and dermatomyositis (PM/DM).

Methods. Radioimmunoprecipitation assays were performed with sera from 91 patients with various inflammatory muscle diseases and from 254 control patients with other rheumatic diseases. Patients with PM/DM were categorized according to autoantibody specificities, and clinical comparisons were made.

Results. Antibodies to aminoacyl transfer RNA (tRNA) synthetases and the signal recognition particle (SRP) were found to be specific for PM/DM. PM/DM patients with antibodies to 3 aminoacyl‐tRNA synthetases (histidyl, threonyl, and glycyl) appeared to form a distinct clinical subset, associated with chronic interstitial lung disease, polyarthritis, and myositis, while 3 patients with antibodies that bound the SRP had severe myositis that was resistant to corticosteroid therapy. In general, the frequency and clinical correlations of anti—aminoacyl‐tRNA synthetase antibodies in Japanese patients were similar to those in North American populations. In contrast, among this Japanese cohort, the occurrence of anti‐PM/ScI appeared to be reduced in frequency, whereas anti‐Ku and anti—U2 RNP antibodies were accentuated in patients with overlap syndromes.

Conclusion. We conclude that racial groups differ somewhat in their characteristic autoimmune responses to individual autoantigens. These differences could reflect variation in immunogenetic background or different etiologic mechanisms which might occur at different geographic locations.
Serologic studies of monozygotic twins with systemic lupus erythematosus
Authors: Reichlin Morris , Harley John B. , Lockshin Michael D.
Published: February 2007

Objective. The goal of these studies was to assess the role of genetic factors and disease expression in the pattern and titer of autoantibodies to several RNA protein antigens in patients with systemic lupus erythematosus (SLE) by studying identical twins concordant and discordant for disease expression.

Methods. Autoantibodies to Ro/SS‐A, La/SS‐B, U1 RNP, and Sm were measured by quantitative enzyme‐linked immunosorbent assay using affinity‐purified antigens.

Results. Detailed serologic studies were performed in 7 pairs of identical twins, 3 of whom were concordant and 4 of whom were discordant for disease expression. Autoantibody titers were higher in affected than in unaffected twins from discordant pairs, but in 3 of 4 pairs, the profile of anti—RNA proteins (e.g., Ro/SS‐A, La/SS‐B, U1 RNP, and Sm) was virtually identical. In the SLE pairs concordant for disease expression, the autoantibody titers were very similar, as were the anti—RNA protein profiles. When the identical twins were matched by sex, race, and age to pairs of nontwin SLE patients, the 6 white twins shared an average of 2.5 (± 1.05 SD) anti—RNA proteins, while the control SLE pairs shared only 0.33 (± 0.82), P < 0.01 (t = 4.0, P < 0.01). In addition, in the white SLE twins, all had elevated levels of anti—U1 RNP while in white nontwin SLE patients, the frequency of anti—U1 RNP was 30%.

Conclusion. These data point to a dominant role for genetic factors in the determination of specific autoantibody profiles.
Differences in t cell receptor restriction fragment length polymorphisms in patients with rheumatoid arthritis
Authors: Funkhouser Sheana Whelan , Concannon Patrick , Charmley Patrick , Vredevoe Donna L. , Hood Leroy
Published: February 2007

Objective. The purpose of this study was to determine whether a T cell receptor (TCR) polymorphism, either by itself or in combination with particular HLA polymorphism, leads to susceptibility to rheumatoid arthritis (RA).

Methods. Eight restriction fragment length polymorphisms (RFLPs) detected with TCR gene segments were investigated in 46 individuals with RA and were compared with data from normal control subjects.

Results. A statistically significant difference in the genotype frequencies of a Taq I RFLP detected with the TCRα constant region (Cα) gene was noted. In addition, when the DR4+ subpopulations were examined, the allelic frequency of a 2‐kb Bam HI fragment detected with a Vβ8 gene was increased in the samples from RA patients (P < 0.0086).

Conclusion. The results of this study suggest that germline differences in the TCR repertoire may be associated with RA, and that there is a contributory effect of DR4+ haplotypes with certain TCR haplotypes in susceptibility to RA.
Autoantibodies to the chromosomal protein HMG‐17 in juvenile rheumatoid arthritis
Authors: Neuer Gunter , Bustin Michael , Michels Hartmut , Truckenbrodt Hans , Bautz Friedlinde A.
Published: February 2007

Objective. To determine the antibody profiles in sera from patients with juvenile rheumatoid arthritis (JRA).

Methods. Immunoblotting using nuclear extracts and recombinant high‐mobility group (HMG) nonhistone chromosomal proteins.

Results. Antibodies directed against HMG‐17 were found in 47% of antinuclear antibody (ANA)–positive patients with pauciarticular‐onset JRA and in 16% of ANA‐positive patients with polyarticular‐onset JRA. HMG‐17 values of 6% and 8%, respectively, were detected in ANA‐negative patients with JRA and in those with nonrheumatic diseases.

Conclusion. There is evidence for a high prevalence of anti—HMG‐17 antibodies in sera of patients with pauciarticular‐onset JRA.
Magnetic resonance imaging detection of aortic and pulmonary artery wall thickening in the acute stage of takayasu arteritis. Improvement of clinical and radiologic findings after steroid therapy
Authors: Tanigawa Ken , Eguchi Katsumi , Kitamura Yoshio , Kawakami Atsushi , Ida Hiroaki , Yamashita Shunichi , Matsunaga Naofumi , Hayashi Kuniaki , Nagataki Shigenobu
Published: February 2007

Objective. Early diagnosis of Takayasu arteritis in the acute stage (prepulseless stage) is extremely difficult. Identification of a useful approach to detecting the initial changes of arteritis is therefore desirable.

Methods. Careful clinical examination of a young woman with persistent fever and dry cough revealed faintly audible bruits at the cervical, supraclavicular, and abdominal regions. Aortographic features suggested thickening of the wall of the descending thoracic aorta. Magnetic resonance imaging (MRI) of this area was diagnostic.

Results. MRI demonstrated involvement of the ascending aorta and right main pulmonary artery. Steroid therapy (prednisolone 60 mg/day) induced dramatic clinical and radiologic improvement in 2 months.

Conclusion. This is the first report of MRI‐documented reduction in the thickness of the walls of both the aorta and the pulmonary artery following steroid therapy.
Effect of food on the bioavailability of low‐dose methotrexate in patients with rheumatoid arthritis
Authors: Oguey D. , Kölliker F. , Gerber N. J. , Reichen J.
Published: February 2007

Objective. To evaluate the influence of food on the bioavailability of an oral dose of methotrexate in patients with rheumatoid arthritis.

Methods. Methotrexate (15 mg) was given intravenously and orally, with or without a meal, to 10 patients. Blood samples were drawn at specific intervals to evaluate drug levels.

Results. Food reduced the peak concentration, from a mean of 0.71 μmoles/liter to 0.49 μmoles/liter (P < 0.02), and slightly increased the time to peak concentration, from a mean of 1.3 hours to 2.0 hours. Bioavailability was highly variable (range 28–94%) but was not affected by food intake.

Conclusion. Bioavailability of oral methotrexate shows marked interindividual variation but is not affected by the presence of food.
CD7– T cells in rheumatoid arthritis
Authors: Lazarovits Andrew I. , White Martin J. , Karsh Jacob
Published: February 2007

Objective. Rheumatoid arthritis (RA) is characterized by decreased expression of CD7 in the peripheral blood and in the synovium. The present study was designed to identify the basis for and functional consequences of this decreased expression.

Methods. Peripheral blood lymphocytes from normal controls and from patients with RA or systemic lupus erythematosus (SLE), and T cell lines derived from rheumatoid synovium, were evaluated using 3‐color fluorescence‐activated cell sorter analysis.

Results. Normal subjects and most SLE patients expressed homogeneous, bright CD7 on CD4+, CD45RA+ cells, whereas RA patients demonstrated a significantly increased proportion of CD7– cells. T cell lines derived from rheumatoid synovium demonstrated a striking deficiency of CD7 on CD4+, CD45RA– cells. CD4+, CD45RA+ cells from RA patients changed phenotype after in vitro activation to CD45RA negativity, with up‐regulation of CD7. CD7–, CD4+, CD45RA– cells were assessed for their ability to induce pokeweed mitogen‐driven IgM and IgM‐rheumatoid factor synthesis, and they were found to be potent helper/inducer cells. An increased population of CD7‐, CD4+ cells in peripheral blood was found to predict a low response to recall antigens.

Conclusion. The low expression of CD7 in RA may explain some of the immune abnormalities which may contribute to the pathogenesis of this disease.
Derivation of the sledai. A disease activity index for lupus patients
Authors: Bombardier Claire , Gladman Dafna D. , Urowitz Murray B. , Caron Dominique , Chang Chi Hsing , Austin A. , Bell A. , Bloch Daniel A. , Corey Paul N. , Decker John L. , Esdaile John , Fries James F. , Ginzler Ellen M. , Goldsmith Charles H. , Hochberg Marc C. , Jones John V. , Riche Nicole G. H. Le , Liang Matthew H. , Lockshin Michael D. , Muenz Larry R. , Sackett David L. , Schur Peter H.
Published: February 2007

Objective. To standardize outcome measures in systemic lupus erythematosus (SLE). Three indices were identified which could adequately describe outcome (disease activity, damage from disease, and health status); we describe here the development of the Disease Activity Index.

Methods. Twenty‐four variables were identified as important factors in a disease activity index. These were used to generate 574 patient profiles, which were rated on a disease activity scale of 0–10 by 14 rheumatologists. A second rating of 10 of the profiles yielded scores that were not significantly different from the first, indicating that experienced clinicians can reliably make global estimates of disease activity. Multiple regression models were used to estimate the relative importance of the 24 clinical variables in the physicians' global rating of disease activity. These were estimated on a ‘training set’ of 75% of physicians' ratings, and then validated on a ‘testing set,’ consisting of the remaining 25% of physicians' ratings.

Results. The explanatory power of the models in the training set was high (R2 = 0.93). The models' regression coefficients for the organ systems were simplified for easier use in clinical practice. This generated a ‘weighted’ index of 9 organ systems for disease activity in SLE, the SLEDAI, as follows: 8 for central nervous system and vascular, 4 for renal and musculoskeletal, 2 for serosal, dermal, immunologic, and 1 for constitutional and hematologic. The maximum theoretical score is 105, but in practice, few patients have scores greater than 45. The SLEDAI predicted well the physicians' ratings in the testing set (Pearson's correlation coefficients = 0.64–0.79).

Conclusion. The SLEDAI is a validated model of experienced clinicians' global assessments of disease activity in lupus. It represents the consensus of a group of experts in the field of lupus research.
Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern chinese
Authors: Doherty Derek G. , Ireland Robin , Demaine Andrew G. , Wang Florence , Veerapan Kiran , Welsh Kenneth I. , Vergani Diego
Published: February 2007

Objective. To investigate the predisposing role of major histocompatibility complex (MHC) genes to systemic lupus erythematosus (SLE) in a Chinese population.

Methods. Polymorphism in the HLA‐DRB, DQB, complement component C4, and 21‐hydroxylase genes was analyzed by restriction fragment length polymorphism analysis and oligonucleotide probing of in vitro‐amplified DNA from 88 Chinese patients with SLE and 69 matched control subjects.

Results. HLA‐DRw15 and DQw1 were significantly more frequent in patients (corrected P < 0.006, relative risk 5.2), but none of the 9 sequence variants of DQw1 were increased. The C4A gene deletion usually associated with SLE in Caucasoid and black patients was absent from all Chinese subjects, but possession of other C4 deletions and of DRw15 conferred the greatest risk (relative risk = 8.3).

Conclusion. Different MHC haplotypes predispose to lupus in Chinese than in other ethnic groups. Our data suggest that the susceptibility lies at, or telomeric to, the DR locus, and that DRw15 and C4 deletions may act synergistically in conferring disease susceptibility.
Restricted epitope recognition by precipitin‐negative anti‐La/SS‐B‐positive sera
Authors: Gordon Tom , Mavrangelos Chris , Mccluskey James
Published: February 2007

Objective. To determine whether anti–La/SS‐B–positive sera that are precipitin negative show a distinct B cell epitope pattern.

Methods. Serum reactivity was tested with recombinant La/SS‐B fusion proteins.

Results. Among the 18 precipitin‐negative anti‐La/SS‐B–positive sera, reactivity was confined to the full‐length recombinant protein (La33.3) in 8 (44%); 5 of 18 (28%) reacted only with La33.3 and with the first 107 N‐terminal amino acids (LaA), and 4 (22%) reacted with La33.3, LaA, and the middle region of the La molecule (LaC; amino acids 111–242). One serum reacted with La33.3 and LaC. None of the 18 precipitin‐negative sera was positive on a carboxy‐terminal fragment (LaL2/3; amino acids 346–408). In contrast, all 26 precipitin‐positive anti–La/SS‐B–positive sera reacted with La33.3, LaA, and LaC, and 92% reacted with LaL2/3. Rheumatoid factor and serum IgG levels were significantly lower in the precipitin‐negative group, providing further evidence of a distinct serologic subset.

Conclusion. The restricted epitope recognition by these sera may explain the lack of precipitin formation and may represent an early autoantibody response to La/SS‐B.
Detection and quantification of anti‐ki antibodies by enzyme‐linked immunosorbent assay using recombinant ki antigen
Authors: Yamanaka Kenjiro , Takasaki Y. , Nishida Y. , Shimada K. , Shibata M. , Hashimoto H.
Published: February 2007

Objective. To establish an enzyme‐linked immunosorbent assay (ELISA) for detecting anti‐Ki antibody, using a bovine recombinant Ki antigen, and studying its specificity.

Methods. Sera from 220 patients with various connective tissue diseases were screened, and a prospective study of fluctuations in anti‐Ki antibody and clinical course of a woman with systemic lupus erythematosus (SLE) was analyzed, by ELISA.

Results. Anti‐Ki antibodies were present in 18.9% of patients with SLE. The titer of anti‐Ki antibody in the woman with SLE rose before the onset of pericarditis and pleuritis in this longitudinal study.

Conclusion. ELISA using a recombinant Ki antigen is useful for the diagnosis of SLE, and it might be useful in estimating disease activity in patients with SLE.
Increased levels of circulating intercellular adhesion molecule 1 in kawasaki disease
Authors: Furukawa Susumu , Imai Kohzoh , Matsubara Tomoyo , Yone Kenji , Yachi Akira , Okumura Ko , Yabuta Keijiro
Published: February 2007

Objective. We investigated whether levels of intercellular adhesion molecule 1 (ICAM‐1) antigen shed into the circulation increase during acute Kawasaki disease (KD). We also compared ICAM‐1 levels in acute KD with those in anaphylactoid purpura (AP) and in measles.

Methods. Serum ICAM‐1 levels were measured by a double‐determinant immunoassay using 2 monoclonal antibodies in the FAST (Falcon assay screening test) system. Serum levels of tumor necrosis factor α (TNFα) were measured by a specific and sensitive sandwich enzyme immunoassay.

Results. Patients with KD, but not those with AP or measles, had increased levels of shed ICAM‐1 antigen in serum samples obtained during acute stages. Moreover, during the acute stage, KD patients with coronary artery lesions (CAL) had still higher levels of shed ICAM‐1 than did those without CAL. We found a positive correlation between serum levels of shed ICAM‐1 and levels of TNFα during acute KD.

Conclusion. Our findings suggest that the serum ICAM‐1 level is an important immunologic parameter for determining the severity of vascular damage during acute KD.
Yersinia–triggered reactive arthritis. use of polymerase chain reaction and immunocytochemical staining in the detection of bacterial components from synovial specimens
Authors: Nikkari Simo , Merilahti‐Palo Riitta , Saario Riitta , Söderstrom Karl‐ove , Granfors Kaisa , Skurnik Mikael , Toivanen Paavo
Published: February 2007

Objective. To investigate whether microbial DNA is present in synovial specimens from patients with Yersinia‐triggered reactive arthritis.

Methods. Synovial specimens from 13 patients with Yersinia enterocolitica O:3‐triggered reactive arthritis and from 16 control patients were studied using polymerase chain reaction and immunocytochemical staining techniques.

Results. Yersinia chromosomal DNA was not found in any of the synovial specimens from Yersinia‐triggered arthritis patients or controls, whereas with immunocytochemical techniques, Yersinia antigens were observed in synovial specimens from all of the patients with Yersinia‐triggered reactive arthritis.

Conclusion. Only stable bacterial degradation products, not whole bacteria, are present at the site of inflammation in Yersinia‐triggered reactive arthritis.
Anticentromere antibody as a predictor of digital ischemic loss in patients with systemic sclerosis
Authors: Wigley Fredrick M. , Wise Robert A. , Miller Robyn , Needleman Barbara W. , Spence Robert J.
Published: February 2007

Objective. To determine the clinical and serologic risk factors for digital ischemic events in patients with systemic sclerosis (SSc).

Methods. Retrospective review of clinical and laboratory data and review of current clinical status of 98 patients with SSc, seen between 1985 and 1990.

Results. Amputation of 1 or more digits due to ischemia occurred in 20.4% of the patients; 9.2% had multiple digit loss. Sclerodactyly alone and anticentromere antibody (ACA) were associated with loss of 1 or more digits. Age, smoking status, duration of disease, or duration of Raynaud's phenomenon were not predictive for loss of digits.

Conclusion. Patients with limited SSc who are positive for ACA have an increased risk of major peripheral vascular occlusive disease.
Lymphokine‐activated killer cell and natural killer cell activities in patients with systemic sclerosis
Authors: Kantor Thomas V. , Whiteside Theresa L. , Friberg Diana , Buckingham Robert B. , Medsger Thomas A.
Published: February 2007

Objective. To determine the ability of T lymphocytes and natural killer (NK) cells from patients with systemic sclerosis (SSc) to respond to cytokines and to generate immune effector cells.

Methods. The numbers and percentages of peripheral blood T and NK cells were examined by 2‐color flow cytometry, and NK and lymphokine‐activated killer (LAK) cell function were measured in 4‐hour 51Cr‐release assays, in 34 patients with SSc. The patients were categorized into 3 subgroups: 10 had diffuse cutaneous disease of ≤3 years disease duration, 11 had diffuse cutaneous SSc of >3 years duration, and 13 had limited cutaneous disease.

Results. Baseline and activated NK and T cell numbers and NK activity were normal in SSc patients. However, mean LAK activity was significantly depressed in all SSc subgroups.

Conclusion. Decreased LAK cell function, despite normal numbers of circulating T and NK cells, indicates that SSc patients have poor ability to produce effector cells in response to interleukin‐2.
Primary idiopathic pulmonary hypertension complicated by pulmonary arterial thrombosis. Association with antiphospholipid antibodies
Authors: Luchi Monica E. , Asherson Ronald A. , Lahita Robert G.
Published: February 2007

Objective. We report an unusual case of primary pulmonary hypertension and review the pertinent literature.

Methods. A 25‐year‐old Caucasian woman presented with progressive dyspnea and was found to have pulmonary hypertension. Antiphospholipid antibodies were present. The patient had a prolonged hospital course, was unresponsive to therapy, and died suddenly.

Results. Postmortem examination revealed a large thrombus affecting the right main pulmonary artery, with plexogenic arteriopathy bilaterally.

Conclusion. This appears to be the first reported case of primary pulmonary hypertension complicated by thrombosis of a main pulmonary artery in association with antiphospholipid antibodies.
Production of natural killer cell activity‐augmenting factor (interleukin‐6) by human epiphyseal chondrocytes
Authors: Malejczyk Jacek , Malejczyk Magdalena , Urbanski Agatha , Luger Thomas A.
Published: February 2007

Objective. We sought to determine the capacity of human epiphyseal chondrocytes to modulate the cytotoxic activity of human natural killer (NK) cells by determining whether they release interleukin‐6 (IL‐6), a cytokine recently shown to stimulate NK cell activity.

Methods. Conditioned medium from human epiphyseal chondrocyte cultures (Ch‐CM) was tested for IL‐6 activity using the B9 cell hybridoma assay. Its NK cell‐stimulating capacity in the presence of K562 (myelogenous leukemia) cells or human chondrocytes was evaluated in a 4‐hour 51Cr‐release assay. Ch‐CM–derived IL‐6/NK cell–augmenting factor activity was partially purified by high‐performance liquid chromatography (HPLC) gel filtration and Western blot.

Results. Ch‐CM contained an NK cell‐augmenting factor (NKAF) which was blocked by IL‐2 or IL‐6 antibodies. Ch‐CM did not contain detectable IL‐2 activity, but it stimulated IL‐2 production by human peripheral blood lymphocytes (PBL). This IL‐2–inducing capacity was inhibited by IL‐6 antibodies, indicating that chondrocytes release an IL‐6–like activity. Ch‐CM significantly enhanced the proliferation of IL‐6–dependent B9 hybridoma cells, and Western blot analysis of Ch‐CM revealed specific bands corresponding to those of highly purified IL‐6. Upon HPLC gel filtration, chondrocyte NKAF copurified with chondrocyte IL‐6. Pure IL‐6 and chondrocyte IL‐6 were tested for their ability to stimulate the cytotoxic activity of human PBL against chondrocytes. Both mediators significantly enhanced chondrocyte killing. Lysis of chondrocytes by PBL was mediated by NK cells, since depletion of CD16+ cells resulted in inhibition of the activity.

Conclusion. Thus, upon stimulation, chondrocytes produce IL‐6 which, through IL‐2 induction, augments the activity of NK cells against K562 target cells as well as against chondrocytes.
Characterization of a spontaneously occurring arthritis in male DBA/1 mice
Authors: Nordling Cecilia , Karlsson‐Parra Alex , Jansson Liselotte , Holmdahl Rikard , Klareskog Lars
Published: February 2007

Objective. We studied the incidence, severity, histopathologic features, and status of infection in a spontaneous polyarthritis which occurs in male DBA/1 mice.

Methods. Over a 25‐week period, the arthritis was evaluated macroscopically in naive mice of different strains. The histopathology was evaluated at different phases of the disease. Virologic and bacteriologic investigations were performed.

Results. The arthritis occurs in ∼80% of aging male DBA/1 mice. The disease is chronic and destructive, and the affected joints are characterized by synovial lining proliferation and infiltration of inflammatory cells, mainly mononuclear. The susceptibility appears to be dependent on both sex‐linked and non‐sex‐linked genes, since female DBA/1 mice are not affected and since male BALB/c housed in the same colony are only marginally affected.

Conclusion. This first description of a spontaneous arthritis in aging male DBA/1 mice should provide new opportunities to study general features of a chronic and intermittent arthritis in a well‐characterized strain, in which no generalized aberrations of the immune system have been described.
Glucocorticoid receptors in rheumatoid arthritis
Authors: Schlaghecke Reiner , Kornely Elisabeth , Wollenhaupt JÜRgen , Specker Christof
Published: February 2007

Objective.Increasing evidence suggests that there is a close interrelationship between the immune system and the hypothalamic–pituitary–adrenal axis. One way these systems are linked is through specific receptor proteins for glucocorticoid hormones in lymphocytes. We sought to determine whether the levels of these receptors differ in patients with rheumatoid arthritis (RA), compared with levels in healthy subjects.

Methods.We determined the density and affinity of lymphocyte glucocorticoid receptors, as well as basal cortisol levels, in 90 patients with active RA and in 200 healthy controls, using a whole cell binding assay.

Results.The number of glucocorticoid receptors in RA patients was significantly lower than in controls (mean ± SD 2,144 ± 500 per cell versus 5,619 ± 1,373 per cell;P< 0.001), whereas there were no differences in binding affinity or cortisol levels. Glucocorticoid receptor density did not correlate with inflammatory disease activity.

Conclusion.Since glucocorticoids are potent immunosuppressive agents, the decrease in their receptors suggests an impairment of the immune–hypothalamic‐pituitary–adrenal axis in patients with RA.
Rheumatoid arthritis in greek and british patients. a comparative clinical, radiologic, and serologic study
Authors: Drosos A. A. , Lanchbury J. S. , Panayi G. S. , Moutsopoulos H. M.
Published: February 2007

Objective. To compare the clinical, radiologic, and serologic expression of rheumatoid arthritis (RA) in 2 different populations.

Methods. Standard protocols and assessment criteria were used in this study of 108 Greek and 107 British patients with RA.

Results. British patients had more severe articular involvement than did Greeks, as judged by the duration of morning stiffness (P < 0.005), grip strength (P < 0.0001), and the numbers of swollen (P < 0.001) and tender (P < 0.0001) joints. The British RA patients also had more severe joint damage on radiologic examination, as evidenced by Steinbrocker stage III (P < 0.005) and IV (P < 0.025) disease and had more extraarticular manifestations (P < 0.0001), including rheumatoid nodules (P < 0.0001) and Raynaud's phenomenon (P < 0.05). Greek RA patients, however, more frequently presented with sicca manifestations (P < 0.001) and serum antibodies to Ro/SS‐A (P < 0.025). Furthermore, Ro/SS‐A antibodies were associated with a high incidence of side effects to D‐penicillamine only in the Greeks.

Conclusion. Genetic and environmental factors may be responsible for these striking differences in disease expression between these 2 European populations with RA.
HLA Class ii sequence polymorphisms and susceptibility to rheumatoid arthritis in greeks. the hla–drβ shared‐epitope hypothesis accounts for the disease in only a minority of greek patients
Authors: Boki Kyriaki A. , Panayi Gabriel S. , Vaughan Robert W. , Drosos Alexandros A. , Moutsopoulos Haralampos M. , Lanchbury Jerry S.
Published: February 2007

Objective. In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA–DRβ found notably in the HLA–DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen.

Methods. We characterized HLA–DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization.

Results. DNA analysis in the RA patients showed that although individual HLA–DR allelic associations were weak, a relatively conserved HLA–DRβ motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA–DRβ1 of 43.5% of the RA patients versus 15.5% of the controls (unconnected P = 0.00004).

Conclusion. Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA–DRβ motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.