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Objective: To compare the extent and type of damage in patients with late onset and earlier onset systemic lupus erythematosus (SLE) using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)., Methods: A total of 86 SLE patients with disease onset after the age of 54 years were matched for center, sex, and ethnic origin with 155 SLE patients with disease onset before the age of 40 years. SDI scores were obtained at one year and 5 years after the diagnosis of SLE. Analysis was based on conditional logistic regression., Results: SDI scores were higher in the late onset group than in younger patients at both one [mean 0.7 (range 0-3) vs 0.3 (range 0-3); p < 0.001] and 5 years [mean 1.6 (range 0-8) vs 0.9 (range 0-7); p < 0.001] after diagnosis. There was also a difference in the pattern of organ damage. While damage to the skin, kidneys, and central nervous system occurred with similar frequency, late onset disease was characterized by significantly more cardiovascular (OR 14.13, p < 0.001), ocular (OR 9.38, p = 0.001), and musculoskeletal (OR 2.68, p = 0.016) damage and malignancy (OR 7.04, p = 0.046)., Conclusion: The occurrence of organ damage assessed by the SDI is greater in patients with late onset SLE than in younger patients and, by this criterion, lupus cannot be judged to be more benign in this age group. Also, the pattern of damage is different, but whether this reflects age per se or the effect of the disease in the elderly remains to be established.

Runx3/Pebp2alphaC null mouse gastric mucosa exhibits hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to growth-inhibitory and apoptosis-inducing action of TGF-beta, indicating that Runx3 is a major growth regulator of gastric epithelial cells. Between 45% and 60% of human gastric cancer cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of human gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression, and a mutation (R122C) occurring within the conserved Runt domain abolished the tumor-suppressive effect of RUNX3, suggesting that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer.

Objectives: The aim of this study was to describe the incidence and clinical characteristics of Mycobacterium tuberculosis infection in SLE and RA patients in Korea where the prevalence rate of active pulmonary tuberculosis in a general population is relatively higher than in Western countries., Patients: We reviewed the medical records of 283 SLE and 284 RA patients retrospectively and then assessed the incidence, risk factors, and clinical characteristics of active tuberculous infection. We then compared the results for the two different groups., Results: Tuberculosis was documented in 15 SLE and 7 RA patients with an incidence rate of 7.9/1,000 patient-years and 2.3/1,000 patient-years, respectively (p = 0.003). SLE-associated tuberculosis cases included 3 of miliary tuberculosis, 7 of pulmonary tuberculosis (including 1 case of diffuse pulmonary involvement with meningitis) predominantly involving two or more lobes at the mid-/lower lungfield, and 5 extra-pulmonary forms (joint, bone, kidney, larynx, pleura). All of the RA-associated tuberculosis cases were pulmonary forms with the majority being localized to single lobe, and only one case had a past history of tuberculosis, whereas a past history of tuberculosis and a longer duration of the underlying disease were significantly correlated with the development of tuberculosis in the SLE patients. Major organ involvement, the mean daily dosage of prednisolone, and a history of over 30 mg of daily prednisolone were not related to the development of tuberculosis. However, when we took only those patients taking corticosteroid until the diagnosis of tuberculosis for analysis, SLE patients with tuberculosis showed a higher daily dosage of prednisolone than those without tuberculosis., Conclusion: Taken together, the characteristics of tuberculosis in SLE patients were: (1) a higher incidence rate, (2) more frequent extra-pulmonary involvement, (3) more extensive pulmonary involvement, and (4) a higher relapse rate than in rheumatoid arthritis. Thus, the contributory role of M. tuberculosis infection in the morbidity and mortality of patients with SLE must be emphasized, especially in areas in which this bacteria is endemic.

Both systemic lupus erythematosus and Sjogren's syndrome are autoimmune diseases. Almost all organs can be involved but the gall bladder is an unusual site. We report a 39-year-old woman with systemic lupus erythematosus and Sjogren's syndrome presenting with acute acalculous cholecystitis. It is a very rare complication and, in the literature review, surgical interventions are mostly applied for treatment. In our case, high dose corticosteroid was tried and clinical manifestations and radiologic findings were improved.

Patients with systemic lupus erythematosus (SLE) have a chance of developing liver involvement in their lifetime. The main cause of liver involvement in SLE patients is previous treatment with hepatotoxic drugs or hepatotropic viral hepatitis. Wilson's disease is a hereditary disorder and is usually diagnosed in patients presenting either neuropsychiatric disorders or manifestations related to chronic liver disease. Fulminant hepatic failure as the initial manifestation of Wilson's disease is rare. The relationship between systemic lupus erythematosus and Wilson's disease has not been established. We report a case of a 12-year-old girl with SLE who presented fulminant hepatic failure as an initial manifestation of Wilson's disease. The diagnosis was established with decreased serum ceruloplasmin level and the presence of Kayser-Fleischer ring. We treated with repeated plasma exchange. Despite repeated plasma exchange she died of multi-organ failure on the 16th hospital day. Considering this case, Wilson's disease should be considered as a cause of fulminant hepatic failure, especially in juvenile age cases.

High-dose intravenous immunoglobulins alter the disease activity of adult-onset Still's disease (AOSD). Because activation status of FcgammaR is possibly dependent on their genetic polymorphisms, we investigated whether the polymorphisms of FcgammaR IIa and IIIa are risk factors, and affect the clinical features of AOSD. Genomic DNA was extracted from 36 patients and from 197 healthy controls. Polymerase chain reaction for FcgammaR IIa and IIIa using the allele-specific primers and direct sequencing of FcgammaR IIIa polymorphic site were performed. The frequencies of FcgammaR IIa/IIIa genotype between patients with AOSD and controls were not different. The allelic frequencies of FcgammaR IIa/IIIa between patients with AOSD and controls were not different, either. However, the FcgammaR IIa-R/R131 genotype was associated with a higher concentration of hemoglobin (p=0.04) and stable liver function (p=0.009) than the other genotypes. The FcgammaR IIIa-F/F176 genotype was associated with significantly lower titers of serum ferritin (p=0.025), and higher serum albumin (p=0.037) and cholesterol (p=0.014) concentrations than the other genotypes. This study suggest that the FcgammaR IIa and IIIa polymorphisms might not be genetic risk factors for AOSD in Korean, but contribute to the activity of disease. FcgammaR IIa-R/R131 and IIIa-F/F176 genotypes, low-binding genotypes for IgG2a and G1, may have more protective effects in acute stage of the disease than the other genotypes.

Undifferentiated spondyloarthropathy (USpA) includes the forms that do not meet criteria for the established categories of spondyloarthropathy. The clinical spectrum of USpA is therefore wide and few studies have been published on USpA, especially peripheral arthritis. A total of 107 patients fulfilling the European Spondyloarthropathy Study Group criteria for SpA were studied retrospectively by a chart review and interview by a rheumatologist. Peripheral arthritis, excluding hip and shoulder involvement, occurred in 97 of the 107 patients (91%). Joint involvement tended to be monoarticular or pauciarticular, and most frequently developed in peripheral joints including the knee and ankle. Among the 97 patients with peripheral arthritis, only 37 (35%) had a persistent arthritis. HLA-B27 was detected in 80 patients (78%). Peripheral arthritis was found in the lower extremities regardless of symmetry or asymmetry and tended to run a benign course with only a few patients having persistent arthritis.

Systemic lupus erythematosus (SLE) is an inflammatory multisystem disease of unknown etiology with immunologic aberrations. Many studies have shown that genetic and environmental factors are implicated in the development of SLE. Angiotensin-converting enzyme (ACE) affects various immune phenomena through the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin II and inactivating bradykinin. We investigated the correlation between insertion/ deletion polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement and lupus nephritis. Two-hundred and eleven Korean patients fulfilling the ACR criteria and 114 healthy subjects were enrolled. The ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. The nephritis patients were classified by the WHO classification. In addition, the activity and chronicity index were used to assess the severity of renal involvement. We evaluated vascular involvement by the presence or absence of hypertension, Raynaud's phenomenon, livedo reticularis, antineutrophil cytoplasmic antibody and the SLICC/ACR Damage Index. The gene frequency of ACE gene polymorphism was as follows: II 39 vs 34%, ID 41 vs 50%, DD 20 vs 16% in SLE patients and controls, respectively. There was no difference in genotype frequency between both groups. There were no significant differences between the distribution of ACE gene genotypes and lupus nephritis and its related parameters, including WHO classification, activity index, chronicity index, renal dysfunction and amount of 24 h urinary protein. The ACE genotypes and alleles did not affect the presence of vascular manifestations evaluated, but the frequency of DD genotype was significantly low in SLE patients with Raynaud's phenomenon compared to those without Raynaud's phenomenon (P = 0.002 for ACE ID vs DD and II, OR 2.7, 95% CI 1.43-5.09; P=0.023 for ACE DD vs ID and II, OR 0.33, 95% CI 0.12-0.89). Also skewing from DD to II genotype was noted in patients with anti-Sm antibody compared to those without anti-Sm antibody (P = 0.025 for ACE DD vs ID and II, OR 0.21, 95% CI 0.05-0.93). The onset age of serositis was older in patients with the ID genotype than the others (ID= 34.5+/-10.8, II + DD = 25.6+/-10.2, P= 0.002). Also the onset age of malar rash was older in patients with II genotype than the others (II=26.7+/-8.4, ID+DD=21.3+/-9.0; P=0.021). The patients with I allele showed a significantly higher frequency of serositis (P = 0.022). Taken together, the I/D polymorphisms of ACE gene did not affect susceptibility of SLE, lupus nephritis and the vascular manifestations, including Raynaud's phenomenon, in Korean SLE patients, although the DD genotype was negatively associated with Raynaud's phenomenon among SLE patients. However, it would be valuable to evaluate the role of other genes potentially related to vascular events, such as endothelin, nitric oxide or angiotensin II receptor as well as ACE gene.

The Caenorhabditis elegans run gene encodes a Runt domain factor. Runx1, Runx2, and Runx3 are the three known mammalian homologs of run. Runx1, which plays an essential role in hematopoiesis, has been identified at the breakpoint of chromosome translocations that are responsible for human leukemia. Runx2 plays an essential role in osteogenesis, and inactivation of one allele of Runx2 is responsible for the human disease cleidocranial dysplasia. To understand the role of run in C. elegans, we used transgenic run::GFP reporter constructs and a double-stranded RNA-mediated interference method. The expression of run was detected as early as the bean stage exclusively in the nuclei of seam hypodermal cells and lasted until the L3 stage. At the larval stage, expression of run was additionally detected in intestinal cells. The regulatory elements responsible for the postembryonic hypodermal seam cells and intestinal cells were separately located within a 7.2-kb-long intron region. This is the first report demonstrating that an intron region is essential for stage-specific and cell type-specific expression of a C. elegans gene. RNA interference analysis targeting the run gene resulted in an early larva-lethal phenotype, with apparent malformation of the hypodermis and intestine. These results suggest that run is involved in the development of a functional hypodermis and gut in C. elegans. The highly conserved role of the Runt domain transcription factor in gut development during evolution from nematodes to mammals is discussed.

Objective: Our aims were to translate WOMAC and Lequesne osteoarthritis (OA) indices into Korean (KWOMAC, KLequesne) and confirm their reliability, validity, and responsiveness., Design: The WOMAC and Lequesne indices were translated into Korean by three translators and translated back into English by three different translators. Fifty consecutive patients with OA were asked to rate the comprehensibility of the questions on a 4-point scale. The comprehensibility (responding with 'good' and 'very good') ranged from 78% to 99%. Test-retest was performed in another 47 patients with knee OA. The final 53 patients with knee OA, within the context of a clinical trial of two non-steroidal antiinflammatory drugs for 4 weeks, were studied to assess the internal consistency, construct validity, and responsiveness of the Korean versions., Results: The test-retest reliability of the KWOMAC 3 subscales and the KLequesne yielded intraclass correlation coefficients of 0.79-0.89 and 0.87. The Cronbach standardized alphas were 0.81-0.96 and 0.75, respectively. For the construct validity, the correlation coefficients of both the KWOMAC subscales and the KLequesne with patient pain assessment and patient global assessment were between 0.30 and 0.70 and the KWOMAC subscales correlated with the KLequesne (0.41-0.55). For responsiveness, the KWOMAC and KLequesne scores significantly improved by 4-week post-treatment compared with pre-treatment; effect size values were between 0.41 and 0.69 for the KWOMAC subscales and 0.70 for the KLequesne; and the relative efficiency values of the KWOMAC subscales vs the KLequesne were between 0.87 and 0.90., Conclusions: The reliability, validity, and responsiveness of the KWOMAC and the KLequesne are confirmed., (Copyright 2001 OsteoArthritis Research Society International.)

We report the synthesis of single-crystalline silver nanowires of atomic dimensions. The ultrathin silver wires with 0.4 nanometer width grow up to micrometer-scale length inside the pores of self-assembled calix[4]hydroquinone nanotubes by electro-/photochemical redox reaction in an ambient aqueous phase. The present subnanowires are very stable under ambient air and aqueous environments, unlike previously reported metal wires of approximately 1 nanometer diameter, which existed only transiently in ultrahigh vacuum. The wires exist as coherently oriented three-dimensional arrays of ultrahigh density and thus could be used as model systems for investigating one-dimensional phenomena and as nanoconnectors for designing nanoelectronic devices.

We report herein the results of the cross-cultural adaptation and validation into the Korean language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. A total of 221 subjects were enrolled: 87 patients with JIA (18% systemic onset, 37% polyarticular onset, 12% extended oligoarticular subtype, and 33% persistent oligoarticular subtype) and 134 healthy children. The CHAQ clinically discriminated between healthy subjects and the four JIA subtypes of patients, with the JIA patients having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the JIA patients having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Korean version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

PEBP2 beta/Cbf beta is the beta subunit of PEBP2/Cbf, which has been demonstrated to have important biological activities in hematopoiesis and osteogenesis. However, PEBP2 beta is ubiquitously expressed, suggesting that PEBP2 has other additionally important physiological activities. In an effort to elucidate other possible functions for PEBP2, we have isolated a novel gene that encodes a PEBP2 beta-interacting protein from a mouse cDNA library. We have called this gene Crl-1 for charged amino acid rich leucine zipper-1 (Crl-1) because it is rich in charged amino acids and contains a putative leucine zipper region. Expression studies in a 17.5 days post-coitum mouse embryo demonstrated Crl-1 expression mainly in the olfactory bulb and cerebral cortex. Post-natally, Crl-1 expression was additionally observed in the cerebellar cortex with strong expression in the hippocampus. These findings show that this novel PEBP2 beta-interacting protein is expressed mainly in subsets of neuronal cells, suggesting that Crl-1 plays some role in the developing mouse brain.

Objective: Health status and disease activity in patients with systemic lupus erythematosus (SLE) and other chronic diseases are strongly associated with social support, which suggests that enhanced social support in medical care might improve SLE outcome. There has been little or no study on identifying patients for whom social support would be most beneficial. It would allow practitioners to enable social support more effectively as a complement to disease management., Methods: A retrospective cohort (200 patients with SLE from 5 centers), balanced by race and insurance status, was studied in a cross sectional design. Demographic, clinical, socioeconomic, and psychosocial factors and disease outcomes [Systemic Lupus Activity Measure (SLAM), Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR), SF-36] were measured. Using multivariate linear regression and ANOVA (outcome = SF-36 physical function, mental health), we examined the interaction between social support and patients' characteristics, including race, age, income, occupation, insurance, employment, education, and social network, and characteristics of the disease itself such as disease activity (SLAM) at diagnosis, damage (SLICC/ACR) at diagnosis, and comorbidity., Results: In multivariate models, higher social support was significantly associated (p < 0.05) with better physical function when respondents were white, had income above poverty level, had Medicare or private insurance (vs Medicaid or no insurance), and had low disease activity at diagnosis. Social support was associated with better mental health, although there was no significant interaction between social support and other predictors of mental health., Conclusion: The data suggest that social support is beneficial for mental health for all groups, but has the greatest opportunity for influence among those already possessing social, economic, and health advantages.

The aim of this study was to determine the distribution of the FcgammaRlla and FcgammaRIIIa polymorphisms and their association with clinical manifestations in Korean lupus patients. Three hundred SLE (systemic lupus erythematosus) patients (48 male, 252 female) meeting 1982 ACR criteria and 197 Korean disease-free controls were enrolled. Genotyping for FcgammaRlla 131 R/H and FcgammaRIIIa 176 F/V was performed by PCR of genomic DNA using allele-specific primers and the FcgammaRIIIa genotype was confirmed by direct sequencing of PCR product in some cases. There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE and the controls (P=0.002 for R/R131 vs R/H131 and H/H131, OR 2.5 (95% Cl 1.4-4.5), but not in FcgammaRIIIa genotypes. FcgammaRIIa-R allele was a significant predictor of lupus nephritis, as compared with SLE patients without nephritis (P=0.034 for R131 vs H131, OR 1.4 (95% Cl 1.03-1.9)), but proliferative nephritis (WHO class III and IV) was less common in patients with FcgammaRlla-R/R131 and in FcgammaRIIa-R allele. In 300 SLE patients, high binding allele combination H131/V176 was less common in SLE with nephritis than in SLE without nephritis. Hemolytic anemia was less common in R131/F176 allele combination among four FcgammaRIIa/FcgammaRIIIa allelic combinations. Male SLE patients showed a higher frequency of renal involvement, serositis, thrombocytopenia, malar rash and discoid rash than female SLE, and male SLE had a higher frequency of FcgammaRIIa-R/R131 or R131-allele than male controls, but FcgammaRIIa or FcgammaRIIIa genotypes had no association with renal involvement in male SLE patients. FcgammaRIIa-H/H131 showed a higher frequency of hemolytic anemia and less pulmonary complications in male SLE. Female SLE patients showed higher frequency of any hematologic abnormality, lymphopenia, anticardiolipin antibody (+) and anti-Ro antibody (+) than male SLE, and had earlier onset of first symptoms. There was no skewing in FcgammaRIIa or FcgammaRIIIa genotypes between female SLE and female controls, but FcgammaRIIa-R131 allele showed skewing between female SLE with nephritis and female SLE without nephritis. The age at onset of thrombocytopenia was earlier in FcgammaRIIa R/R131 among three FcgammaRIIa genotypes, and serositis in FcgammaRIIIa-F/F176 among three FcgammaRIIIa genotypes. FcgammaRIIa-R131 homozygote was a major predisposing factor to the development of SLE and FcgammaRIIa-RI31 homozygote and R131 allele were a predisposing factor, and H131/V176 was a protective allele combination in lupus nephritis. In contrast to other ethnic patients, in our study cohort, clinical manifestation was different between male and female, and FcgammaRIIa and FcgammaRIIIa showed somewhat different clinical associations between the genders.

Background: When C2C12 pluripotent mesenchymal precursor cells are treated with transforming growth factor-beta1 (TGF-beta1), terminal differentiation into myotubes is blocked. Treatment with bone morphogenetic protein-2 (BMP-2) not only blocks myogenic differentiation but also induces osteoblastic differentiation. However, the molecular mechanisms governing the ability of TGF-beta and BMP to induce ligand-specific responses and inhibit myogenic differentiation are not known. The objective of our studies was to elucidate the molecular mechanisms that block myoblastic differentiation and induce osteoblastic differentiation in C2C12 cells., Methods: Induction of RUNX2/PEBP2alphaA/Cbfa1 by TGF-beta and BMP was examined by electrophoretic mobility shift assay (EMSA) and Northern blot analysis. C2C12 cells stably expressing RUNX2 or Smad, or both, were established, and the role of these genes in the process of osteoblastic differentiation was analyzed by examining the expression of osteoblast-specific markers., Results: Treatment of C2C12 with TGF-beta and BMP-induced RUNX2/PEBP2alphaA/Cbfa1, a global regulator of osteogenesis. Cooperation between RUNX2 and BMP-activated Smad induced osteoblastic differentiation., Conclusions: Both TGF-beta and BMP activate transcription of RUNX2, which is sufficient to inhibit myogenesis. To induce osteogenesis, BMP-induced RUNX2 must cooperate with BMP-activated Smads.

This case illustrates a young man with an 11 y history of systemic lupus erythematosus who developed lupus flare after a 9-month use of growth hormone (GH) for the treatment of growth retardation. The course of disease was improving after GH cessation and treatment with high dose corticosteroids and intravenous cyclophosphamide pulse therapy.

New clinical scales for semiquantitating disease activity in systemic lupus erythematosus (SLE) are widely used in research. They are reliable and valid measures. One of the original scales, the Systemic Lupus Activity Measure (SLAM), has been modified based on experience with it in multi-observer studies and training of individuals in its use. We tested the psychometric properties of the revised SLAM (SLAM-R). SLAM-R was tested on 30 SLE patients, who fulfilled 1997 revised ACR criteria and were selected to represent a range of disease activity. The patients were evaluated independently by two physicians, who studied the instruction booklet and who had never used SLAM-R, on two occasions 2-4 weeks apart. At the first visit, the physician's global assessment of activity using visual analog scale, anti-dsDNA Ab, C3 and C4 were checked for construct validity. The psychometric properties were analyzed with nested analysis of variance and Pearson's correlation coefficient using SAS. All patients were female, the median age was 31 (15-52) y, and the mean score of SLAM-R was 10.5 +/- 5.3 (3-26). Estimates of reliability were 0.78 of inter-rater, 0.61 of inter-visit, 0.76 of physician 1 between visits, and 0.56 of physician 2 between visits. Among subcategories except 'Eye,' the 'Gastrointestinal' category had the highest (0.96) and the 'Neuromotor' category had the lowest inter-rater reliability (0.50). With respect to construct validity, the correlation of SLAM-R scores with the disease activity variables except C4 was high and statistically significant. In conclusion, the SLAM-R is reliable and valid for measuring clinical disease activity in SLE.

Evans' syndrome is characterised by the simultaneous or sequential occurrence of Coombs'-positive haemolytic anaemia (AIHA) and immune thrombocytopenia without underlying aetiology. It has been found to be associated with collagen vascular diseases, especially systemic lupus erythematosus (SLE) and scleroderma. However, Evans' syndrome with dermatomyositis is very rare. A 59-year-old woman, who had been taking high-dose prednisolone for a month and cyclosporin for 10 days for dermatomyositis, developed purpura on the left popliteal fossa. The platelet and haemoglobin levels decreased to 77,000/mm3 and 9.8 g/dl, respectively. Antiplatelet antibody was positive. Thrombocytopenia responded to intravenous immunoglobulin (IVIG) for a short time, but further decreased in a week. Her blood film showed features of haemolytic anaemia. Laboratory findings showed reticulocytosis and a positive direct Coombs' test. Bone marrow examination showed a mild hyperplasia of erythroid precursors and megakaryocytes. The patient was successfully treated with cyclophosphamide in addition to oral prednisolone. AIHA in connective tissue disease may develop gradually and show a benign clinical course in most patients. Therefore, we suggest that patients with dermatomyositis and anaemia should always be checked for haemolysis if there is no other explanation.

Ankylosing spondylitis (AS) is characterised by its effects on the axial skeleton. The cervical spine is also vulnerable to the disease process. Our aim was to determine the frequency of radiologic changes to the cervical spine and their correlation with clinical variables. We also used the Bath Ankylosing Spondylitis Radiology Index (BASRI) system, which is one of the reliable scoring systems of radiography, to score the global radiologic changes to the cervical and lumbar spine and the hip joints in our AS cohort. There were 181 patients with anteroposterior and lateral full-flexion views on radiography of the cervical spine here included in the study. A radiologist examined the radiologic changes to all anatomical compartments of the cervical spine in detail and graded them according to the BASRI system. We used the clinical and demographic data of our AS cohort to determine their relation to the radiographic changes. Eighty-eight patients (48.6%) showed radiological changes to the cervical spine; to the discovertebral joint 35.9%; the apophyseal joint 26.0%; atlantoaxial articulation 22.1% (atlantoaxial subluxation 13.8%); the costovertebral joint 18.2%; and to the posterior ligamentous attachment 11.6%. Using the BASRI system, 73 patients (40.3%) showed radiologic changes to the cervical spine and were graded as score 1 (1.7%), 2 (22.7%), 3 (6.6%) or 4 (9.4%). Among those graded as normal by the BASRI system, 17 showed some changes the cervical spine, such as atlantoaxial joint subluxation or narrowing, and severe osteoporosis with no other radiographic changes. Current age, disease duration, inflammatory back pain and cervical symptoms were associated with the radiographic changes to the cervical spine. The BASRI-cervical spine score correlated with the BASRI-lumbar spine and hip joint score, sacroiliitis, disease duration, and duration of inflammatory back pain and cervical symptoms. Our data suggest that radiographic changes to the cervical spine are frequent in AS, and can be predicted in the patients with old age, long duration of disease and inflammatory back pain, and cervical symptoms. Also, the BASRI scoring system showed similar results as a detailed assessment of the cervical spine in our study.

When C2C12 pluripotent mesenchymal precursor cells are treated with transforming growth factor beta1 (TGF-beta1), terminal differentiation into myotubes is blocked. Treatment with bone morphogenetic protein 2 (BMP-2) not only blocks myogenic differentiation of C2C12 cells but also induces osteoblast differentiation. The molecular mechanisms governing the ability of TGF-beta1 and BMP-2 to both induce ligand-specific responses and inhibit myogenic differentiation are not known. We identified Runx2/PEBP2alphaA/Cbfa1, a global regulator of osteogenesis, as a major TGF-beta1-responsive element binding protein induced by TGF-beta1 and BMP-2 in C2C12 cells. Consistent with the observation that Runx2 can be induced by either TGF-beta1 or BMP-2, the exogenous expression of Runx2 mediated some of the effects of TGF-beta1 and BMP-2 but not osteoblast-specific gene expression. Runx2 mimicked common effects of TGF-beta1 and BMP-2 by inducing expression of matrix gene products (for example, collagen and fibronectin), suppressing MyoD expression, and inhibiting myotube formation of C2C12 cells. For osteoblast differentiation, an additional effector, BMP-specific Smad protein, was required. Our results indicate that Runx2 is a major target gene shared by TGF-beta and BMP signaling pathways and that the coordinated action of Runx2 and BMP-activated Smads leads to the induction of osteoblast-specific gene expression in C2C12 cells.

Secondary amyloidosis is an occasional complication of ankylosing spondylitis (AS) and in most cases renal amyloidosis presents with proteinuria, nephrotic syndrome and decreased renal function. We describe a 32-year-old male patient with AS manifested by frequent diarrhea, intermittent abdominal pain and low serum albumin levels. He has suffered from severe inflammatory back pain for 14 years with multiple peripheral joint involvement. Protein-losing enteropathy due to gastrointestinal amyloidosis was diagnosed with 99mTc-human albumin scintigraphy, fecal alpha-1 antitrypsin clearance and colonoscopic biopsy with Congo red staining. Somatostatin analogue octreotide and prednisolone were introduced with successful result.

Parasymphyseal insufficiency fractures are uncommon. Furthermore, none have been reported in systemic rheumatic diseases other than rheumatoid arthritis. In this article we report on parasymphyseal insufficiency fractures in a patient with mixed connective tissue disease.

We report a 25-year-old Korean woman with Adult onset Still's disease (AOSD) presented with renal amyloidosis, which had developed four years after disease onset. We successfully treated her with prednisolone, colchicine and cyclophosphamide. A review of the literature uncovered about 10 cases, most of which were treated by various regimens that resulted in poor outcomes. Renal amyloidosis should be suspected in patients with AOSD who have unexplained proteinuria. Although the mechanism of renal amyloid deposition is not well known, earlier histopathologic diagnosis and choice of regimen may affect prognosis.

Gold salts have been used for many years in the treatment of rheumatoid arthritis. The common side effects are mucocutaneous reactions, but hepatotoxic reaction and isolated neutropenia are rare complications. We report a 62-year-old woman with rheumatoid arthritis who had developed hepatitis and neutropenia simultaneously after receiving 137.5 mg of sodium aurothiomalate.

Objective: Sulfasalazine (SSZ) is an anti-rheumatic drug that has been used to treat chronic arthritis. In many reports, the use of SSZ in children with systemic onset juvenile rheumatoid arthritis (JRA) revealed frequent side effects which required discontinuation of the drug. We examined whether there were frequent side effects of SSZ in patients with adult-onset Still's Disease (AOSD)., Methods: From July 1990 to April 1998, we followed 41 AOSD patients. Ten were given SSZ for the treatment of arthritis and the side effects were studied. We also studied 109 consecutive patients with RA who had been given SSZ, as a control group. In addition, we retrospectively studied the side effects and efficacy of SSZ in both groups through their medical records., Results: Six patients (60%, p < 0.01) with AOSD experienced side effects ranging from mild ones like abdominal pain, nausea and vomiting, urticaria, and facial flushing to severe ones such as high fever, hypotension, and severe myelosuppression as well as fulminant hepatitis, which led to the death of one patient. However, 16 patients (14.7%) with RA stopped using SSZ due to mild side effects such as rash, urticaria, gastrointestinal troubles, mild leukopenia, and fever. Three AOSD patients (30%, p = 0.053) and 15 RA patients (13.8%) stopped using SSZ due to its inefficacy., Conclusion: We conclude that SSZ appears to have frequent severe side effects in AOSD, as in systemic onset JRA. These potential adverse effects of SSZ should be considered when it is used to treat chronic arthritides with systemic symptoms. Further study of SSZ in the treatment of AOSD in a multi-center, placebo-controlled environment is needed.

The chromosomal translocation t(12;21) (p12;q22) which results in the TEL-AML1 fusion gene is the most frequent genetic rearrangement in childhood B-lineage acute lymphoblastic leukemia (ALL). The rearrangement in this locus, however, is only rarely observed by routine karyotypic analysis. We established a nested-reverse transcriptase-polymerase chain reaction (nested-RT-PCR) technique for the detection of the TEL-AML1 transcript, and used this to investigate the incidence of the rearrangement, and to characterize the disease present in TEL-AML1-positive B-lineage ALL patients. The TEL-AML1 fusion transcript was detected in nine of fourteen patients. These patients were relatively homogeneous in that they were young and had low presenting leukocyte counts, both features of which are associated with a favorable prognosis. Furthermore, we could detect the TEL-AML1 transcript in the peripheral blood of t(12;21)-positive patients and we used this to assess minimal residual disease (MRD) in patients during chemotherapy. The data demonstrate that nested-RT-PCR is a suitable tool for diagnosing t(12;21)-positive ALL, that these patients constitute a clinically distinct subgroup of ALL patients, and that the method could also be used to monitor MRD in these patients.

PEBP2/CBF is a heterodimeric transcription factor composed of alpha and beta subunits. The essential roles of mammalian PEBP2alpha genes, PEBP2aA/CBFA1 and PEBP2alphaB/CBFA2 in osteogenesis and hematopoiesis have been well documented. The PEBP2alpha proteins contain a 128 amino acid (aa) region which is highly homologous to Drosophila melanogaster runt and lozenge. The evolutionarily conserved region has been named the Runt domain. In this study, we isolated a cDNA encoding the Caenorhabditis elegans homolog of mammalian PEBP2alpha. The cDNA encodes a 301-aa protein with a highly conserved Runt domain. In addition, a IWRPF five aa motif is present at the C-terminal end.

This case illustrates that a child having severe neuropsychiatric systemic lupus erythematosus (NPSLE) with seizure and cerebral vascular disease showed excellent clinical outcome in response to intravenous methylprednisolone and cyclophosphamide pulse, and presented unexplained red ears phenomenon.

Members of the new PEBP2 (Polyomavirus Enhancer Binding Protein 2) family of heterodimeric transcriptional regulatory protein are composed of two subunits, alpha and beta. One of the genes encoding the alpha subunit, AML1/PEBP2 alpha B, was identified at the breakpoints of various chromosome translocations, including t(8;21) and t(12;21) associated with acute myeloid leukemia and acute lymphoblastic leukemia, respectively. The gene encoding the beta subunit (PEBP2 beta/CBFB) was also shown to be the target of the inversion of chromosome 16, another chromosomal anomaly associated with acute myeloid leukemia. Targeted disruption of either the Aml1/Pebp2 alpha B or Pebp2 beta/Cbfb gene resulted in strikingly similar phenotypes such as lack of definitive hematopoiesis of the fetal liver and accompanying hemorrhage of the central nervous system. These observations suggest that both alpha and beta subunits of PEBP2 are indispensable for its in vivo function. However, the heterodimerization of the alpha and beta subunit does not seem to occur readily suggesting that their capacity to associate might be an important rate limiting step in PEBP2 site-dependent transcription regulation. In this review, we concentrate on the possible regulatory mechanisms of PEBP2 activity in relation to leukemogenesis.

We explored a biological role of SET as it relates to cell proliferation and differentiation. Immunohistochemical staining demonstrated that the expression of SET was ubiquitous and diffuse over the whole embryo on gestational day 15. At a later stage of development, SET was expressed at relatively lower levels and localized to specific tissues and cells. On embryonic day 19, specific SET immunoreactivity was found in the epithelium of skin, respiratory tract, intestine, and retina as well as in muscle and cartilage. In these cells SET was stained mostly in the nucleus, which was supported indirectly by nuclear transport of enhanced green fluorescence protein-SET fusion proteins in ECV304 endothelial cells. Set mRNA expression was further confirmed in various cultured cells, including NIH 3T3 cells, L6 myoblast cells, human umbilical vein endothelial cells, and ECV304 cells. Using F9 teratocarcinoma cell lines, which were stimulated to differentiate into the two different cell lineages of parietal and visceral endoderm, we have further examined the role of SET. The expression of set mRNA and SET protein was diminished about three-fold in both differentiated endoderm cells compared to the undifferentiated F9 cells. However, when F9 cells were subjected to serum starvation, reduction of set mRNA abundance also took place at a similar level to that observed in response to differentiation. Consistent with this, quiescent L6 myoblast showed a marked downregulation of set mRNA compared to proliferating cells. These results suggest that SET is involved mainly in the regulation of cell proliferation rather than differentiation during embryonic development.

Both acute myeloid leukemia 1 and c-Fos are regulatory factors of hematopoietic cell differentiation. We identified that the c-fos promoter contains an acute myeloid leukemia 1 binding site at nucleotide positions -6-+14. c-fos promoter activity was induced by transient overexpression of acute myeloid leukemia 1 in Jurkat T-cells, but not by that of the short form of acute myeloid leukemia 1-MTG8, a chimeric acute myeloid leukemia 1 protein. In 32Dcl3 myeloid cells, stable overexpression of acute myeloid leukemia 1-MTG8 blocked the c-fos gene transcription and cell differentiation, but that of acute myeloid leukemia did not. These data suggest that acute myeloid leukemia 1 and acute myeloid leukemia 1-MTG8 reciprocally regulate the myeloid cell differentiation, possibly by the way of regulating c-fos gene transcription.

Objective: To describe and analyze how investigators handled concurrent steroid intake in SLE clinical trials; to identify remaining methodological problems and to discuss potential solutions., Methods: A review of the literature was performed in Medline to identify randomized controlled trials (RCT) in lupus published during the past decade. A set of criteria was defined a priori to analyze these trials covering different aspects of steroid use in RCTs with regard to eligibility, randomization, post-randomization steroid use, analysis and reporting., Results: Seventeen trials met the inclusion criteria and were analyzed. Median sample size was 30, ranging from 10-71. In three trials corticosteroid application was the study intervention. Three reports did not address steroid use among study subjects at all. In seven trials steroid use was part of the eligibility criteria in some way. Of the trials that allowed concurrent steroid use, seven checked for equal distribution of baseline steroids. In some cases clinically relevant differences did not reach statistical significance as sample sizes were very small. In only one study was randomization stratified for steroid use. Instructions for post-randomization steroid use were specified in only 3 of 14 trials where steroids were not part of the intervention. In 11 RCTs concurrent steroid use was free or no information was provided. Steroid dosing during the intervention was reported as a secondary outcome measure in four trials., Conclusions: As sample sizes are often small, simple randomization is not reliable to avoid relevant between-group differences in baseline steroids. The power of statistical testing for group differences is limited for the same reason. Stratified randomization is rarely used. Free concurrent steroid use during the intervention is frequently allowed in lupus RCTs despite the risk of bias. Better data and accepted standards for a priori specified steroid regimens in RCTs are highly warranted.

Objective: The Health Assessment Questionnaire (HAQ) is a widely used, easily administered functional scale that has high reliability and validity. Although translated versions of HAQ are available, no Korean version exists. Our aim was to translate and confirm the reliability and validity of a Korean language version of the HAQ., Methods: HAQ was translated into Korean by 3 translators and translated back into English by 3 different translators. Four questions were modified for the Korean culture. Fifty-six consecutive patients with RA were asked to rate the comprehensibility of the questions on a 4 point scale. The comprehensibility (responding with "3 or above") ranged from 76 to 98%. Another 60 consecutive patients with RA were studied for the psychometric properties of the Korean version., Results: The test-retest reliability of the Korean HAQ (KHAQ) yielded an intraclass correlation coefficient of 0.99. The Cronbach standardized alpha was 0.95 among 20 items. For construct validity, the correlation of KHAQ scores with disease severity [tender joint count, swollen joint count, patient's self-assessment of pain, erythrocyte sedimentation rate (ESR), Ritchie Index] was high and statistically significant, except for ESR. The 4 revised items were appropriate expressions of physical function since the correlations between each of the revised items and the first principal component are similar in magnitude to those between the 16 unchanged items and the principal component., Conclusion: The reliability and validity of the KHAQ is confirmed. The evaluation of responsiveness of the KHAQ is in progress.

Chromosomal translocations involving the genes encoding the alpha and beta subunits of the Pebp2/Cbf transcription factor have been associated with human acute myeloid leukemia and the preleukemic condition, myelodysplasia. Inv(16)(p13;q22) fuses the gene encoding the beta subunit of Pebp2 to the MYH11 gene encoding a smooth muscle myosin heavy chain (Smmhc). To examine the effect of the inv(16)(p13;q22) on myelopoiesis, we used the hMRP8 promoter element to generate transgenic mice expressing the Pebp2betaSmmhc chimeric fusion protein in myeloid cells. Neutrophil maturation was impaired in PEBP2betaMYH11 transgenic mice. Although the transgenic mice had normal numbers of circulating neutrophils, their bone marrow contained increased numbers of immature neutrophilic cells, which exhibited abnormal characteristics. In addition, PEBP2betaMYH11 inhibited neutrophilic differentiation in colonies derived from hematopoietic progenitors. Coexpression of both PEBP2betaMYH11 and activated NRAS induced a more severe phenotype characterized by abnormal nuclear morphology indicative of granulocytic dysplasia. These results show that PEBP2betaMYH11 can impair neutrophil development and provide evidence that alterations of Pebp2 can contribute to the genesis of myelodysplasia.

The polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor (CBF) is a transcription factor composed of two subunits, alpha and beta. The gene encoding the beta subunit is disrupted by inv(16), resulting in the formation of a chimeric protein, beta-SMMHC, which is associated with acute myelogenous leukemia. To understand the effect of beta-SMMHC on PEBP2-mediated transactivation, we used a luciferase assay system in which contribution of both the alpha and beta subunits was absolutely required to activate transcription. Using this system, we found that the minimal region of the beta subunit required for transactivation resides between amino acid 1 and 135, which is known to dimerize with the alpha subunit. In contrast, beta-SMMHC, despite having this minimal region for dimerization and transactivation, failed to support transcription with the alpha subunit. Furthermore beta-SMMHC blocked the synergistic transcription achieved by PEBP2 and CCAAT/enhancer binding protein alpha. By using a construct in which the PEBP2 alpha subunit was fused to the glucocorticoid receptor ligand binding domain, we demonstrated that coexpressed beta-SMMHC tightly sequestered the alpha subunit in the cytoplasm and blocked dexamethasone-dependent nuclear translocation of the alpha subunit. Thus, the result suggess that beta-SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the alpha subunit. Lastly proliferation of ME-1 cells that harbor inv(16) was blocked by an antisense oligonucleotide complementary to the junction of the chimeric mRNA, suggesting that beta-SMMHC contributes to leukemogenesis by blocking the differentiation of myeloid cells.

The polyomavirus enhancer binding protein 2alphaB (AML1/PEBP2alphaB/Cbfa2) plays a pivotal role in granulocyte colony-stimulating factor (G-CSF)-mediated differentiation of a myeloid progenitor cell line, 32Dc13. In this article, we report the identification of a PEBP2alphaB interacting protein, Ear-2, an orphan member of the nuclear hormone receptor superfamily that directly binds to and can inhibit the function of PEBP2alphaB. Ear-2 is expressed in proliferating 32Dc13 cells in presence of interleukin 3 but is down-regulated during differentiation induced by G-CSF. Interestingly, AML1/ETO(MTG8), a leukemogenic chimeric protein can block the differentiation of 32Dc13 cells, which is accompanied by the sustained expression of ear-2. Overexpression of Ear-2 can prevent G-CSF-induced differentiation, strongly suggesting that ear-2 is a key negative regulator of granulocytic differentiation. Our results indicate that a dynamic balance existing between PEBP2alphaB and Ear-2 appears to determine the choice between growth or differentiation for myeloid cells.

PEBP2/CBF is a heterodimeric transcription factor composed of alpha and beta subunits. There are at least three closely related genes, PEBP2alphaA/Cbfa1, AML1/PEBP2alphaB/Cbfa2 and PEBP2alphaC/Cbfa3, encoding the alpha subunit and one beta subunit encoding gene. Structural alterations of AML1 and the beta subunit gene by chromosome translocations are frequently associated with several types of human leukemia. Structural changes of any of these gene products would have potential to affect the function of others. In this study, we isolated the human PEBP2alphaA cDNA by which we mapped the gene to 6p12.3-p21.1. Human chromosome 6p21 is the locus for cleidocranial dysplasia, an autosomal dominant bone disease. Recent gene disruption study revealed that PEBP2alphaA/Cbfa1 plays an essential role in osteogenesis (Komori et al., Cell, 1997, in press). Therefore, a close relationship between human PEBP2alphaA/CBFA1 and this bone disease is strongly implicated.

The gene AML1/PEBP2 alphaB encodes the alpha subunit of transcription factor PEBP2/CBF and is essential for the establishment of fetal liver hematopoiesis. Rearrangements of AML1 are frequently associated with several types of human leukemia. Three types of AML1 cDNA isoforms have been described to date; they have been designated AML1a, AML1b, and AML1c. All of these isoforms encode the conserved-Runt domain, which harbors the DNA binding and heterodimerization activities. We have identified a new isoform of the AML1 transcript, termed AML1 deltaN, in which exon 1 is directly connected to exon 4 by alternative splicing. The AML1 deltaN transcript was detected in various hematopoietic cell lines of lymphoid to myeloid cell origin, as revealed by RNase protection and reverse transcriptase PCR analyses. The protein product of AML1 deltaN lacks the N-terminal region of AML1, including half of the Runt domain, and neither binds to DNA nor heterodimerizes with the beta subunit. However, AML1 deltaN was found to interfere with the transactivation activity of PEBP2, and the molecular region responsible for this activity was identified. Stable expression of AML1 deltaN in 32Dcl3 myeloid cells blocked granulocytic differentiation in response to granulocyte colony-stimulating factor. These results suggest that AML1 deltaN acts as a modulator of AML1 function and serves as a useful tool to dissect the functional domains in the C-terminal region of AML1.

To clarify the aspects affected by the PEBP2beta/MYH11 fusion gene involved in the inv(16), we analysed immunophenotypes in myelomonoblastic leukaemias. We found high expressions of CD34 and c-KIT antigens in myelomonoblastic cells from all patients carrying this fusion gene, including two with M4 and one CML blastic phase, in contrast to those with M4 without the fusion gene. These findings indicate that immunophenotyping is useful for detecting a leukaemia with the fusion gene in myelomonoblastic leukaemias and that the PEBP2beta/MYH11 gene is involved in immature cells expressing CD34 and c-KIT antigens.

We describe a case of pericardial tamponade as an initial manifestation of systemic lupus erythematosus (SLE). Although pericarditis or pericardial effusion is the common cardiac complication of SLE, tamponade is unusual. Treatment consists of pericardiocentesis, administration of high dose glucocorticoid an antimalarial drug.

The promyelocyte (PML)-retinoic acid receptor alpha (RARalpha) fusion gene results from a t(15;17) chromosome translocation in acute promyelocytic leukaemia. We have analysed the oncogenic potential of the human fusion PML-RARalpha product in chicken using retrovirus vectors. We show that PML-RARalpha transforms very early haematopoietic progenitor cells in vitro and induces acute leukaemias. Neither PML nor RARalpha domains alone achieve such a transformation. The PML-RARalpha viruses recovered from the transformed cells carry two point mutations in the PML domain, one of which alters both the pattern of intracellular localization of the fusion protein and its functional interference with AP-1, thus defining an essential domain in PML for oncogenic transformation.

We cloned the human cDNA corresponding to the cDNA (PEBP2alphaB-451) encoding the mouse polyomavirus enhancer-binding protein 2alphaB-451, representing a major splice variant from acute myeloid leukemia gene 1 (AML1). Genomic DNA clones of AML1 were also isolated and the exon/intron structure was determined. Furthermore, we determined and compared the genomic structures of three mammalian Runt domain-containing genes, PEBP2alphaA,AML/PEBE2alphaB and PEBP2alphaC.

Lymphadenopathy induced by wear debris after total joint arthroplasty is very rare. In this article we report on a patient with rheumatoid arthritis who developed multiple lymphadenopathy after total knee joint replacement.

The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene promoter contains a consensus sequence for the polyomavirus enhancer binding-protein 2 (PEBP2) transcription factor, which consists of alpha and beta subunits. There are at least two genes, alpha A and alpha B, encoding the alpha subunit. alpha B is the mouse homologue of human AML1 gene detected at the breakpoints of t(8;21) and t(3;21) myeloid leukemias. We examined alpha A1 (an alpha A-gene product) and alpha B1 and alpha B2 (two alpha B-encoded isomers) for their effects on the GM-CSF promoter. PEBP2 alpha A1, alpha B1, and alpha B2 proteins bound the PEBP2 site within the mouse GM-CSF promoter. PEBP2 alpha A1 and alpha B1 enhanced the expression of the GM-CSF promoter-driven reporter plasmid in unstimulated and 12-O-tetradecanoylphorbol 13-acetate/phytohemagglutinin-stimulated human Jurkat T cells. In contrast, the promoter activity was suppressed by alpha B2. Coexpression of alpha B1 and alpha B2 showed that the promoter activity could be determined by the alpha B1/alpha B2 ratio. Jurkat cell extract contained PEBP2 site-binding protein(s) that cross-reacted with antimouse alpha A1 antibodies. Northern blot analysis indicated the expression of human PEBP2 alpha A, alpha B (AML1), and beta genes in Jurkat cells. Although further studies are required to determine the precise role of PEBP2 in the GM-CSF promoter activity, the present findings suggested the importance of the relative ratio of different PEBP2 isoforms in regulating the levels of the promoter activity.