bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐photon–emission computed tomography analysis of cerebral blood flow in the evaluation of central nervous system involvement in patients with systemic lupus erythematosus
Authors: Rubbert A. , Marienhagen J. , Pirner K. , Manger B. , Grebmeier J. , Engelhardt A. , Wolf F. , Kalden J. R.
Published: February 2007

Objective. Single‐photon–emission computed tomography (SPECT) scanning was used to detect potential central nervous system (CNS) involvement in patients with systemic lupus erythematosus (SLE), by determining cerebral blood flow abnormalities.

Methods. SPECT scans were performed on 35 SLE patients, grouped into 3 categories: those without neuropsychiatric symptoms (n = 10), those with definite neurologic or psychiatric disorders (n = 10), and those with mild symptoms such as headache or memory disturbances (n = 15). SPECT scan features were classified as normal or as focal or diffuse defects in uptake.

Results. SPECT findings were normal in 9 of the 10 patients without CNS symptoms, and abnormal in 9 of the 10 patients with overt neuropsychiatric disease (with motor or sensory deficits). Interestingly, only 4 of the 15 patients (26.7%) with mild symptoms suggestive of CNS disease had normal SPECT findings; the 11 remaining patients showed focal (53.3%) or diffuse (20%) uptake defects. An association between SPECT findings and disease duration was also observed, but there was no correlation of SPECT results with overall disease activity, serologic findings, or medications used.

Conclusion. Our data suggest that in a substantial proportion of patients, SPECT analysis may provide additional information on potential CNS involvement, and may therefore be useful in therapeutic decisionmaking and disease monitoring in order to prevent CNS damage.
Nucleotide sequence analysis of thel and vh domains of five human igm directed to lamin b. evidence for an antigen‐driven process in the generation of human autoantibodies to lamin b
Authors: Mariette Xavier , Brouet Jean‐Claude , Danon Françoise , Tsapis Andréas , Lassoued Kaïss
Published: February 2007

Objective. To gain insight into the genetic origin of human antilamin autoantibodies, we determined the nucleotide sequence of the light and heavy chain variable region (VL and VH) domains of 5 IgM antibodies directed to lamin B. These antibodies represent a distinct subset of antinuclear antibodies, and their presence is associated with a particular lupus‐like syndrome.

Methods. We derived and cloned lymphoblastoid cell lines from peripheral blood B cells of 3 patients, selected anti–lamin B–producing subclones, and sequenced the messenger RNA coding for Ig heavy and light chains.

Results. We isolated 2 subclones (1 IgMκ, 1 IgMλ) from one patient (FUR) and 2 subclones (both IgMλ) from another (HER). In contrast, all 8 lines derived from B cells isolated from the third patient (BEN) synthesized identical anti–lamin B IgMκ antibodies: All VL and VH domains from these 5 IgM were encoded by different VL or VH genes. DH regions were all different, and there was no restriction in the use of JL or JH segments. Analysis of the nucleotide sequence of the VL domains allowed the identification of the putative germinal gene in 3 instances (VκIV, Humkv325, and VλIII.1); the overall ratios of replacement:silent mutations (R:S) were 6.5 and 1.2 in the complementarity‐determining regions (CDRs) and framework regions (FRs), respectively. The 2 other λ sequences belonged to the VλIII family. With regard to VH domains, 3 of 5 derived from previously identified germline genes (VHIV 4.19, VHIV 4.22, and VHIII 9.1); the overall R:S ratio for these genes was 8 and 1.5 in CDRs and FRs, respectively.

Conclusion. Taken together, these data provide evidence that the repertoire of human antilamin autoantibodies is not restricted and that the antigen (or another kind of selective pressure) plays a role in the generation of autoantibodies to lamin B. This hypothesis is in accordance with the reactivity of these antibodies to discrete epitopes of lamin B.
Association between reactive arthritis and antecedent infection with shigella flexneri carrying a 2‐md plasmid and encoding an hla–b27 mimetic epitope
Authors: Stieglitz H. , Lipsky P.
Published: February 2007

Objective. To determine whether Shigella flexneri strains that cause enteric infection and are associated with reactive arthritis (ReA) carry a 2‐Md plasmid, pHS‐2, which encodes an HLA–B27 mimetic epitope.

Methods. Plasmid DNA from Shigella isolates was characterized by DNA–DNA hybridization, restriction endonuclease digestion, and sequencing.

Results. S flexneri strains associated with ReA carried a 2‐Md plasmid homologous to pHS‐2.

Conclusion. The finding of pHS‐2 in additional Shigella strains associated with ReA underscores its potential importance in the etiology of the disease.
A quantitative assessment of limited joint mobility in patients with diabetes
Authors: Schulte L. , Roberts M. S. , Zimmerman C. , Ketler J. , Simon L. S.
Published: February 2007

Objective. The syndrome of limited joint mobility is a common but not widely recognized musculoskeletal complication of diabetes. The purpose of this study was to further characterize this syndrome using quantitative goniometric measures.

Methods. Cross‐sectional analysis of a sample population was performed to establish the prevalence, location, and severity of limited joint mobility and to determine its relationship to extraarticular manifestations and complications of diabetes. Passive range of motion of both upper extremities was measured by goniometry in 70 adult patients with insulin‐dependent diabetes mellitus and 70 nondiabetic controls who were group‐matched for age, sex, and general activity level. Joint mobility was assessed by both individual joint motions and a composite scoring technique.

Results. Analysis of individual joints and composite scores revealed significant differences between dominant and nondominant extremities in both the control and the diabetic groups. Diabetic patients were generally less flexible than nondiabetic subjects throughout the arm, especially in shoulder and finger joints. In the full study population, multivariate analysis revealed that advanced age, male sex, and the presence of diabetes were associated with decreased passive range of motion for a majority of joints (P < 0.05). In the diabetes group, passive range of motion was significantly correlated (P < 0.05) with age, sex, duration of diabetes, and to a variable extent, glucose control, but was not correlated with the presence of clinically significant neuropathy, retinopathy, nephropathy, or peripheral vascular disease, with activity level, or with hand dominance. Stepwise regression analysis failed to identify single key joint motion(s) to serve as possible screening tests in predicting generalized limited joint mobility of the upper extremity. Finally, the effect of limb usage on range of motion in flexion may differ in diabetic and nondiabetic subjects.

Conclusion. Limited joint mobility is a generalized phenomenon occurring throughout the upper extremities of many diabetic patients. It is significantly related to age, sex, and to a variable extent duration of diabetes and glucose control. It is not related to the standard complications of diabetes as defined in this study.
Long‐distance running causes site‐dependent decrease of cartilage glycosaminoglycan content in the knee joints of beagle dogs
Authors: Arokoski Jari , Kiviranta Ilkka , Jurvelin Jukka , Tammi Markku , Helminen Heikki J.
Published: February 2007

Objective. To study the effects of a long‐term (1‐year) program of running exercise (up to 40 km/day) on the thickness and glycosaminoglycan (GAG) content of articular cartilage in the knee and humeral head cartilage of young dogs.

Methods. Samples for histologic analysis were obtained from 12 different locations of the joints. We conducted a detailed, area‐specific analysis, measuring the thickness of articular cartilage and analyzing the distribution of Safranin O stain that binds stoichiometrically to GAG as determined by quantitative microspectrophotometry.

Results. Running exercise decreased the GAG content of the uncalcified articular cartilage in the weight‐bearing summits of the femoral condyles by 5–13% (P < 0.05), while at margins of these areas the GAG content was equivalent to control levels. In the lateral condyle of the femur, the reduction was most prominent in the superficial zone (up to 28% decrease; P < 0.05), and extended into the intermediate zone (11% decrease; P < 0.05). GAG content was also significantly reduced in the superficial zone at the lateral condyle of the tibia and the head of the humerus, by 35% (P < 0.01) and 15% (P < 0.05), respectively. Running did not alter GAG concentration in the patellofemoral region.

Conclusion. The GAG depletion caused by 40‐km/day running exercise is restricted to prominent weight‐bearing areas of the joint and begins from the superficial cartilage without signs of degeneration. The different degree and type of joint loading can explain the site‐dependent cartilage response to long‐distance running. The loss of GAGs was possibly due to breakdown of proteoglycans, which could not be compensated for by neosynthesis of molecules. With time, this may affect the condition of articular cartilage, especially if the joint is exposed to loading for lengthy periods.
Myopathy with mitochondrial alterations in patients with primary biliary cirrhosis and antimitochondrial antibodies
Authors: Varga John , Heiman‐Patterson Terry , Muñoz Santiago , Love Lori A.
Published: February 2007

Objective. To describe a syndrome of severe progressive myopathy, cardiomyopathy, and gastrointestinal dysmotility in 2 patients with asymptomatic primary biliary cirrhosis (PBC) and circulating anti‐mitochondrial autoantibodies, and to review pertinent literature concerning this syndrome.

Methods. Clinical, electrophysiologic, serologic, and pathologic studies of the 2 affected patients were conducted.

Results. Skeletal muscle involvement was manifested by progressive weakness of the proximal muscles, marked diaphragmatic dysfunction with consequent hypoventilation and respiratory failure, and moderately elevated levels of muscle‐associated enzymes. Serum from both patients contained antimitochondrial antibodies that reacted with components of the mitochondrial keto acid dehydrogenase enzyme complex. Results of electromyography were consistent with a myopathic process. The microscopic and ultrastructural changes in the skeletal muscles were distinct from those of typical myositis, and were notable for striking subsarcolemmal aggregation of abnormal mitochondria in the absence of significant inflammation.

Conclusion. Severe skeletal muscle, cardiac, and gastrointestinal pathology with abnormalities of the muscle mitochondria develops in a subset of patients with mild PBC and antimitochondrial antibodies. The pathogenesis of this syndrome is unclear, but may be related to the presence of the antimitochondrial autoantibodies.
Regulation of human normal and osteoarthritic chondrocyte interleukin‐1 receptor by antirheumatic drugs
Authors: Pelletier Jean‐Pierre , Mccollum Robert , Dibattista John , Loose Leland D. , Cloutier Jean‐Marie , Martel‐Pelletier Johanne
Published: February 2007

Objective. To determine the effect of antirheumatic drugs and corticosteroids on interleukin‐1 receptor (IL‐1R) levels in, and IL‐1–stimulated metalloprotease synthesis and expression by, normal and osteoarthritic (OA) human articular chondrocytes.

Methods. IL‐1R affinity and density of human chondrocytes were determined using radioligand binding experiments. Collagenase and stromelysin synthesis activities were analyzed by 14C‐labeled type I collagen and Azocoll assays, respectively. Their messenger RNA (mRNA) levels were determined by Northern blot analysis. IL‐1α, IL‐1β, IL‐1 receptor antagonist, and β2‐microglobulin were measured using enzyme‐linked immunosorbent assays. Protein synthesis was determined by 3H‐leucine incorporation.

Results. Antirheumatic drugs reduced the IL‐1R level in normal and OA chondrocytes in a dose‐dependent manner. In normal chondrocytes, tenidap reduced the IL‐1R level by 44% at 5 μg/ml to 88% at 100 μg/ml (50% inhibition constant [IC50] 10.1 μg/ml), indomethacin reduced IL‐1R by 6% at 1.5 μg/ml to 43% at 60 μg/ml, and naproxen reduced IL‐1R by 10% at 10 μg/ml to 41% at 300 μg/ml; the effects observed with indomethacin and naproxen occurred only when the drugs were used at levels above their therapeutic concentrations. In OA chondrocytes, the effect of indomethacin and naproxen on the IL‐1R level was greatly reduced, whereas tenidap still had a marked effect (IC50 22.5 μg/ml). Dexamethasone and hydrocortisone had no consistent effect on the IL‐1R level. At a therapeutic concentration (20 μg/ml), tenidap was found to reduce the IL‐1R level in a time‐dependent manner, with maximum inhibition (98%) by 48 hours. Tenidap was also found to markedly reduce collagenase and stromelysin synthesis and mRNA levels in IL‐1–stimulated chondrocytes.

Conclusion. The suppressive effects of tenidap on IL‐1–stimulated metalloprotease synthesis and expression in OA and normal chondrocytes are likely related to a decrease in IL‐1R levels. At therapeutic concentrations, tenidap has a greater effect on the IL‐1R level than is seen with indomethacin or naproxen, and glucocorticoids have no effect on IL‐1R.
A canadian study of the total medical costs for patients with systemic lupus erythematosus and the predictors of costs
Authors: Clarke Ann E. , Esdaile John M. , Bloch Daniel A. , Lacaille Diane , Danoff Deborah S. , Fries James F.
Published: February 2007

Objective. We conducted a cost identification analysis on 164 consecutive patients with systemic lupus erythematosus (SLE) who entered the Montreal General Hospital Lupus Registry between January 1977 and January 1990, compared their costs to the population of Quebec, and determined the predictors of cost.

Methods. In January 1990 and 1991, participants completed questionnaires on health services utilization and on employment history over the preceding 6 months, as well as on functional, psychological, and social well‐being. The societal burden of SLE was determined in terms of direct costs (all resources consumed in patient care) and indirect costs (wages lost due to lack of work force participation because of morbidity).

Results. The mean total annual cost for 1989, as assessed in January 1990 and expressed in 1990 Canadian dollars, was $13,094. Although only 44% of the patients were fully employed, indirect costs were responsible for 54% of this total ($7,071). Ambulatory costs, primarily diagnostic procedures, medications, and visits to health care professionals, comprised 55% of direct costs ($3,331). The results of the 1990 cost determination were similar. On average, hospitalizations among SLE patients were 4 times more frequent than among the general population of Quebec (matched for age and sex), and the number of ambulatory visits to physicians was double that for the average resident of Quebec. Higher 1989 values of creatinine and a poorer level of physical functioning were the best predictors of higher 1990 direct costs (R2 = 0.29). A poorer SLE well‐being score, a combination of education and employment status, and a weaker level of social support were the best predictors of higher indirect costs (R2 = 0.29).

Conclusion. The direct and indirect costs for patients with SLE are substantial, and their respective predictors are distinct. Direct costs arise from organic complications which induce functional disability. Predictors of indirect costs are potentially amenable to psychological or social interventions and may be more easily modified than the determinants of direct costs, thereby improving patient outcome while simultaneously reducing disease costs.
Isolated congenital heart block. long‐term outcome of mothers and characterization of the immune response to ss‐a/ro and to ss‐b/la
Authors: Julkunen Heikki , Kurki Pekka , Kaaja Risto , Heikkilä Ritva , Immonen Ilkka , K. L. Chan Edward , Wallgren Eric , Friman Claes
Published: February 2007

Objective. To study the long‐term outcome of mothers of children with isolated congenital heart block (CHB) and to characterize the maternal autoantibody response to SS‐A/Ro and SS‐B/La.

Methods. A retrospective clinical study of 33 mothers a mean of 11.2 years (SD 9.2 years, range 0–32 years) after the delivery of their first child with CHB. A clinical and immunologic study of 31 of these mothers, compared with 89 healthy mothers, 45 mothers with systemic lupus erythematosus (SLE), and 19 mothers with primary Sjögren's syndrome (SS), all of whom had healthy children. The specificity of the autoantibody responses to SS‐A/Ro and SS‐B/La was studied by enzyme‐linked immunosorbent assays using purified human recombinant antigens and affinity‐purified antigens.

Results. By the time of the analysis, 2 (6%) of the 33 mothers of CHB children had died and 6 (18%) had met the criteria for SLE. As a group, mothers of CHB children had clinical and immunologic characteristics more closely related to primary SS than to SLE or any other connective tissue disease. The predominant autoantibody response was to the SS‐A/Ro antigens, notably to the 52‐kd SS‐A/Ro protein (prevalence 97%). Compared with controls with SLE, mothers of CHB children had higher titers of antibodies to recombinant 52‐kd and 60‐kd SS‐A/Ro proteins and to the affinity‐purified SS‐A/Ro antigen (P < 0.05, P < 0.01, and P < 0.001, respectively). Compared with controls with primary SS, the autoantibody responses were similar.

Conclusion. The predominant autoimmune disorder in mothers of children with CHB is subclinical primary SS. Antibodies to SS‐A/Ro appear to be a prerequisite for the development of CHB.
U1—70‐kd autoantibody–positive mixed connective tissue disease in children. A longitudinal clinical and serologic analysis
Authors: Hoffman Robert W. , Cassidy James T. , Takeda Yoshihiko , Smith‐Jones Elaine I. , Wang Grace S. , Sharp Gordon C.
Published: February 2007

Objective. To obtain longitudinal data on the clinical, serologic, and immunogenetic features of children with mixed connective tissue disease (MCTD).

Methods. Eleven children with MCTD were followed up for a mean of 9.8 years. Enzyme‐linked immunosorbent assay and immunoblotting were used to analyze sera for autoantibodies to small nuclear ribonucleoprotein polypeptides. HLA types were determined in 9 patients, by microcytotoxicity and DNA typing.

Results. All 11 children had anti–U1–70‐kd autoantibodies. Six of 9 were positive for HLA–DR2, 4 of 9 for HLA–DR4, and 9 of 9 for either HLA–DR2 or DR4. Outcomes were favorable with no functional impairment in 8 of the 11 children and were poor in 3.

Conclusion. The frequency of HLA–DR2/DR4 is increased among children with anti–U1–70‐kd autoantibody positive MCTD.
Inflammatory polyarthritis in mice transgenic for human t cell leukemia virus type i
Authors: Yamamoto Hiroaki , Sekiguchi Toyozo , Itagaki Keiko , Saijo Shinobu , Iwakura Yoichiro
Published: February 2007

Objective. We have recently reported that arthropathy develops in high incidence among transgenic mice carrying the pX region of human T cell leukemia virus type I (HTLV‐I). In the present study, the histopathologic features of the joints in these mice were examined in order to compare the animal disease with rheumatoid arthritis (RA) in humans.

Methods. Paraffin sections of limbs (right and left fingers, wrists, elbows, shoulders, toes, knees, and ankles) were stained with hematoxylin and eosin, periodic acid–Schiff, azan‐Mallory, or phosphotungstic acid hematoxylin, and examined by light microscopy.

Results. Abnormalities of the limbs began to occur as early as 3 weeks of age, and the incidence gradually increased until the mice were 12 months old. The incidence of arthropathy was 22% (48 of 217) at 3 months of age and 28% (18 of 64) at 6 months. The severity of the histopathologic changes in the joints of the transgenic mice ranged from grade I to grade IV.

Conclusion. The major histopathologic features in the joints of HTLV‐I transgenic mice are similar to those in humans with RA. Thus, these mice may represent a useful model for the study of the disease in humans.
Management of work disability. resources for vocational rehabilitation
Authors: Allaire Saralynn H. , Partridge Alison J. , Andrews Howard F. , Liang Matthew H.
Published: February 2007

Objective. To review the state–federal vocational rehabilitation (SF‐VR) system and its utilization by persons with rheumatic conditions.

Methods. SF‐VR system instruction manuals, and literature on rheumatology rehabilitation, work disability, and rehabilitation counseling were reviewed. National and Massachusetts state SF‐VR system data on persons with “arthritis and rheumatism” were analyzed.

Results. The SF‐VR system is used by a small proportion of persons with rheumatic diseases. Fifty‐two percent of clients with arthritis are employed after receiving services.

Conclusion. Although evidence indicates that VR services for persons with rheumatic conditions improves their chances for reemployment, the SF‐VR system is underutilized.
Incidence of rheumatoid arthritis in central massachusetts
Authors: Chan Kin‐Wei A. , Felson David T. , Yood Robert A. , Walker Alexander M.
Published: February 2007

Objective. To determine whether there is a secular decline in the incidence of rheumatoid arthritis (RA), as has been suggested by previous studies.

Methods. In the absence of comprehensive data in the United States population, we estimated RA incidence in a health maintenance organization population from 1987 through 1990 and compared the rates with those in an earlier, similarly performed study from Rochester, Minnesota, which covered the years 1950 through 1974. RA estimates were based on our review of medical records of patients who had been diagnosed as having RA or related diseases during the period of January 1, 1987 through December 31, 1990.

Results. Annual age‐standardized incidence of classic or definite RA (according to the American College of Rheumatology [formerly, the American Rheumatism Association] 1958 criteria) in patients aged 18 or older was 22 per 100,000 in men and 60 per 100,000 in women. The incidence of RA increased with age, with a marked increase in women older than 50.

Conclusion. We found no secular change in RA incidence compared with the similarly ascertained historical data.
Generalized osteoarthritis associated with increased insulin‐like growth factor types i and ii and transforming growth factor β in cortical bone from the iliac crest. possible mechanism of increased bone density and protection against osteoporosis
Authors: Dequeker J. , Mohan S. , Finkelman R. D. , Aerssens J. , Baylink D. J.
Published: February 2007

Objective. To investigate whether growth factors stored in bone might explain the increased bone density and resistance to osteoporosis in generalized osteoarthritis.

Methods. Levels of insulin‐like growth factor (IGF) types I and II and transforming growth factor β (TGFβ) were measured in extracts of cortical bone from the iliac crest obtained at necropsy from subjects with or without osteoarthritis of the hands.

Results. Concentrations of IGF‐I, IGF‐II, and TGFβ were significantly higher in extracts of bone powder from subjects in the osteoarthritis group than in extracts from subjects in the control group.

Conclusion. The results suggest that the increased bone density and resistance to osteoporosis in patients with osteoarthritis may be associated with increased skeletal concentrations of IGF‐I, IGF‐II, and TGFβ and may reflect a generally increased biosynthetic activity of osteoblasts in these patients.
Physician Variation in Diagnostic Testing for Low Back Pain. Who You See Is What You Get
Authors: Cherkin Daniel C. , Deyo Richard A. , Wheeler Kimberly , Ciol Marcia A.
Published: February 2007

Objective. This study examined patterns of diagnostic test use for patients with low back pain. Three specific questions were addressed: 1) What tests do physicians recommend for patients with 3 common types of low back pain? 2) Do physicians in various specialties differ in the tests they would order? and 3) How appropriate are physicians' choices of tests, based on current medical knowledge and expert recommendations?

Methods. A stratified national random sample of 2,604 physicians in 8 specialties was mailed questionnaires asking about the tests they would order for hypothetical patients with acute back pain, sciatica, or chronic low back pain. Physicians were also asked which procedures they generally used to evaluate suspected lumbar nerve root compression. These responses were compared with guidelines that have been suggested by the Quebec Task Force on Spinal Disorders, based on comprehensive evaluation of the scientific literature.

Results. Approximately 1,100 physicians responded to the survey (43% response rate). Magnetic resonance imaging was the most frequently used procedure for evaluating suspected lumbar nerve root compression, although a majority of neurosurgeons would still use myelography. Neurosurgeons and neurologists were twice as likely as other specialists to order an imaging study for patients with acute nonradiating pain or chronic back pain. Physiatrists and neurologists were more than 3 times as likely as other specialists to order electromyograms for acute back pain with sciatica or chronic back pain. Rheumatologists were almost twice as likely as other specialists to order laboratory tests for both acute and chronic back pain. The reported use of imaging and electrodiagnostic tests was generally premature and more extensive than that recommended by the Quebec Task Force.

Conclusion. There is little consensus, either within or among specialties, on the use of diagnostic tests for patients with back pain. Thus, the diagnostic evaluation depends heavily on the individual physician and his or her specialty, and not just the patient's symptoms and findings. Furthermore, many physicians may be ordering imaging studies too early and for patients who do not have the appropriate clinical indications. These results suggest a need for additional clinical guidelines as well as better adherence to existing guidelines.
Enhanced Synthesis of Cysteinyl Leukotrienes in Juvenile Rheumatoid Arthritis
Authors: Fauler J. , Thon A. , Tsikas D. , Hardt H. Von Der , Frölich J. C.
Published: February 2007

Objective. Endogenous synthesis of cysteinyl leukotrienes in juvenile rheumatoid arthritis (JRA) was investigated.

Methods. Cysteinyl leukotriene synthesis was assessed by measuring the excretion of leukotriene E4 (LTE4) in urine by radioimmunoassay. The identity of urinary LTE4 was investigated by gas chromatography—mass spectrometry (GC‐MS), and 2,3‐dinor‐thromboxane B2 was measured with GC‐MS.

Results. Excretion of LTE4 into urine was significantly (P < 0.05) enhanced in children with JRA compared with that in healthy children (n = 10). Aspirin, in a dosage of 2.5 gm/day, had no effect on urinary LTE4 levels, but it reduced urinary 2,3‐dinorthromboxane B2 levels by more than 85% in healthy adults. There was a positive correlation between LTE4 excretion and the number of affected joints.

Conclusion. This study demonstrates a markedly enhanced cysteinyl leukotriene synthesis and a positive correlation between LTE4 excretion and the number of affected joints in children with JRA.
Human Osteoarthritic Chondrocytes Possess an Increased Number of Insulin‐Like Growth Factor 1 Binding Sites but are Unresponsive to its Stimulation
Authors: Doré Sylvain , Pelletier Jean‐Pierre , Dibattista John A. , Tardif Ginette , Brazeau Paul , Martel‐Pelletier Johanne
Published: February 2007

Objective. To characterize the insulin‐like growth factor 1 (IGF‐1) receptor in human osteoarthritic (OA) and normal adult chondrocytes. The biologic response of chondrocytes to IGF‐1 stimulation was examined, as was the presence and synthesis of IGF binding proteins (IGFBP) in these cells.

Methods. Binding studies, Northern blot, immunohistochemical analysis, and affinity cross‐linking experiments were performed for characterization of the IGF receptor, and the latter method was also used for IGFBP determination. The biologic response was estimated via the incorporation of radiolabeled proline into a newly synthesized protein.

Results. Binding experiments revealed a single class of binding sites. The mean ± SEM affinity (Kd) of normal chondrocytes was 1.4 ± 0.4 nM, with 26.8 ± 5.5 x 103 binding sites/cell. OA chondrocytes had a lower affinity (Kd 15.4 ± 4.7 nM) and a higher density (1,178.3 ± 299.5 x 103 binding sites/cell) compared with normal cells (P < 0.004 and P < 0.001, respectively). Immunohistochemical studies with a monoclonal antibody (MAb) against the type 1 IGF receptor (αIR3) showed increased staining in OA cartilage compared with normal tissue. Biologic responses of chondrocytes after IGF‐1 stimulation revealed that OA chondrocytes were unresponsive, whereas a 2.5‐fold increase in new protein synthesis was observed in normal cells. Competition studies in normal chondrocytes revealed that both IGF‐1 and IGF‐2 displaced radiolabeled IGF‐1 in a comparable manner; however, insulin at high concentration weakly competes. Moreover, MAb αIR3 effectively blocked specific binding in normal chondrocytes (77%), but not in OA chondrocytes (26%). Northern blot and covalent cross‐linking analyses revealed the specific band characteristic of type 1 receptor. With the latter technique, other bands corresponding to the IGFBPs were also detected. Comparison between normal and OA chondrocytes showed increased intensity of the IGFBP bands, particularly those corresponding to the IGFBP‐3 doublet.

Conclusion. It is shown that type 1 IGF receptor is expressed in human articular cartilage and that the level of binding sites is significantly increased in OA chondrocytes. Interestingly, despite the higher level of binding sites in OA cells, no response to IGF‐1 stimulation was found in these cells. Our data suggest that this increase in specific binding may involve not only the type 1 IGF receptor but also IGFBP on the cell surface. The latter, by binding the IGF‐1, will diminish the bioavailability of IGF‐1 and thus prevent its anabolic action.
Clinical Correlations of Osteoarthritis Associated with a Single‐Base Mutation (Arginine519 to Cysteine) in Type II Procollagen Gene
Authors: Pun Yvonne L. , Moskowitz Roland W. , Lie Sutek , Sundstrom Walter R. , Block Sidney R. , Mcewen Currier , Williams H. James , Bleasel Jane F. , Holderbaum Daniel , Haqqi Tariq M.
Published: February 2007

Objective. To investigate the occurrence and clinical correlation of the arg519‐to‐cys mutation in the type II procollagen gene in patients with osteoarthritis (OA).

Methods. Sixty‐six subjects from 7 families with a strong family history of generalized OA and 13 patients with erosive OA were evaluated clinically and radiologically. Blood samples from 58 subjects in the familial OA group and from all 13 patients with erosive OA were obtained for DNA analysis. Exon 31 of COL2A1, which spans residue 519, was amplified by polymerase chain reaction.

Results. The arg519‐to‐cys mutation was detected in 2 of the 7 families with generalized OA. In these 2 families, the mutation was present in the 2 probands and in 19 other clinically affected family members, as well as in 3 (so‐far) clinically unaffected family members (ages 25, 14, and 11 years). It was absent in 18 clinically unaffected members tested. The mutation was associated with a distinctive pattern of early‐onset, aggressive, generalized OA with a mild spinal chondrodysplasia. Inheritance was autosomal dominant. No mutation was found in any of the patients with erosive OA.

Conclusion. The arg519‐to‐cys mutation defines a new pathogenic factor in generalized OA with characteristic clinical and radiologic features. The demonstration of a mutation in 3 of 8 families with OA studied thus far suggests a significant incidence of genetically related clinical OA.
Methotrexate for Rheumatoid Arthritis
Authors: Kremer Joel M. , Alarcón Graciela S. , Lightfoot Robert W. , Willkens Robert F. , Furst Daniel E. , Williams H. James , Dent Peter B. , Weinblatt Michael E.
Published: February 2007

Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4–8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12‐month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number of patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.
A Cost‐Utility Analysis of Misoprostol Prophylaxis for Rheumatoid Arthritis Patients Receiving Nonsteroidal Antiinflammatory Drugs
Authors: Gabriel Sherine E. , Campion Mary E. , O'Fallon W. Michael
Published: February 2007

Objective. To determine the cost‐utility of low‐dose misoprostol prophylaxis in rheumatoid arthritis (RA) patients treated with nonsteroidal antiinflammatory drugs (NSAIDs).

Methods. Prospectively collected, population‐ased data on 57 RA patients' preferences (obtained using the category scaling and time trade‐off techniques), charge data from a consecutive, populationbased cohort of 36 RA patients with NSAID‐related gastric ulcer, and literature‐derived probability estimates were incorporated into a decision analysis model.

Results. Probabilistic sensitivity analysis using 10,000 Monte Carlo simulations demonstrated that, on average, prophylaxis resulted in modest additional costs and no additional quality‐of‐life benefits. At best, the incremental cost per quality‐adjusted life year gained was $9,333. At worst, prophylaxis reduced quality of life. Prophylaxis was cost‐saving if the ulcer complication rate was > 1.5%, or if the 3‐month price of misoprostol was ≤$95.

Conclusion. Whereas prophylaxis may be costsaving among high‐risk NSAID users, from some patients' perspective, it reduces quality of life. Although these data may not be generalizable to other clinical populations, they illustrate the importance of incorporating patient preferences into economic evaluations.
Transforming Growth Factor β1 Regulates Tissue Inhibitor of Metalloproteinases—1 Expression in Differentiated Human Articular Chondrocytes
Authors: Günther Monika , Haubeck Hans‐Dieter , Van De Leur Eddy , Bläser Jörg , Bender Sven , Gütgemann Ines , Fischer Dagmar‐Christiane , Tschesche Harald , Greiling Helmut , Heinrich Peter C. , Graeve Lutz
Published: February 2007

Objective. To investigate the role of interleukin‐6 (IL‐6) and transforming growth factor β1 (TGF β1) in the regulation of tissue inhibitor of metalloproteinases—1 (TIMP‐1) synthesis in human articular chondrocytes.

Methods. Articular cartilage was obtained from human knee joints 24 hours after death. Chondrocytes were isolated by collagenase digestion and embedded in low‐gelling‐temperature agarose. After stimulation by cytokines, total RNA was isolated and analyzed by Northern blotting. TIMP‐1 protein levels were determined using a competitive enzyme‐linked immunosorbent assay.

Results. Human chondrocytes in agarose culture expressed messenger RNA (mRNA) for the IL‐6 receptor (gp80) and its signal‐transducing subunit gp130. In contrast to the findings in a previous study, IL‐6 did not stimulate TIMP‐1 expression in these cells, whereas TGF β1 was an important inducer of TIMP‐1 mRNA and protein synthesis.

Conclusion. Our findings suggest that TGF β1 has a protective effect on the extracellular matrix of human articular chondrocytes.
Exacerbation of Established Collagen‐Induced Arthritis in Mice Treated with An Anti—T Cell Receptor Antibody
Authors: Maeda Takeshi , Saikawa Isao , Hotokebuchi Takao , Sugioka Yoichi , Eto Masatoshi , Murakami Yoshiyuki , Nomoto Kikuo
Published: February 2007

Objective. To investigate the effect of T cell depletion on established collagen‐induced arthritis (CIA) in mice, using monoclonal antibodies (MAb) to T cell receptor α/β (TCRα/β). In addition, experiments using anti‐CD3 MAb were performed for comparison.

Methods. CIA was induced in male DBA/1 mice by immunizing them twice with bovine type II collagen (CII). The arthritis score and anti‐CII antibody titers were examined serially. Proportions of T cells were determined by fluorescence‐activated cell sorter (FACS) analysis on spleen cells or peripheral blood cells.

Results. When anti‐TCRα/β MAb was injected on the day of CII priming, no arthritis was detected in association with depressed anti‐CII antibody titers. Unexpectedly, however, when MAb was given after arthritis was established, a rapid exacerbation of arthritis was observed, which resulted in ankylosis of most joints. Anti‐CII antibody titers were not affected. The addition of anti‐TCRγ/δ MAb had no effect on the augmented arthritis. T cell depletion by anti‐CD3 MAb during established CIA also caused an enhancement of arthritis, which was, however, weak and only transient. FACS analysis revealed that the early improvement of arthritis after the transient augmentation seen in the mice treated with anti‐CD3 MAb paralleled the early recovery of α/β T cells in the periphery.

Conclusion. The present results support the concept that α/β T cells, in general, may play a regulatory role in the clinical course of murine CIA after disease onset. Therefore, caution is recommended when using intensive T cell—targeted therapy in patients with rheumatoid arthritis.
Intraarticular Injections with Methylprednisolone Acetate Reduce Osteoarthritic Lesions in Parallel with Chondrocyte Stromelysin Synthesis in Experimental Osteoarthritis
Authors: Pelletier Jean‐Pierre , Mineau FrançOis , Raynauld Jean‐Pierre , Woessner J. Frederick , Gunja‐Smith Zeenat , Martel‐Pelletier Johanne
Published: February 2007

Objective. To examine the effect of intraarticular injections of methylprednisolone acetate (MA) on osteoarthritic lesions and chondrocyte stromelysin synthesis in experimental osteoarthritis (OA).

Methods. In 15 mongrel dogs, the anterior cruciate ligament of the right knee was sectioned by a stab wound. Eight dogs received intraarticular injections of MA (20 mg) at the time of surgery and 4 weeks later; 7 had no treatment. The dogs were killed 8 weeks after surgery. Five normal dogs were used as controls. Macroscopic evaluation of the lesions, including measurements of osteophytes and areas of surface lesions on the condyles and plateaus, was conducted, along with histologic evaluation of the severity of lesions. Immunohistochemical analysis was carried out using a rabbit polyclonal antibody against stromelysin, followed by evaluation of matrix and chondrocyte staining using morphometric analysis.

Results. Treatment with MA significantly reduced the incidence (P < 0.0004) and size (P < 0.0001) of osteophytes. The histologic grading of cartilage lesions was also significantly reduced both on condyles (P < 0.01) and on plateaus (P < 0.002). Immunohistochemical studies revealed, for OA cartilage, a marked increase (P < 0.002) in the percentage of chondrocytes positive for stromelysin and in the intensity of staining throughout all the layers of the cartilage, as well as specific matrix staining (P < 0.005). Treatment with MA reduced staining at both the chondrocyte (P < 0.002) and the matrix (P < 0.01) levels toward normal.

Conclusion. These findings provide additional evidence for the protective effect of corticosteroid injections on OA lesions, and indicate that the effect of this drug may be mediated through the suppression of stromelysin synthesis.
Variation among rheumatologists in the use of prednisone and second‐line agents for the treatment of rheumatoid arthritis
Authors: Criswell Lindsey A. , Redfearn William J.
Published: February 2007

Objective. To test for and estimate variation among rheumatologists in their prescribing of prednisone and second‐line agents for the treatment of rheumatoid arthritis (RA), after taking into account the characteristics of their patients.

Methods. Multiple logistic regression incorporating random effects for rheumatologists, with adjustment for patient characteristics.

Results. Values for the likelihood‐ratio statistic provided strong evidence of such variation. Random‐effect variance estimates showed that the variation is of great magnitude.

Conclusion. Even after patient characteristics have been taken into account, the data show that the rheumatologist may strongly influence the use of prednisone and second‐line agents by a patient.
Diacerhein in the treatment of osteoarthritis of the hip
Authors: Nguyen Minh , Dougados Maxime , Berdah Laurent , Amor Bernard
Published: February 2007

Objective. To determine the efficacy and safety of diacerhein, a potential new therapeutic agent with properties differing from those of existing nonsteroidal anti‐inflammatory drugs (NSAIDs), and of a combination of diacerhein and an NSAID (tenoxicam) in the treatment of osteoarthritis (OA) of the hip.

Methods. Two hundred eighty‐eight patients with painful OA of the hip were enrolled in an 8‐week randomized, double‐blind, placebo‐controlled, 2 x 2 factorial design study. Four treatment groups were defined: 1) diacerhein placebo and tenoxicam placebo, 2) tenoxicam and diacerhein placebo, 3) diacerhein and tenoxicam placebo, and 4) diacerhein and tenoxicam. The daily dosages of diacerhein and tenoxicam were 100 mg and 20 mg, respectively.

Results. Analyses of efficacy showed no interaction between diacerhein and tenoxicam in terms of efficacy, a clinically significant rapid (≤2 weeks) and persisting effect of tenoxicam during the 8 weeks of the study, and a slow‐acting (6 weeks) effect of diacerhein. Moderate, transient diarrhea was the most frequent side effect observed in the diacerhein group (37%) compared with the placebo group (4%).

Conclusion. Both tenoxicam and diacerhein appear to be superior to placebo, and neither agent appears to significantly enhance or detract from the efficacy of the other when they are administered concomitantly. The onset of action of diacerhein appears to be delayed (≥4 weeks).
Expression of sequences homologous to htlv‐i tax gene in the labial salivary glands of japanese patients with sjögren's syndrome
Authors: Sumida Takayuki , Yonaha Fumiko , Maeda Toshiro , Kita Yasuhiko , Iwamoto Itsuo , Koike Takao , Yoshida Sho
Published: February 2007

Objective. To address the question of whether the human T cell leukemia virus type I (HTLV‐I) gene is associated with the etiology of Sjögren's syndrome (SS).

Methods. RNA expression of HTLV‐I gag, pol, env, and tax genes in labial salivary glands (LSGs) from SS patients who were seronegative for antibodies to HTLV‐I was examined using reverse transcription and polymerase chain reaction techniques.

Results. The HTLV‐I tax gene, but not the HTLV‐I gag, pol, or env genes, was detected in LSG samples from 4 of 14 patients (29%). The nucleotide sequences of the HTLV‐I pXIV region in these 4 patients' LSGs showed 100% homology to the HTLV‐I pXIV gene from the MT‐2 cell line.

Conclusion. These findings suggest that products encoding sequences homologous to the HTLV‐I pXIV gene in SS patients' LSGs might be candidates for self‐antigen and/or lead to activation of autoreactive T lymphocytes through trans‐acting transcriptional activation.
Determination of the blood lactate:pyruvate ratio as a noninvasive test for the diagnosis of zidovudine myopathy
Authors: Chariot Patrick , Monnet Isabelle , Mouchet Manuela , Rohr Magali , Lefaucheur Jean‐Pascal , Dubreuil‐Lemaire Marie‐Laure , Chousterman Michel , Gherardi Romain
Published: February 2007

Objective. To evaluate the use of the lactate: pyruvate ratio as a test for the detection of zidovudine myopathy.

Methods. Twenty consecutive human immunodeficiency virus–infected patients with muscle involvement and 20 without muscle involvement were studied prospectively. Blood lactate and pyruvate levels and serum creatine kinase levels were tested, muscle involvement was assessed both clinically and electrophysiologically, and muscle biopsy was performed in patients with myopathy.

Results. Nine patients had biopsy‐proven zidovudine myopathy. All 9 had a high lactate:pyruvate ratio, with elevations on 2 of 2 determinations in 6 patients and on 1 of 2 in 3 patients. Two of 11 patients with other myopathies and 2 of 20 patients without myopathy had a high lactate:pyruvate ratio on 1 of 2 determinations.

Conclusion. The lactate:pyruvate ratio, when determined repeatedly, is a sensitive test for detecting mitochondrial muscular toxicity of zidovudine.
Minocycline in active rheumatoid arthritis
Authors: Kloppenburg Margreet , Breedveld Ferdinand C. , Terwiel JACK P. H. , Mallee Constant , Dijkmans BEN A. C.
Published: February 2007

Objective. To determine the efficacy of minocycline in the treatment of rheumatoid arthritis (RA).

Methods. Minocycline (maximal oral daily dose 200 mg) or placebo was administered in a 26‐week, randomized, double‐blind study to 80 patients with active RA, who were treated or had previously been treated with at least one disease‐modifying antirheumatic drug.

Results. There were 15 premature discontinuations: 6 (5 taking minocycline) because of adverse effects, 8 (all taking placebo) because of lack of efficacy, and 1 (taking placebo) because of intercurrent illness. There was a statistically significant improvement in the minocycline group over the placebo group. There was a pronounced improvement in laboratory parameters of disease activity; however, improvement in clinical parameters was less impressive. The observed adverse effects attributable to minocycline were mainly gastrointestinal symptoms and dizziness.

Conclusion. The results of the present study suggest that minocycline is beneficial and relatively safe in RA patients.