bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolated diffusing capacity reduction in systemic sclerosis
Authors: Steen Virginia D. , Graham Galen , Conte Claudia , Owens Gregory , Medsger Thomas A.
Published: February 2007

Objective. To determine the long‐term outcome of patients with systemic sclerosis (SSc) and an isolated reduction in the diffusing capacity for carbon monoxide (DLco) at the time of initial evaluation.

Methods. Patients with an isolated reduction in DLco (i.e., normal forced vital capacity [FVC] and normal ratio of the forced expiratory volume in one second [FEV1] to the FVC) on initial evaluation were identified from among 815 patients with SSc who were carefully followed up throughout their illness. We requested that patients have repeat pulmonary function testing (PFT), and the outcomes of these tests, as well as cardiopulmonary and survival outcomes, were determined.

Results. An isolated reduction in DLco, with a normal FVC was detected in 152 (19%) of the 815 patients. A subset of those with an isolated reduction in DLco (11%) developed isolated pulmonary hypertension and had severely reduced survival rates. Pulmonary hypertension was strongly associated with an initial DLco of < 55% of predicted normal and a FVC (% predicted)/DLco (% predicted) ratio of > 1.4. Among all patients in whom this ratio was > 1.4, 22% developed isolated pulmonary hypertension, compared with only 2% of those whose ratio was <1.4 (P < 0.01). Of the 152 patients with isolated DLco reduction, 73 (48%) underwent PFTs a mean of 5.4 years (range 2.0–13.2) after the initial PFT. Only 6 (8%) of these 73 patients ever had serious pulmonary disease: 5 had isolated pulmonary hypertension, and 1 had severe pulmonary fibrosis. Half of the patients with a low initial DLco demonstrated a significant improvement (>20%) at followup testing that could not be explained by the demographic, clinical, or laboratory findings at the first visit.

Conclusion. Isolated reduction in DLco is a frequent abnormality in SSc. Overall, it is associated with a good prognosis for survival and for pulmonary morbidity. A small subset of patients (11%) who have a very low DLco (<55% of predicted) have developed isolated pulmonary hypertension, all of whom had limited scleroderma.
Adhesion of peripheral blood mononuclear cells to vascular endothelium in patients with systemic sclerosis (scleroderma)
Authors: Rudnicka Lidia , Majewski Slawomir , Blaszczyk Maria , Skiendzielewska Anna , Makiela Barbara , Skopinska Magdalena , Jablonska Stefania
Published: February 2007

Objective. Perivascular infiltrates in skin, subcutaneous tissue, and internal organs are a characteristic feature of early systemic sclerosis (SSc). We studied the first step of migration of peripheral blood mononuclear cells (PBMC) through the vessel wall to the extravascular space, i.e., adhesion of PBMC to endothelial cells (EC), in patients with various forms of SSc (limited scleroderma, diffuse scleroderma, and the transitional form).

Methods. Radioisotope‐labeled patient PBMC were coincubated with umbilical cord EC in vitro, and the percentage adhesion was measured.

Results. Adhesion of PBMC to EC was markedly decreased, while adhesion of isolated active rosetteforming cells (ARFC) was significantly increased, in SSc patients compared with healthy controls. Decreased adhesion of PBMC to EC was found to correlate with a diminished percentage of ARFC in the peripheral blood. Preincubation of PBMC from healthy donors with interleukin‐2 (IL‐2) enhanced their adhesion to EC, while preincubation of PBMC from SSc patients with this cytokine resulted in a decrease in adhesion in 10 of 14 individuals. IL‐1, interferon‐γ, and transforming growth factor β had no significant effect on adhesion of SSc patient PBMC to EC. Differences in adhesion of PBMC to EC among the SSc subgroups were not significant.

Conclusion. Our findings suggest that in SSc, activation of subpopulations of PBMC leads to their enhanced adhesion to vascular endothelium in vivo and to migration of these cells to the extravascular space, resulting in the elimination from the peripheral blood of those PBMC with high ability to adhere to EC.
A Controlled study of the prevalence of cognitive dysfunction in randomly selected patients with systemic lupus erythematosus
Authors: Ginsburg Katherine S. , Wright Elizabeth A. , Larson Martin G. , Fossel Anne H. , Albert Marilyn , Schur Peter H. , Liang Matthew H.
Published: February 2007

Objective. To investigate the prevalence of cognitive dysfunction in randomly selected patients with systemic lupus erythematosus (SLE).

Methods. Randomly selected, ambulatory patients with SLE (n = 49) or with rheumatoid arthritis (RA) (n = 40) completed neuropsychological tests. These included Associate Learning, Switching Attention, Continuous Performance, Associate Recall, Hand–Eye Coordination, Pattern Comparison, Pattern Memory, the Stroop Color and Word Test, and the Symptoms Checklist–90R. Results were evaluated by multiple linear regression analysis.

Results. SLE patients had poorer performance than RA patients on the test of attention (P = 0.002) and tests of visuospatial ability (P = 0.03 and P = 0.04), independent of age, education, or steroid use. The conservative level of statistical significance, adjusting for multiple comparisons, was 0.005. SLE patients reported more symptoms of cognitive difficulty.

Conclusion. Cognitive dysfunction is common in ambulatory SLE patients as measured by standardized tests and is a cause of distress and impaired functioning. Self‐reported cognitive difficulty appears to correlate with objective performance.
Recombinant human interleukin‐1 β–induced increase in levels of proteoglycans, stromelysin, and leukocytes in rabbit synovial fluid
Authors: Mcdonnell Joseph , Hoerrner Lori A. , Lark Michael W. , Harper Coral , Dey Tanvi , Lobner Julie , Eiermann George , Kazazis Diana , Singer Irwin I. , Moore Vernon L.
Published: February 2007

Objective. To evaluate the effects of intraarticular injection of recombinant human interleukin‐1β (IL‐1β) on levels of proteoglycans, stromelysin, and leukocytes in rabbit synovial fluid (SF), and to determine the effects of leukocyte depletion on SF proteoglycan and stromelysin levels.

Methods. Levels of leukocytes and of proteoglycans, stromelysin, and collagenase were evaluated 12 hours after the intraarticular injection of various doses of IL‐1, and over a 24‐hour period after injection at a single dose level. We used a monoclonal antibody (MAb) against leukocyte integrins, which markedly depressed leukocyte accumulation in SF, to evaluate the role of synovial leukocytes on IL‐1–induced increases in SF proteoglycan and stromelysin levels.

Results. Levels of both proteoglycans and stromelysin increased in the IL‐1–injected joints between 4 hours and 24 hours after the injection of a single 200‐ng dose of IL‐1. The highest levels of stromelysin and proteoglycans were achieved with IL‐1 doses ≥ 100 ng. Infiltration of polymorphonuclear cells (PMN) into the joint fluid of the IL‐1–injected rabbits also increased, in a dose‐dependent manner. Treatment of rabbits with MAb 1B4 markedly reduced infiltration of PMN into the joint, without affecting either stromelysin or proteoglycan levels.

Conclusion. Taken together, the data suggest that there is a coordinate increase in SF stromelysin and proteoglycan levels in rabbits injected with IL‐1, and that leukocytes play a minimal role in the accumulation of proteoglycans and stromelysin in the SF.
Type x collagen synthesis in human osteoarthritic cartilage. indication of chondrocyte hypertrophy
Authors: Von Der Mark K. , Kirsch T. , Nerlich A. , Kuss A. , Weseloh G. , Glückert K. , Stöss H.
Published: February 2007

Objective. To investigate the appearance of hypertrophic chondrocytes in osteoarthritic (OA) cartilage, using type X collagen as a specific marker.

Methods. The biosynthesis of type X collagen was examined by metabolic labeling of freshly isolated articular chondrocytes with 3H‐proline, immunoprecipitation, and sodium dodecyl sulfate–polyacrylamide gel electrophoresis of the synthesized collagens. Extracellular deposition of types X and II collagen was analyzed immunohistochemically.

Results. Immunostaining revealed an irregular distribution of type X collagen, which was localized around chondrocyte clusters in fibrillated OA cartilage, but was absent from the noncalcified region of normal articular cartilage. Freshly isolated OA chondrocytes synthesized predominantly type X collagen, while control chondrocytes synthesized mostly type II collagen.

Conclusion. Our findings indicate focal premature chondrocyte differentiation to hypertrophic cells in OA cartilage.
Progressive aortic valve inflammation occurring despite apparent remission of relapsing polychondritis
Authors: Buckley Lenore M. , Ades Philip A.
Published: February 2007

We describe a patient with relapsing polychondritis in whom aortic valve inflammation developed 3 years after diagnosis, when the polychondritis had been in apparent remission for an extended period of time. Infection and cardiac involvement can be significant complications of relapsing polychondritis. Recommendations for monitoring and treatment of patients with this disease are discussed.
Antibodies to glycyl–transfer rna synthetase in patients with myositis and interstitial lung disease
Authors: Targoff Ira N. , Trieu Edward P. , Plotz Paul H. , Miller Frederick W.
Published: February 2007

Objective. We have previously described anti‐EJ antibodies, and provided evidence that these antibodies react with glycyl–transfer RNA (gly‐tRNA) synthetase. The aim of the present study was to identify patients with anti‐EJ antibodies and describe the clinical associations of the antibody, in particular, whether it is associated with the syndrome of myositis and interstitial lung disease (ILD) that has been previously associated with autoantibodies to the aminoacyl‐tRNA synthetases for histidine, threonine, and alanine.

Methods. Sera from patients with suspected or proven polymyositis or dermatomyositis (DM), sera with anticytoplasmic patterns, and control sera were tested for anti‐EJ antibodies by immunoprecipitation (IPP). Positive sera and controls were tested for the ability to inhibit gly‐tRNA synthetase by preincubation of the enzyme source with the serum.

Results. Anti‐EJ antibodies were demonstrated in the sera of 5 patients, by IPP of characteristic tRNAs and protein. Original serum EJ and each of the new sera significantly inhibited the enzymatic activity of gly‐tRNA synthetase but not histidyl‐tRNA synthetase. All 5 of the new patients had inflammatory myopathy, a typical DM rash, and ILD. One, who had an overlap syndrome with systemic lupus erythematosus, had anti‐EJ at least 4 months before the development of clinical myositis. Arthritis and Raynaud's phenomenon, other features associated with antisynthetases, were also seen.

Conclusion. Anti‐EJ is associated with the syndrome of myositis and lung disease that is seen in association with other antisynthetases. The finding of specific inhibition of gly‐tRNA synthetase by all anti‐EJ–positive sera strongly supports the identification of EJ antigen as gly‐tRNA synthetase.
Malignant angioendotheliomatosis (intravascular lymphomatosis) clinically simulating primary angiitis of the central nervous system
Authors: Lie J. T.
Published: February 2007

Primary angiitis of the central nervous system (PACNS) and malignant angioendotheliomatosis (MAE) are two unrelated and lethal diseases that frequently affect the brain. Both are uncommon and both require histologic documentation of their characteristic lesions for a definitive diagnosis. Because brain biopsies are not routinely included in the diagnostic workup of nonneoplastic CNS diseases, a number of unconfirmed nonvasculitic conditions may mimic PACNS. To my knowledge, MAE simulating PACNS clinically and angiographically has not been previously reported, and 3 such cases are described herein.
Effect of gold compounds on the activity of adenylyl cyclase in human lymphocyte membranes
Authors: Lazarevic Milenko B. , Yan Kun , Swedler William I. , Rasenick Mark M. , Skosey John L.
Published: February 2007

Objective. To determine the effects of aurothioglucose, aurothiomalate, and auranofin on basal and forskolin‐activated adenylyl cyclase activity in human total lymphocyte membranes, and in membranes of T and B lymphocyte subsets.

Methods. Membranes were isolated from human total lymphocytes and T and B cell subsets. The effects of gold compounds on basal and forskolin‐stimulated activity of adenylyl cyclase were measured by radioassay.

Results. The gold compounds inhibited adenylyl cyclase activity. This inhibitory effect required the presence of both the sulfhydryl ligands and aurous cation.

Conclusion. Regulation of lymphocyte adenylyl cyclase by gold compounds represents a potential mode of action of these drugs in rheumatic diseases.
Analysis of intraarticular fibrinolytic pathways in patients with inflammatory and noninflammatory joint diseases
Authors: Alain J. , Abbink Janna J. , Boer Jan‐Paul De , Roem Dorina , Nieuwenhuys Ed J. , Kamp Angela M. , Swaak Tom J. G. , Erik Hack C.
Published: February 2007

Objective. Intraarticular activation of the fibrinolytic system has been suspected to occur in patients with arthritis. We undertook the present study to investigate the relation of this activation to clinical symptoms, and the molecular pathways involved.

Methods. We quantitatively assessed levels of plasmin–α2‐antiplasmin (PAP) complexes in synovial fluid (SF) from 25 patients with rheumatoid arthritis (RA), 7 with seronegative spondylarthropathy (SSA), and 10 with osteoarthritis (OA), and conducted an analysis to determine the plasminogen‐activating pathway via which these complexes were generated. In addition, we studied the relationship of intraarticular fibrinolysis to clinical and biochemical parameters.

Results. All patients studied had increased SF levels of PAP complexes. Levels in patients with RA and SSA were slightly higher than those in patients with OA. These complexes were probably formed by activation of urokinase‐type plasminogen activator (u‐PA), and not tissue‐type plasminogen activator (t‐PA), since SF levels of both u‐PA antigen and u‐PA–plasminogen activator inhibitor (PAI) complexes were increased in 27 of the 42 patients. Conversely, SF levels of t‐PA were below normal in all but 1 patient. In some patients, activation of factor XII presumably also contributed to plasminogen activation in SF, since levels of factor XIIa–C1 inhibitor in SF were increased in 8 of the 42 patients and correlated, as did u‐PA–PAI levels, with levels of PAP complexes. Several of the parameters of fibrinolysis in SF, particularly u‐PA antigen and u‐PA‐PAI–1 complexes, were found to correlate with clinical and biochemical parameters.

Conclusion. Our results suggest that plasminogen is frequently activated in the joints of patients with inflammatory or noninflammatory arthropathy and that this activation mainly occurs via a u‐PA–, and in some cases also via a factor XII–, dependent pathway. The possible relation of this activation process to stimulation of synovial cells by cytokines is discussed.
Autoradiographic localization and analysis of endothelin‐1 binding sites in human synovial tissue
Authors: Wharton John , Rutherford Richard A. D. , Walsh David A. , Mapp Paul I. , Knock Gregory A. , Blake David R. , Polak Julia M.
Published: February 2007

Objective. To determine the localization of endothelin binding sites and immunoreactivity in human synovial tissues.

Methods. Quantitative in vitro autoradiographic and immunohistochemical techniques were used to localize and characterize 125I‐labeled endothelin‐1 (125I–ET‐1) binding sites and endothelin‐like immunoreactivity in sections of rheumatoid, osteoarthritic, and normal synovium.

Results. Specific 125I–ET‐1–binding sites, characteristic of the ETA receptor, were localized to the media of synovial blood vessels in all 3 groups. No difference was found in vascular binding site density in rheumatoid and osteoarthritic synovium. Endothelin‐like immunoreactivity was localized to endothelial cells in blood vessels displaying 125I–ET‐1 binding sites.

Conclusion. We conclude that endothelin may act locally, modulating synovial perfusion and exacerbating hypoxia in chronic arthritis.
A rheumatoid factor from a normal individual encoded by VH2 and VkII gene segments
Authors: Stüber Frank , Lee Soo Kon , Bridges S. Louis , Koopman William J. , Schroeder Harry W. , Gaskin Felicia , Fu Shu Man
Published: February 2007

Objective. To gain insight into the immunoglobulin variable‐region repertoire of anti‐IgG antibodies (rheumatoid factors [RF]), we characterized the VH and Vk gene segments utilized in an IgM‐RF–secreting lymphoblastoid cell line (SSH23) isolated from a normal individual.

Methods. The cell line SSH23 was established by Epstein‐Barr virus transformation of peripheral blood non–T mononuclear cells. First‐strand complementary DNA (cDNA) was generated and used for polymerase chain reaction amplification of the heavy and light chain variable domains. The amplified variable domains were sequenced and compared with an extensive database of germline and cDNA V gene segments.

Results. The VH sequence was found to be identical to a previously described fetal VH2 incomplete cDNA and to differ by only 3 nucleotides from a JH proximal germline VH2 gene segment. To our knowledge, this is the first example of a VH2 rheumatoid factor. The Vk2–Jk4 light chain contains an uncommon 10–amino acid third complementarity‐determining region (CDR 3).

Conclusion. Utilization of preimmune fetal VH gene segments and unusual light chain junctional diversity appear to be features shared by many physiologic and pathologic rheumatoid factors.
The immunoglobulin kappa light chain repertoire expressed in the synovium of a patient with rheumatoid arthritis
Authors: Lee Soo Kon , Bridges S. Louis , Koopman William J. , Schroeder Harry W.
Published: February 2007

Objective. To analyze the nature of the B cell response in the synovial tissue of a patient with rheumatoid arthritis (RA). Specifically, we sought to determine if the pattern of immunoglobulin expression was consistent with polyclonal stimulation of B cells or an antigen‐driven response.

Methods. We generated an unrestricted complementary DNA (cDNA) library from the diseased synovium of a rheumatoid factor (RF)–positive patient with an 18‐year history of RA. A random sample of k light chain recombinants was identified, and sequence analysis was performed. The variable domains were compared with an extensive database of germline and cDNA k sequences.

Results. We found a light chain repertoire enriched for k transcripts containing 2 Vk gene segments (Humkv325 and Humkv328) that are frequently associated with paraproteins expressing RF activity. Kappa variable domains from synovium contained numerous somatic mutations which resulted in frequent replacement of amino acids that encode the classic antigenbinding site. Unexpectedly, many of these k transcripts contained non–germline‐encoded nucleotides (N regions) at the site of Vk–Jk joining. The combination of N‐region addition and variation in the sites of Vk–Jk splicing generated unusually long complementarity‐determining region 3 regions and charged amino acids near the Vk–Jk splice site.

Conclusion. The pattern of somatic mutations found in this patient sample supports the hypothesis that these synovium‐derived plasma cells are the product of immunoglobulin receptor–dependent (i.e., antigen‐driven) selection. The extent of N‐region addition raised the additional possibility that these antibodies derive from an unusual set of B lymphocytes that have escaped normal regulation.
Immunopathology of rheumatoid arthritis
Authors: Kurki Pekka , Aho Kimmo , Palosuo Timo , Heliövaara Markku
Published: February 2007

Objective. We sought to determine whether circulating antikeratin antibodies (AKA) precede the onset of rheumatoid arthritis (RA).

Methods. By matching the registers of 2 previous population studies with the registry of patients receiving antirheumatic drugs several years later, pre‐illness serum specimens could be obtained from 39 individuals who subsequently developed RA. AKA were assayed with the standard indirect immunofluorescence technique.

Results. Ten of 39 serum specimens from individuals who subsequently developed seropositive RA, and 1 of 15 sera from individuals who developed seronegative RA, were positive for IgG‐class AKA by immunofluorescence assay. The AKA‐positive sera were also positive for rheumatoid factors.

Conclusion. The findings focus attention on the role of pre‐illness immunologic events in the pathogenesis of RA.
Utility of high‐resolution ultrasound for the diagnosis of dialysis‐related amyloidosis
Authors: Kay Jonathan , Benson Carol B. , Lester Susan , Corson Joseph M. , Pinkus Geraldine S. , Michael Lazarus J. , Owen William F.
Published: February 2007

Objective. To evaluate the utility of real‐time, high‐resolution ultrasound of the shoulder in the diagnosis of dialysis‐related amyloidosis.

Methods. We performed a case series study of 2 groups of patients seen at a referral‐based clinic in a tertiary care hospital. The shoulders of 13 patients with normal renal function and of 38 patients receiving long‐term hemodialysis were studied by real‐time, high‐resolution ultrasound. All hemodialysis patients were evaluated clinically for the presence of dialysis‐related amyloidosis. Surgical specimens of joints were available for all 13 patients with normal renal function and for 17 of the 38 hemodialysis patients. These specimens were evaluated for the presence of β2‐microglobulin (β2m) amyloid by Congo red and immunohistochemical staining.

Results. Two ultrasonographic findings were selectively observed in the dialysis patients with clinical and histologic evidence of β2m amyloid in comparison with patients with normal renal function and no evidence of amyloid: rotator cuffs >8 mm in thickness and echogenic pads between muscle groups of the rotator cuff. The presence of at least 1 of these 2 findings corresponded to the presence of clinically and histologically evident β2m amyloid with a sensitivity of 79% and a specificity of 100%. When additional patients without surgical specimens for histologic confirmation of amyloidosis were included, the sensitivity of these 2 sonographic findings was 72% and the specificity was 97%.

Conclusion. Real‐time, high‐resolution ultrasound is a relatively sensitive and highly specific noninvasive adjunct to the clinical diagnosis of β2m amyloidosis in patients receiving long‐term hemodialysis.
Anti–interleukin‐6 autoantibodies in rheumatic diseases
Authors: Takemura Hiroyuki , Suzuki Hiroshi , Yoshizaki Kazuyuki , Ogata Atsushi , Yuhara Takamichi , Akama Takao , Yamane Kazuhide , Kashiwagi Heihachiro
Published: February 2007

Objective. To investigate the presence and the roles of anti–interleukin‐6 (anti–IL‐6) autoantibodies in rheumatic diseases, and to further elucidate clinical and pathophysiologic significance of anticytokine autoantibodies.

Methods. Anti–IL‐6 IgG autoantibodies were measured by the 125I–IL‐6 binding activity of IgG, which was isolated from serum by protein A–Sepharose.

Results. Nine of 52 sera (17.3%) from patients with systemic sclerosis (SSc) contained anti–IL‐6 antibodies, whereas only 1.9% of sera from normal subjects and 0–5% of sera from patients with other rheumatic diseases were positive for the antibodies. Moreover, anti–IL‐6 autoantibodies were found predominantly among patients with the limited form of SSc (42.9%), compared with those with the diffuse form (7.9%).

Conclusion. Anti–IL‐6 IgG autoantibodies were detected in patients with SSc, particularly those with the limited form of the disease, at a significantly increased frequency compared with normal subjects and patients with other rheumatic diseases. These results suggest that the development of anti–IL‐6 autoantibodies and IL‐6 may have a role in the pathophysiology of SSc.
Anti–Ro/SS‐A and Anti–La/SS‐B autoantibody levels in relation to systemic lupus erythematosus disease activity and congenital heart block
Authors: Derksen Ronald H. W. M. , Meilof Jan F.
Published: February 2007

Objective. To analyze the anti–Ro/SS‐A and anti–La/SS‐B autoantibody responses, both quantitatively and qualitatively, in relation to the occurrence of congenital heart block (CHB) and disease activity in a patient with systemic lupus erythematosus.

Methods. The patient's course was carefully documented for a period of 80 months. Specific enzyme‐linked immunosorbent assays, a HeLa cell immunoblotting test, and an RNA precipitation assay were used to determine autoantibody levels and fine specificities.

Results. Anti–Ro/SS‐A and anti–La/SS‐B antibody did not disappear. Levels of anti–Ro/SS‐A appeared to fluctuate more frequently than levels of anti–La/SS‐B. Fluctuations were unrelated to disease activity or immunosuppressive treatment. There was no characteristic relationship between levels of these antibodies and the occurrence of CHB.

Conclusion. The occurrence of CHB cannot be predicted by frequent measurement of anti–Ro/SS‐A and anti–La/SS‐B levels. The immunoregulatory control of anti–Ro/SS‐A and anti–La/SS‐B antibodies differs from that of anti‐DNA and anti–tetanus toxoid antibodies.
Evaluation of the efficacy and safety of oral tiludronate in paget's disease of bone
Authors: Reginster J. Y. , Colson F. , Morlock G. , Combe B. , Ethgen D. , Geusens P.
Published: February 2007

Objective. To assess the optimal dosage of oral tiludronate in Paget's disease of bone.

Methods. We studied 149 patients with Paget's disease, in a double‐blind, randomized, placebo‐controlled trial. Patients were randomly assigned to 1 of 5 therapeutic groups: a daily dose of 100 mg, 200 mg, 400 mg, or 800 mg of oral tiludronate, or a placebo. Treatment was for 3 months, followed by 3 months of placebo‐controlled followup. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatinine (OH/Cr) were measured monthly, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self‐evaluated from a visual analog scale and a global pain index.

Results. Statistical analysis revealed that beginning at a dosage of 200 mg/day, there was a direct dose‐dependent effect on the reduction of SAP and OH/Cr levels. Reduction of SAP levels was clinically significant at a dosage of 400 mg (44.9 ± 4.2% reduction at 90 days and 49.2 ± 4.5% at 180 days, mean ± SEM) and at 800 mg (53.4 ± 5% at 90 days and 59.3 ± 4.6% at 180 days). There was a significant reduction in pain in all groups, including the group taking placebo. In only those taking 800 mg/day of tiludronate was there a significant frequency of complete resolution of pain (versus placebo). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance of all 5 regimens was good. Exhaustive biochemical investigations failed to reveal significant toxicity of tiludronate up to the 800‐mg daily dose investigated.

Conclusion. Because of its significantly better antiresorptive effects and greater analgesic properties (compared with lower dosages), combined with the excellent clinical and biochemical tolerance, the 800‐mg daily dose of tiludronate appears to be optimal for the treatment of Paget's disease of bone.
Vasculitic neuropathy mimicking guillain‐barré syndrome
Authors: Suggs S. P. , Thomas T. D. , Joy J. L. , Lopez‐Mendez A. , Oh S. J.
Published: February 2007

Vasculitic neuropathy classically manifests as a subacute mononeuritis multiplex or polyneuropathy. Patients with a Guillain‐Barré syndrome (GBS)–like presentation are usually not considered to have an underlying vasculitis. We describe 2 patients with rapidly progressive areflexic paralysis that was initially diagnosed as GBS, in whom vasculitic neuropathy was found histologically.
Selection of T cell receptor Vβ elements by HLA‐DR determinants predisposing to Rheumatoid Arthritis
Authors: Weyand Cornelia M. , Oppitz Ulrich , Hicok Kevin , Goronzy Jörg J.
Published: February 2007

Objective. Rheumatoid arthritis (RA) is genetically linked to a sequence motif encoding for the middle portion of the α‐helical loop, which is adjacent to the antigen‐binding groove of the HLA‐DR molecule. The disease‐associated element might be involved in binding the antigen or in interacting with the T cell receptor (TCR). To investigate the contribution of the disease‐associated element in T cell recognition events, we studied structural requirements in the interaction of T cell clones with HLA‐DR determinants.

Methods. T cell clones restricted to disease‐associated HLA‐DR determinants were established by allogeneic stimulation of HLA–DRB1*0401+ or *0401–responders with HLA–DRB1*0404/8+ stimulators. Allele‐specific primer sets were used to identify the Vβ gene segment expressed by individual clones. Sequence analysis was applied to study the diversity of the TCR β‐chain junctional regions.

Results. The repertoire of TCR Vβ elements was strongly biased toward the usage of Vβ6. HLA–DRB1*0401+ and *0401– donors preferentially recruited Vβ6+ T cells to recognize the disease‐associated HLA–DR determinant. Sequence data revealed that the Vβ6.6/7 and Vβ6.8/9 subtypes of the Vβ6 multigene family were overrepresented. The TCR β chains were characterized by a high degree of junctional diversity, supporting the view that a multitude of peptide–DR complexes were recognized and that the preferential use of Vβ6 was dictated by the TCR β chain–DRβ1 chain contact.

Conclusion. T cells reactive with the disease‐associated HLA–DR structure are nonrandomly selected. The HLA‐DR component predisposing to RA might define molecular requirements that restrict the TCR–HLA interaction. Thus, the phenomenon of HLA association in RA might reflect a genetic control of T cell recognition, through the selection of the TCR repertoire.
Evidence for the presence of androgen receptors in the synovial tissue of rheumatoid arthritis patients and healthy controls
Authors: Cutolo Maurizio , Accardo Silvano , Villaggio Barbara , Clerico Paolo , Indiveri Francesco , Carruba Giuseppe , Fecarotta Emanuela , Castagnetta Luigi
Published: February 2007

Objective. To study the presence of androgen receptors in the synovial tissue of male and female patients with rheumatoid arthritis (RA) and matched healthy controls.

Methods. Both site I (high affinity, low binding capacity) and site II (reduced affinity, higher binding capacity) androgen receptors were investigated in soluble and nuclear fractions of homogenized synovial samples, using the dextran‐coated charcoal method. The finding of pure, high‐affinity site I receptors in both fractions was considered indicative of androgen receptor positivity. In order to determine what type of synovial cell was positive for androgen receptors, cryosections of synovial tissues were immunostained with a specific monoclonal anti‐androgen receptor antibody (MAb), using both immunofluorescence and immunoperoxidase techniques. Double immunostaining with this MAb and specific MAb directed toward different macrophage/granulocyte antigens was also performed.

Results. Remarkable differences were found between male and female controls: Most males were positive for androgen receptors, and most females were negative. The femtomolar content of androgen receptor in the nuclear fraction was fairly constant, but the soluble fraction showed a higher femtomolar concentration in female RA patients than in controls of either sex, as well as in male RA patients compared with female RA patients. The androgen receptor‐positive cells in both RA and control synovial cryosections were found by immunostaining to be macrophage‐like synoviocytes, and were also found to be HLA‐DR positive.

Conclusions. The immunosuppressive action exerted by androgens might, at least in part, be mediated through their interaction with macrophage‐like synoviocytes functioning as antigen‐processing and antigen‐presenting cells in rheumatoid synovia.
Assessment of disease activity and impending flare in patients with systemic lupus erythematosus. Comparison of the use of complement split products and conventional measurements of complement
Authors: Buyon Jill P. , Tamerius John , Belmont H. Michael , Abramson Steven B.
Published: February 2007

Objective. To determine whether increased levels of the complement split products generated in the activation of the alternative or classical pathway accompany more severe disease activity in patients with systemic lupus erythematosus (SLE) and whether these measurements are useful in predicting flares of disease.

Methods. Levels of Ba, Bb, SC5b‐9, and C4d were measured in 380 plasma samples obtained from 86 SLE patients who were prospectively followed up for 15 months.

Results. In the 20 patients who had inactive disease at the initiation of the study, the mean values of all of the complement split products at entry were within the normal range. In the 47 patients with stable or moderate disease activity, levels of Ba were significantly increased, while the mean values for Bb, SC5b‐9, and C4d did not differ significantly from those in patients with inactive disease. The mean entry value of each analyte was highest in the group of 19 patients who had the most severe disease activity at initial evaluation. Traditional measurements of complement, i.e., C3, C4, and CH50, followed similar trends, but did not discriminate between the 3 groups of patients as well as did measurements of the split products. Analysis of the disease course in the patients with inactive or stable/moderate disease revealed that an elevated level of C4d had the most sensitivity with regard to subsequent flare, while an elevated Bb level had the highest specificity and the greatest predictive value.

Conclusion. These data suggest that elevated levels of complement split products, particularly products of alternative and terminal pathway activation, more accurately reflect disease activity than do conventional measurements of complement in SLE and may be useful in the prediction of impending disease flares.
Neuropathologic findings in multi‐infarct dementia associated with anticardiolipin antibody. Evidence for endothelial injury as the primary event
Authors: Westerman Eric M. , Miles Janet M. , Backonja Miroslav , Sundstrom Walter R.
Published: February 2007

Objective. There are few reports describing histopathologic changes associated with the antiphospholipid antibody syndrome. We describe a patient with multi‐infarct dementia and antiphospholipid antibody syndrome, in whom a brain biopsy was performed.

Methods. Biopsy material from the left frontal cortex, including meninges, cortex, and underlying subcortical white matter, was investigated. Microscopic examination and special staining were performed.

Results. Microscopic examination showed lumenal occlusion by thrombi, and marked endothelial hyperplasia of small meningeal and cortical arterioles.

Conclusion. These findings suggest that the pathogenesis of this cerebral vasculopathy is noninflammatory and is associated with reactive endothelial hyperplasia and thrombosis of small arterioles.
Presence of small proteoglycan fragments in normal and arthritic human cartilage
Authors: Witsch‐Prehm Petra , Miehlke Rolf , Kresse Hans
Published: February 2007

Objective. To characterize the small proteoglycans decorin and biglycan in normal human patellar cartilage and in cartilage from individuals with chronic polyarthritis.

Methods. Cartilage extracts were chromatographed on DEAE‐Trisacryl and further separated by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis before and after enzymatic degradation of the glycosaminoglycan chains. Decorin and biglycan were visualized after Western blotting, using core protein‐specific polyclonal and monoclonal antibodies.

Results. Core protein fragments of both proteoglycans were observed even in normal cartilage. In the case of decorin they amounted to up to 15% of the immunoreactive material, and up to 5% of the core protein was glycosaminoglycan free. The quantity of decorin core protein was reduced in arthritic cartilage, but the core protein fragments represented up to 45% of the immunoreactive material. Different zones of cartilage differed in their content of the fragments. Evidence for an increased proportion of biglycan fragments was not obtained.

Conclusion. Chronic polyarthritis leads to increased degradation of small proteoglycans. A considerable proportion of decorin fragments is retained in the tissue. These alterations may have a negative influence on the mechanical stability of tissue.
Effect of intraarticular glycosaminoglycan polysulfate treatment on patellofemoral pain syndrome. A prospective, randomized double‐blind trial comparing glycosaminoglycan polysulfate with placebo and quadriceps muscle exercises
Authors: Kannus Pekka , Natri Antero , Niittymäki Seppo , Järvinen Markku
Published: February 2007

Objective. To compare the effects of intraarticular (IA) injections of glycosaminoglycan polysulfate (GAGPS) plus basic conservative treatment with the effects of placebo injections plus conservative treatment and with the effects of conservative treatment alone in patients with chronic patellofemoral pain syndrome (PFPS).

Methods. We treated 53 patients who presented with chronic PFPS in 1 knee, according to 1 of the 3 protocols, in a prospective, randomized, double‐blind study. Basic conservative treatment consisted of a 6‐week program of quadriceps muscle exercise, elimination of symptom‐producing activities, and oral doses of nonsteroidal antiinflammatory drugs. Physiologic saline served as placebo for injection. During the 6‐week treatment period, 5 injections were given 1 week apart. Along with measurements of quadriceps strength, standardized subjective, functional, and clinical assessments were performed at presentation, after 6 weeks of treatment, and after 6 months.

Results. Results at 6 months indicated that IA injections of GAGPS or saline did not result in significant improvement beyond the good results achieved by the basic conservative treatment alone. More than two‐thirds of the patients in each group experienced complete recovery.

Conclusion. Neither the GAGPS injections nor the physiologic saline injections are more effective than conservative therapy in the treatment of chronic PFPS. Restoration of normal quadriceps muscle function to the affected knee seems to be crucial in treating PFPS.
Appendicular and vertebral bone mass in ankylosing spondylitis. A comparison of plain radiographs with single‐ and dual‐photon absorptiometry and with quantitative computed tomography
Authors: Devogelaer Jean‐Pierre , Maldague Baudouin , Malghem Jacques , De Deuxchaisnes Charles Nagant
Published: February 2007

Objective. We assessed the prevalence, severity, and anatomic distribution of ankylosing spondylitis (AS)‐related osteopenia (OP).

Methods. We studied 70 patients (60 males, 10 premenopausal females) with AS (according to the New York criteria) to determine the frequency of OP. Bone mass was measured by plain radiographs of the spine, by single‐photon absorptiometry (SPA) of the distal and midshaft of the radius on the nondominant side, by dual‐photon absorptiometry (DPA) of the lumbar spine (L2‐L4), and by quantitative computed tomography (QCT) of the lumbar spine.

Results. SPA values for the radius mass were normal in males and in females, both at the distal and midshaft sites. In contrast, spine radiographs showed diminished density of the vertebral bodies in 69% of the males and 50% of the premenopausal females. Two male patients had had a vertebral compression fracture, and one female patient had had two. DPA values for the spine mass were significantly diminished in the male patients compared with the controls, but not in the female patients. Males with less severe AS also had the largest reduction in lumbar bone mineral content. In patients with more severe disease, lumbar bone mineral content was not statistically different from that in controls. QCT of the lumbar spine performed in 10 patients disclosed low density of the trabecular bone of the vertebral bodies, more so in those with more severe AS and syndesmophyte formation and/or apophyseal joint fusion, which contrasts with the normal values on DPA in these patients.

Conclusion. Male patients with AS have axial osteopenia. In those who have very severe AS with new bone formation, DPA demonstrates normal values as a result of two opposite trends: central osteopenia (as assessed from QCT) and peripheral new‐bone formation, which transforms vertebral bodies into long bones. This could modify the mechanical resistance of the spine and account for the propensity for anteroposterior transvertebral and transdiscal fractures after trauma in AS.
Signal transduction in Sjögren's syndrome T cells. Abnormalities associated with a newly described human A‐type retrovirus
Authors: Flescher Eliezer , Dauphinée Michael J. , Fossum Donna , Ledbetter Jeffrey , Talal Norman
Published: February 2007

Objective. To study the effects of a novel A‐type retrovirus, detected in cocultures of lip biopsy specimens from Sjögren's syndrome (SS) patients and a human T cell line, on the infected T cells.

Methods. Interleukin‐2 (IL‐2) and IL‐6 secretion were measured by bioassay and enzyme‐linked immunosorbent assay, respectively, in the infected and noninfected cell lines. Surface antigen expression was determined by flow cytometry, using monoclonal antibodies. Protein kinase C (PKC) activity was measured using an enzyme assay kit, and calcium mobilization was assessed with a fluorescent probe.

Results. Infected cells expressed less CD4 and IL‐6 receptor, but more HLA‐DR, compared with noninfected cells. Infected cells also produced less IL‐2 and displayed reduced PKC activation and calcium mobilization. A similar defect in calcium mobilization was detected in T cells from SS patients.

Conclusion. These data suggest a possible involvement of the newly described retrovirus in T cell abnormalities.
Quantitative immunohistologic criteria are superior to the lymphocytic focus score criterion for the diagnosis of Sjögren's syndrome
Authors: Bodeutsch C. , De Wilde P. C. M. , Kater L. , Van Houwelingen J. C. , Van Den Hoogen F. H. J. , Kruize A. A. , Hené R. J. , Van De Putte L. B. A. , Vooijs G. P.
Published: February 2007

Objective.The aim of the present study was to evaluate the diagnostic value of quantitative immunohistologic criteria for Sjögren's syndrome (SS) in labial salivary gland biopsies.

Methods.Quantitative immunohistologic examination was performed on labial salivary gland biopsy samples from 80 healthy controls, 32 patients with primary SS, 14 patients with secondary SS, 5 with “probable” SS, 36 with keratoconjunctivitis sicca (KCS) with a lymphocytic focus score <1 on the lip biopsy, and 18 with rheumatoid arthritis (RA) without clinical evidence of SS.

Results.This is the first study to show that immunohistologic criteria for SS, based on the percentages of IgA‐containing and IgG‐containing plasma cells, are able to 1) confirm the diagnosis of SS in labial salivary glands of KCS patients in the absence of grade IV lymphocytic adenitis; and 2) distinguish between a grade IV focal lymphocytic adenitis in the labial salivary glands of SS patients and of RA patients without SS.

Conclusion.Quantitative immunohistologic criteria were shown to be much more sensitive and disease specific than the widely accepted grade IV lymphocytic adenitis criterion, which corresponds to a lymphocytic focus score >1, and these criteria should be included in the international diagnostic criteria for Sjögren's syndrome.
Elevated serum levels of soluble interleukin‐2 receptor in patients with Wegener's granulomatosis. Association with disease activity
Authors: Schmitt Wilhelm H. , Heesen Christoph , Csernok Elena , Rautmann Annegret , Gross Wolfgang L.
Published: February 2007

Objective. To investigate whether soluble interleukin‐2 receptor (sIL‐2R), a marker of T cell activation, could be a useful marker of disease activity in Wegener's granulomatosis (WG).

Methods. Soluble IL‐2R levels were determined by enzyme‐linked immunosorbent assay. WG disease activity in 102 patients was assessed according to clinical features and levels of classic antineutrophil cytoplasmic antibody (c‐ANCA) and C‐reactive protein (CRP).

Results. Soluble IL‐2R levels were higher in patients with generalized and active disease than in those with limited and inactive disease. In 25 patients with complete clinical remission, sIL‐2R levels were significantly elevated, although levels of CRP and c‐ANCA were normal. Eight of these 25 patients had disease relapses within 6 months. Levels of sIL‐2R were significantly higher in patients who had relapses than in those who did not. Patients with clinically active WG but low c‐ANCA or CRP levels had elevated levels of sIL‐2R.

Conclusion. Levels of sIL‐2R correlate with disease activity in patients with WG, and may indicate imminent relapse.
Tryptophan metabolism via the kynurenine pathway in patients with the eosinophilia–Myalgia syndrome
Authors: Silver Richard M. , McKinley Kevin , Smith Edwin A. , Quearry Bonnie , Harati Yadollah , Sternberg Esther M. , Heyes Melvyn P.
Published: February 2007

Objective. To investigate the metabolism of L‐tryptophan (LT) via the kynurenine pathway in patients with the eosinophilia–myalgia syndrome (EMS).

Methods. Measurement of LT, L‐kynurenine, and quinolinic acid in plasma and cerebrospinal fluid (CSF) from subjects with EMS, from asymptomatic users of LT, and from normal subjects.

Results. Plasma LT concentrations were lower in untreated EMS patients (n = 5) than in corticosteroid‐treated EMS patients (n = 5; P < 0.05) and in asymptomatic users of LT (n = 5; P < 0.05). Untreated EMS patients, who had discontinued LT weeks to months prior to study, had significantly higher plasma levels of L‐kynurenine and quinolinic acid than did corticosteroid‐treated EMS patients (P < 0.05), normal subjects (P < 0.02), and asymptomatic users of LT (P < 0.05). EMS patients also had significantly elevated levels of L‐kynurenine (P < 0.05) and quinolinic acid (P < 0.001) in CSF compared with normal subjects. After a 1‐gm oral dose of LT, untreated EMS patients (n = 4) showed lower peak levels of LT and accentuated synthesis of L‐kynurenine and quinolinic acid, compared with these values in corticosteroid‐treated EMS patients (n = 2), who responded like normal subjects (n = 5).

Conclusion. These data demonstrate that during the active phase of EMS, LT metabolism via the kynurenine pathway was accentuated, probably secondary to induction of the enzyme indoleamine‐2,3‐dioxygenase. Ingestion of large amounts of LT (median daily dose 1.5 gm) resulted in high concentrations of kynurenine‐pathway metabolites in blood and extrahepatic tissues, which was accentuated in EMS patients and which may have played a significant role in the pathogenesis of the disease.
Fecundity before disease onset in women with rheumatoid arthritis
Authors: Lee Nelson J. , Koepsell Thomas D. , Dugowson Carin E. , Voigt Lynda F. , Daling Janet R. , Hansen John A.
Published: February 2007

Objective. To examine fecundity prior to disease onset in women with rheumatoid arthritis (RA).

Methods. Two hundred fifty‐nine RA patients with an opportunity for pregnancy were compared with 1,258 control women as part of a prospective case‐control study of recent‐onset RA in women.

Results. A 12‐month or longer interval to pregnancy was found in 42% of RA cases compared with 34% of controls (odds ratio = 1.44, 95% confidence interval 1.10, 1.91). This difference was not accounted for by an older age when attempting to become pregnant among the RA cases compared with the controls. The result was unrelated to rheumatoid factor or HLA‐DR4 status.

Conclusion. Women with RA were found to have decreased fecundity prior to disease onset, compared with control women.