bluuebunny/crossref_metadata_2025 huggingface dataset:
The lateral view radiograph for assessment of the tibiofemoral joint space in knee osteoarthritis: Its reliability, sensitivity to change, and longitudinal validity
Authors: LaValley Michael P. , McLaughlin Sara , Goggins Joyce , Gale Daniel , Nevitt Michael C. , Felson David T.
Published: October 2005

Objective

To evaluate the reliability, validity, and sensitivity to change of tibiofemoral (TF) narrowing on lateral radiographic views.

Methods

In a natural history study of symptomatic knee osteoarthritis (OA), both lateral view and fluoroscopically positioned posteroanterior (PA) semiflexed view radiographs of the knee in 30° of flexion and with weight bearing were obtained at baseline and at 30 months. Test–retest reliability was evaluated using repeat radiographs, with joint space width measured using electronic calipers. All radiographs were scored on a 0–3 scale, and progression of joint space loss was defined as narrowing of the joint space by 1 grade. We evaluated sensitivity to change compared with the PA view. We evaluated validity by examining whether knees with progression showed expected malalignment on full‐limb films.

Results

Test–retest reliability of the TF joint space using the lateral view had a root mean square error of 0.303 mm, with 92.5% of repeats within 1 mm. More knees showed progression on the lateral view alone (n = 41) than on the PA view alone (n = 27). Compared with knees without joint space loss, knees with medial compartment loss on the lateral view only were more varus malaligned (P < 0.001), while those with lateral compartment loss were more valgus malaligned (P = 0.008).

Conclusion

In the assessment of TF joint space loss, lateral view radiographs are reliable, valid, and more sensitive to change than fluoroscopically positioned PA radiographs.
Does hand osteoarthritis predict future hip or knee osteoarthritis?
Authors: Dahaghin S. , Bierma‐Zeinstra S. M. A. , Reijman M. , Pols H. A. P. , Hazes J. M. W. , Koes B. W.
Published: October 2005

Objective

To evaluate the risk of future hip or knee osteoarthritis (OA) in subjects with hand OA at baseline and to evaluate whether the concurrent presence of hand OA, other risk factors for OA, or an OA biomarker (type II collagen C‐telopeptide degradation product [CTX‐II]) further increases the risk.

Methods

Radiographs of the hands (baseline) and the hips and knees (baseline and 6.6 years later) were obtained in a randomly selected subset of participants in the Rotterdam Study who were ages 55 years and older. Radiographs were scored for the presence of OA using the Kellgren/Lawrence (K/L) system. A total of 1,235 subjects without OA of the hip/knee (K/L score 0–1) at baseline were included in the study. CTX‐II levels were measured at baseline. The independent risk of future hip/knee OA in subjects with hand OA at baseline was assessed by logistic regression, as stratified for age, sex, body mass index, family history of OA, and heavy workload.

Results

Overall 12.1% of the participants (19.7% of those with hand OA versus 10.0% of those without) developed hip or knee OA (odds ratio [OR] 2.1 [95% confidence interval (95% CI) 1.3–3.1]). Subjects with hand OA had an increased risk of future hip OA (OR 3.0 [95% CI 1.6–5.4]), which was further increased in those with a family history of OA. Subjects with hand OA had an OR of 1.6 [95% CI 1.0–2.8) for the future development of knee OA, which was further increased in those who were overweight. Concurrent hand OA and high levels of CTX‐II further increased the risk of having hip or knee OA at followup (OR 4.2 [95% CI 2.3–7.8]).

Conclusion

The presence of hand OA at baseline showed an increased risk of future hip/knee OA (higher for hip OA than for knee OA). The concurrent presence of hand OA and other OA risk factors or high CTX‐II levels further increased the risk of future hip/knee OA.
Involvement of subchondral bone marrow in rheumatoid arthritis: Lymphoid neogenesis and in situ relationship to subchondral bone marrow osteoclast recruitment
Authors: Bugatti Serena , Caporali Roberto , Manzo Antonio , Vitolo Barbara , Pitzalis Costantino , Montecucco Carlomaurizio
Published: October 2005

Objective

To evaluate the presence and immunohistochemical characteristics of subchondral bone marrow inflammatory infiltrate in rheumatoid arthritis (RA) and to determine the in situ relationship between marrow inflammation and osteoclast recruitment.

Methods

Bone samples and paired synovia from 8 RA patients undergoing joint surgery were analyzed by immunohistochemistry and in situ hybridization for specific lymphoid neogenetic features, such as T and B cell composition, follicular dendritic cell (FDC) networks, peripheral lymph node addressin (PNAd)–positive high endothelial venules, and lymphoid chemokine expression. Osteoclasts were identified as multinucleated tartrate‐resistant acid phosphatase (TRAP)–positive and cathepsin K–positive cells adherent to the bone surface.

Results

An inflammatory infiltrate with perivascular aggregates of variable size was detected in 7 (87.5%) of 8 synovial samples and in paired bone samples. Lymphoid neogenetic features typical of rheumatoid synovium were also recognized in the bone marrow. PNAd+ blood vessels were found in 4 of 8 patients, CD21+ FDC networks in 2 patients, CXCL13+ cells in 5 patients, and CCL21+ cells in 6 patients. TRAP‐positive and cathepsin K–positive osteoclasts were identified on both the synovial and marrow sides of the bone surface. Bone marrow samples showing a higher degree of inflammation were characterized by a significantly increased number of osteoclasts adherent to the subchondral bone.

Conclusion

Our data demonstrate that lymphoid aggregates with lymphoid neogenetic features are detectable on the subchondral side of the joint in established RA. Moreover, the local inflammation/aggregation process appears to be related to osteoclast differentiation on the marrow side of subchondral bone, supporting a functional role of the bone compartment in local damage.
Inhibition of lupus disease by anti–double‐stranded DNA antibodies of the IgM isotype in the (NZB × NZW)F1 mouse
Authors: Werwitzke Sonja , Trick David , Kamino Kenji , Matthias Torsten , Kniesch Katja , Schlegelberger Brigitte , Schmidt Reinhold E. , Witte Torsten
Published: October 2005

Objective

In systemic lupus erythematosus (SLE), immune complexes (ICs) containing pathogenic IgG anti–double‐stranded DNA (anti‐dsDNA) autoantibodies are deposited in renal capillaries and initiate glomerulonephritis (GN) by the activation of complement and effector cells. In contrast, it has been demonstrated that the presence of IgM anti‐dsDNA antibodies correlates negatively with the development of GN in SLE. The aim of this study was to determine whether anti‐dsDNA antibodies of the IgM isotype protect against IC‐mediated organ damage in SLE.

Methods

Lupus‐prone (NZB × NZW)F1 mice (females) were treated with murine monoclonal IgM anti‐dsDNA antibodies. Treatment was delivered by subcutaneous injection at a dosage of 100 μg/week starting at 16 weeks of age (prophylactic) or at 24 weeks of age (therapeutic).

Results

Mice treated with IgM anti‐dsDNA exhibited a delayed onset of proteinuria and a reduced degree of renal pathology, which resulted in significantly improved survival as compared with control mice. Serum concentrations of IgG anti‐dsDNA antibodies were not significantly modified. However, glomerular deposition of ICs was markedly reduced in both treatment protocol groups. In contrast, higher amounts of IgG and IgM and increased expression of Fcγ receptor were demonstrated in liver sections from the treated mice compared with the untreated mice, suggesting an enhanced clearance of soluble ICs from phagocytic cells of the reticuloendothelial system.

Conclusion

These data demonstrate the efficacy of IgM anti‐dsDNA treatment in inhibiting the pathologic changes of lupus in (NZB × NZW)F1 mice. Lower glomerular IC deposition is associated with a reduced inflammatory response and impaired organ damage. The reduced frequency of GN in SLE patients who have IgM anti‐dsDNA antibodies may therefore reflect a disease‐modifying effect of this class of autoantibodies that has potential therapeutic implications. Our findings should encourage the development of new therapeutic modalities using IgM anti‐dsDNA antibodies in humans with SLE.
The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis
Authors: Giusti Betti , Serratì Simona , Margheri Francesca , Papucci Laura , Rossi Luciana , Poggi Filippo , Magi Alberto , Del Rosso Angela , Cinelli Marina , Guiducci Serena , Kahaleh Bashar , Matucci‐Cerinic Marco , Abbate Rosanna , Fibbi Gabriella , Del Rosso Mario
Published: October 2005

Objective

Postnatal angiogenesis relies on a proper response of endothelial cells to angiogenic stimuli. In systemic sclerosis (SSc), endothelial cells are unresponsive to angiogenic factors. Since circumstantial and experimental evidence points to tissue kallikreins as powerful effectors of the angiogenic response, we undertook this study to investigate the kallikrein pattern of normal and SSc endothelial cells in order to identify differences that can account for defective angiogenesis.

Methods

Expression of 14 tissue kallikreins was studied by a microarray approach, by reverse transcription–polymerase chain reaction, and by Western blotting in endothelial cells isolated from the skin of clinically healthy subjects and SSc patients. Cell proliferation was quantified by direct cell counting. Invasion and capillary morphogenesis were evaluated in a Boyden chamber and in culture flasks layered with Matrigel. Cyclic nucleotide production was measured by enzyme immunoassay. MAP kinase and ERK activation were measured by Western blotting.

Results

Endothelial cells from SSc patients showed poor expression of kallikreins 9, 11, and 12 compared with endothelial cells from normal subjects. Antibodies against the relevant kallikreins on normal endothelial cells revealed that while kallikreins 9, 11, and 12 induced cell growth, only kallikrein 12 regulated invasion and capillary morphogenesis. Buffering of kallikrein 12 with antibodies resulted in the acquisition of an SSc‐like pattern by normal cells in in vitro angiogenesis. Reduction of cAMP and cGMP production and of ERK phosphorylation upon administration of antikallikrein antibodies revealed that the activity of kallikreins 9, 11, and 12 was mediated by kinins.

Conclusion

Reduction of tissue kallikreins 9, 11, and 12 may be relevant to reduced angiogenesis in SSc patients.
Utility of corticosteroid injection for temporomandibular arthritis in children with juvenile idiopathic arthritis
Authors: Arabshahi Bita , Dewitt Esi Morgan , Cahill Ann Marie , Kaye Robin D. , Baskin Kevin M. , Towbin Richard B. , Cron Randy Q.
Published: October 2005

Objective

To assess the effects of computed tomography (CT)–guided injection of corticosteroid into the temporomandibular joint (TMJ) in children with juvenile idiopathic arthritis (JIA) and clinical and magnetic resonance imaging (MRI) evidence of TMJ inflammation.

Methods

Twenty‐three children ages 4–16 years with JIA and MRI evidence of TMJ inflammation received CT‐guided TMJ injections of corticosteroid (triamcinolone acetonide [n = 16] or triamcinolone hexacetonide [n = 7]). Jaw pain or dysfunction and maximal incisal opening (MIO) distance were assessed before and after injection. Fourteen patients had followup MRI studies of the TMJ 6–12 months after injection.

Results

Of the 13 patients with symptoms of jaw pain prior to corticosteroid treatment, 10 (77%) had complete resolution of pain (P < 0.05). Prior to corticosteroid injection, MIO in all 23 patients was below age‐matched normal values. After injection, the MIO was improved by at least 0.5 cm in 10 patients (43%) (P = 0.0017). Patients under 6 years of age at the time of injection showed the best response, with a postinjection MIO similar to that in age‐matched controls (P = 0.2267). There was involvement of 23 TMJs in the 14 patients who had followup MRI studies; resolution of effusions was observed in 11 (48%) of the TMJs. Other than short‐term facial swelling in 2 patients, there were no side effects.

Conclusion

The majority of children with symptomatic TMJ arthritis improved after intraarticular corticosteroid injection. Approximately half the patients experienced significant improvement in MIO and TMJ effusion. These data suggest that corticosteroid injection may be a useful procedure for the prevention and treatment of morbidities associated with TMJ arthritis in JIA.
Extracellular superoxide dismutase and oxidant damage in osteoarthritis
Authors: Regan Elizabeth , Flannelly Joanne , Bowler Russell , Tran Karen , Nicks Michael , Carbone Beth Duda , Glueck Deborah , Heijnen Harry , Mason Roger , Crapo James
Published: October 2005

Objective

To use human cartilage samples and a mouse model of osteoarthritis (OA) to determine whether extracellular superoxide dismutase (EC‐SOD) is a constituent of cartilage and to evaluate whether there is a relationship between EC‐SOD deficiency and OA.

Methods

Samples of human cartilage were obtained from femoral heads at the time of joint replacement surgery for OA or femoral neck fracture. Samples of mouse tibial cartilage obtained from STR/ort mice and CBA control mice were compared at 5, 15, and 35 weeks of age. EC‐SOD was measured by enzyme‐linked immunosorbent assay, Western blotting, and immunohistochemistry techniques. Real‐time quantitative reverse transcription–polymerase chain reaction was used to measure messenger RNA for EC‐SOD and for endothelial cell, neuronal, and inducible nitric oxide synthases. Nitrotyrosine formation was assayed by Western blotting in mouse cartilage and by fluorescence immunohistochemistry in human cartilage.

Results

Human articular cartilage contained large amounts of EC‐SOD (mean ± SEM 18.8 ± 3.8 ng/gm wet weight of cartilage). Cartilage from patients with OA had an ∼4‐fold lower level of EC‐SOD compared with cartilage from patients with hip fracture. Young STR/ort mice had decreased levels of EC‐SOD in tibial cartilage before histologic evidence of disease occurred, as well as significantly more nitrotyrosine formation at all ages studied.

Conclusion

EC‐SOD, the major scavenger of reactive oxygen species in extracellular spaces, is decreased in humans with OA and in an animal model of OA. Our findings suggest that inadequate control of reactive oxygen species plays a role in the pathophysiology of OA.
Delayed gadolinium‐enhanced magnetic resonance imaging of cartilage in knee osteoarthritis: Findings at different radiographic stages of disease and relationship to malalignment
Authors: Williams Ashley , Sharma Leena , McKenzie Charles A. , Prasad Pottumarthi V. , Burstein Deborah
Published: October 2005

Objective

Delayed gadolinium‐enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) is used to examine the distribution of glycosaminoglycan in cartilage. This study sought to characterize dGEMRIC in the evaluation of knee osteoarthritis (OA) according to various radiographically determined disease parameters, and to examine the relationship between alignment of the knee joint and the lateral:medial dGEMRIC ratio.

Methods

Thirty‐one patients with knee OA underwent MRI with a dGEMRIC protocol at 1.5T. Semiflexed knee radiographs and full‐limb radiographs were also obtained for assessment of alignment.

Results

Compartments of the knee joint without joint space narrowing had a higher dGEMRIC index than those with any level of narrowing (mean 408 msec versus 365 msec; P = 0.001). In knees with 1 unnarrowed (spared) and 1 narrowed (diseased) compartment, the dGEMRIC index was greater in the spared versus the diseased compartment (mean 395 msec versus 369 msec; P = 0.001). In spared compartments, there was a trend toward a lower dGEMRIC index with increasing Kellgren/Lawrence (K/L) radiographic severity grade; the spared compartments of knees with a K/L grade 2 had a higher dGEMRIC index than those of knees with a K/L grade 4 (mean 425 msec versus 371 msec; P < 0.05). There was a range of dGEMRIC values in the spared compartments within a given K/L grade, demonstrating biochemical differentiation of disease in radiographically comparable compartments. Almost all compartments with narrowing had dGEMRIC indices of <400 msec. Valgus‐aligned knees tended to have lower dGEMRIC values laterally, and varus‐aligned knees tended to have lower dGEMRIC values medially; as a continuous variable, alignment correlated with the lateral:medial dGEMRIC ratio (Pearson's R = 0.43, P = 0.02).

Conclusion

The biochemical information provided by dGEMRIC scans may augment radiography by improving the differentiation of disease status within a given radiographic grade, especially in early OA.
Effects of antirheumatic treatments on the prostaglandin E2 biosynthetic pathway
Authors: Korotkova Marina , Westman Marie , Gheorghe Karina R. , af Klint Erik , Trollmo Christina , Ulfgren Ann Kristin , Klareskog Lars , Jakobsson Per‐Johan
Published: October 2005

Objective

Microsomal prostaglandin E synthase 1 (mPGES‐1) is up‐regulated in experimental arthritis and markedly expressed in synovial tissue biopsy samples from patients with rheumatoid arthritis (RA). This study was carried out to determine the effects of tumor necrosis factor (TNF) blockers and glucocorticoids on mPGES‐1 and cyclooxygenase (COX) expression, as well as biosynthesis of PGE2 in rheumatoid joints.

Methods

In vitro effects of TNF blockers and dexamethasone on the PGE2 biosynthetic pathway were examined in RA synovial fluid mononuclear cells (SFMCs) by flow cytometry. PGE2 levels in culture supernatants were measured by enzyme immunoassay. Expression of enzymes responsible for PGE2 synthesis ex vivo was evaluated by immunohistochemistry in synovial biopsy samples obtained from 18 patients before and after treatment with TNF blockers and from 16 patients before and after intraarticular treatment with glucocorticoids. Double immunofluorescence was performed using antibodies against mPGES‐1, COX‐1, COX‐2, and CD163.

Results

Double immunofluorescence revealed that mPGES‐1 and COX‐2 were colocalized in SFMCs as well as in RA synovial tissue cells. The addition of either TNF blockers or dexamethasone suppressed lipopolysaccharide‐induced mPGES‐1 and COX‐2 expression in synovial fluid monocyte/macrophages in vitro and decreased the production of PGE2. Intraarticular treatment with glucocorticoids significantly reduced both mPGES‐1 and COX‐2 expression in arthritic synovial tissue ex vivo. The number of COX‐1–expressing cells in synovial tissue was also significantly decreased by glucocorticoid treatment. In contrast, neither mPGES‐1 nor COX‐2 expression in synovial tissue was significantly suppressed by anti‐TNF therapy.

Conclusion

These data are the first to demonstrate the effects of antirheumatic treatments on mPGES‐1 expression in RA and suggest that the inhibition of PGE2 biosynthesis, preferably by targeting mPGES‐1, might complement anti‐TNF treatment for optimal antiinflammatory results in RA.
Influence of HLA–DR genes on the production of rheumatoid arthritis–specific autoantibodies to citrullinated fibrinogen
Authors: Auger Isabelle , Sebbag Mireille , Vincent Christian , Balandraud Nathalie , Guis Sandrine , Nogueira Leonor , Svensson Björn , Cantagrel Alain , Serre Guy , Roudier Jean
Published: October 2005

Objective

Antibodies directed against citrullinated fibrinogen are highly specific for rheumatoid arthritis (RA). This study was undertaken to test whether RA‐associated HLA–DR alleles are associated with anti–citrullinated fibrinogen in RA patient sera and whether replacement of arginyl by citrullyl residues on fibrinogen peptides modifies their binding to HLA–DR molecules and their recognition by T cells.

Methods

Antikeratin, antifilaggrin, and anti–citrullinated fibrinogen antibodies were assayed in RA patients who had undergone HLA–DR typing. Direct assays were performed to investigate binding of citrullinated or native fibrinogen peptides (encompassing the entire α‐ and β‐chains of fibrinogen) to purified HLA–DR molecules. T cell proliferative responses to citrullinated or native fibrinogen peptides were measured in RA patients and controls.

Results

HLA–DRB1*0404 was associated with anti–citrullinated fibrinogen in RA sera (P = 0.002). For the RA‐associated alleles HLA–DRB1*0401 and HLA–DR1, there was a nonsignificant trend toward association (P = 0.07). Multiple peptides from the α‐ and β‐chains of fibrinogen bound many HLA–DR alleles; DRB1*0404 was the best fibrinogen peptide binder. Citrullination did not influence fibrinogen peptide binding to HLA–DR or fibrinogen peptide recognition by T cells. Peripheral blood T cells that recognized native or citrullinated fibrinogen peptides were common in RA patients but not in healthy controls.

Conclusion

The RA‐associated HLA–DRB1*0404 allele is also associated with production of antibodies to citrullinated fibrinogen. DRB1*0401 and DRB1*01 tend to be associated with anti–citrullinated fibrinogen, but this is not statistically significant. Citrullination of fibrinogen peptide does not influence peptide–DR–T cell interaction. Finally, T cell proliferation in response to citrullinated or uncitrullinated fibrinogen peptides is frequent in RA patients and very infrequent in controls.
A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium
Authors: Lally Frank , Smith Emily , Filer Andrew , Stone Michael A. , Shaw John S. , Nash Gerard B. , Buckley Christopher D. , Ed Rainger G.
Published: October 2005

Objective

Rheumatoid arthritis (RA) is classically thought of as a Th1, T lymphocyte–driven disease of the adaptive immune system. However, cells of the innate immune system, including neutrophils, are prevalent within the diseased joint, and accumulate in large numbers. This study was undertaken to determine whether cells of the rheumatoid stromal microenvironment could establish an inflammatory environment in which endothelial cells are conditioned in a disease‐specific manner to support neutrophil recruitment.

Methods

Human umbilical vein endothelial cells (ECs) and fibroblasts isolated from the synovium or skin of RA patients were established in coculture on opposite sides of porous transwell filters. After 24 hours of EC conditioning, the membranes were incorporated into a parallel‐plate, flow‐based adhesion assay and levels of neutrophil adhesion to ECs were measured.

Results

ECs cocultured with synovial, but not skin, fibroblasts could recruit neutrophils in a manner that was dependent on the number of fibroblasts. Antibody blockade of P‐selectin or E‐selectin reduced neutrophil adhesion, and an antibody against CD18 (the β2 integrin) abolished adhesion. Blockade of CXCR2, but not CXCR1, also greatly inhibited neutrophil recruitment. Interleukin‐6 (IL‐6) was detectable in coculture supernatants, and both IL‐6 and neutrophil adhesion were reduced in a dose‐dependent manner by hydrocortisone added to cocultures. Antibody blockade of IL‐6 also effectively abolished neutrophil adhesion.

Conclusion

Synovial fibroblasts from the rheumatoid joint play an important role in regulating the recruitment of inflammatory leukocytes during active disease. This process may depend on a previously unsuspected route of IL‐6–mediated crosstalk between fibroblasts and endothelial cells.
Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin‐like receptor KIR3DL2 in spondylarthritis
Authors: Chan A. T. , Kollnberger S. D. , Wedderburn L. R. , Bowness P.
Published: October 2005

Objective

The spondylarthritides (SpA) are strongly associated with possession of HLA–B27. We hypothesized that the expression of abnormal forms of HLA–B27 in SpA may have a pathogenic role through interaction with cells bearing natural killer (NK) receptors, in particular, killer immunoglobulin‐like receptor (KIR) KIR3DL2, a receptor for HLA–B27 homodimer (B272). We therefore undertook the present study to determine the number and function of NK and T cells bearing KIR3DL2 in SpA.

Methods

Expression of KIR3DL2 on NK and T cells was quantified in peripheral blood (PB) from 35 patients with SpA and 5 patients with juvenile enthesitis‐related arthritis (juvenile ERA); samples were compared with samples from healthy and rheumatoid arthritis (RA) controls. Paired synovial fluid (SF) was studied where available. Expression of other KIRs as well as activation, memory, and homing markers on KIR3DL2+ NK and T cells was quantified. NK cell survival was assessed using the apoptotic markers annexin V and 7‐aminoactinomycin D, and cytotoxicity by 51Cr release assay.

Results

In SpA, an increased number of PB and SF NK and CD4+ T cells expressed the KIR3DL2 receptor compared with controls. In ERA, KIR3DL2 expression was increased in PB and SF CD4 T cells (and SF NK cells) compared with RA controls. KIR3DL2+ NK cells had an activated phenotype, and were protected from apoptosis by culture with a cell line expressing B272. SpA PB mononuclear NK cells from SpA patients showed greater cytotoxicity than those from controls.

Conclusion

KIR3DL2 expression on NK cells and CD4 lymphocytes is increased in SpA and ERA. These cells are activated and may have a pathogenic role.
Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus
Authors: Popovic Karin , Ek Monica , Espinosa Alexander , Padyukov Leonid , Harris Helena Erlandsson , Wahren‐Herlenius Marie , Nyberg Filippa
Published: October 2005

Objective

To investigate the role of the novel cytokine high mobility group box chromosomal protein 1 (HMGB‐1) in the pathogenesis of cutaneous lupus erythematosus (CLE).

Methods

Punch biopsy specimens of lesional and unaffected skin from 10 patients with CLE and 3 healthy control subjects were investigated. Immunohistochemical staining for HMGB‐1, tumor necrosis factor α (TNFα), and interleukin‐1β (IL‐1β) was performed on consecutive sections. Analysis of single‐nucleotide polymorphisms of −308 TNF was performed on DNA extracted from peripheral blood mononuclear cells.

Results

An altered expression of HMGB‐1 was observed both in the epidermis and in the dermal infiltrates of lesional skin. Expression of HMGB‐1 in the epidermis and dermis was increased (P < 0.01 and P < 0.001, respectively, versus unaffected skin), and translocation to the cytoplasm as well as the extracellular presence of secreted HMGB‐1 were found. Increased levels of TNFα and IL‐1β were also observed in the dermal infiltrates of lesional skin (P < 0.01 and P < 0.05, respectively, versus unaffected skin). The carrier frequency of the −308A TNF polymorphism was 80% in patients with subacute CLE, but this was not related to higher expression of TNFα in biopsy specimens from the CLE group.

Conclusion

The high amount of extracellular HMGB‐1 observed in skin lesions indicates that HMGB‐1 is involved in the inflammatory process of CLE. TNFα and IL‐1β may form a proinflammatory loop with HMGB‐1, since they can induce the release of each other. The extracellular HMGB‐1 observed by immunostaining of the epidermis indicates that keratinocytes may be an as yet unrecognized source of secreted HMGB‐1, underscoring the role of the target organ in the rheumatoid autoimmune inflammatory process.
Investigating the aspartic acid (D) repeat of asporin as a risk factor for osteoarthritis in a UK Caucasian population
Authors: Mustafa Zehra , Dowling Barbara , Chapman Kay , Sinsheimer Janet S. , Carr Andrew , Loughlin John
Published: October 2005

Objective

A compelling genetic association with osteoarthritis (OA) of 2 functional alleles in the aspartic acid (D) repeat of the asporin gene was recently reported in a Japanese population. Allele D13 of the repeat encoded OA protection, whereas allele D14 encoded OA susceptibility. The 2 alleles mediate differences in the capacity of asporin to inhibit the cartilage growth factor transforming growth factor β, with the D14 allele being a particularly potent inhibitor. Our objective was to assess whether the D repeat is associated with OA in UK Caucasians.

Methods

The repeat was genotyped in 1,247 patients who had undergone elective joint replacement of the hip or the knee due to end‐stage primary OA and in 748 age‐matched controls.

Results

The D13 allele was more common in controls, and the D14 allele was more common in patients. However, this trend was significant only for men who had undergone hip replacement (P = 0.016, odds ratio 1.48, 95% confidence interval 1.09–2.01).

Conclusion

Our data suggest that the asporin polymorphism is not a major influence on OA etiology in Caucasians. The results of our study do not question the veracity of the Japanese report. Instead, our study highlights the complex, heterogeneous nature of OA genetic susceptibility.
Circadian pattern of spontaneous behavior in monarthritic rats: A novel global approach to evaluation of chronic pain and treatment effectiveness
Authors: Millecamps Magali , Jourdan Didier , Leger Sabine , Etienne Monique , Eschalier Alain , Ardid Denis
Published: October 2005

Objective

Preclinical evaluation is an essential step in the assessment of new antiinflammatory or analgesic drugs. This study was undertaken to develop a new mode of evaluation of drug effectiveness based on behavior indicating well‐being in a rat model of chronic inflammatory pain. We chose to examine the circadian pattern of spontaneous behavior.

Methods

The work was performed with a model of chronic monarthritis induced by Freund's complete adjuvant. Variations in behavioral patterns during the time course of arthritis were analyzed. In a second phase, the impact of acetaminophen and 2 nonsteroidal antiinflammatory drugs (aspirin and celecoxib), which are currently used in clinical practice to treat chronic inflammation, was studied after 7 days of treatment.

Results

The nocturnal pattern of activity of healthy rats comprised 3 main bursts. Chronic painful monarthritis altered this spontaneous pattern of nocturnal behavior (normal period of activity). Monarthritic rats showed a decrease in the total time spent in activity during the night, and lost their pattern of activity. These behavioral disturbances were reversed after long‐term treatment with acetaminophen or celecoxib, with celecoxib appearing to be more effective. Aspirin was ineffective.

Conclusion

These results enabled us to test this new procedure as a means of assessing well‐being or ill‐ being during stages of chronic inflammatory pain in rats, and the effectiveness of repeated pharmacologic treatments.
Characterization and consequences of pain variability in individuals with fibromyalgia
Authors: Harris Richard E. , Williams David A. , McLean Samuel A. , Sen Ananda , Hufford Michael , Gendreau R. Michael , Gracely Richard H. , Clauw Daniel J.
Published: October 2005

Objective

A growing body of evidence suggests that real‐time electronic assessments of pain are preferable to traditional paper‐and‐pencil measures. We used electronic assessment data derived from a study of patients with fibromyalgia (FM) to examine variability of pain over time and to investigate the implications of pain fluctuation in the context of a clinical trial.

Methods

The study group comprised 125 patients with FM who were enrolled in a randomized, placebo‐controlled trial of milnacipran. Pain intensity levels were captured in real time by participants using electronic diaries. Variability in pain was assessed as the standard deviation of pain entries over time (pain variability index [PVI]).

Results

Substantial between‐subject differences in pain variability were observed (mean ± SD PVI 1.61 ± 0.656 [range 0.27–4.05]). The fluctuation in pain report was constant over time within individuals (r = 0.664, P < 0.001). Individuals with greater variability were more likely to be classified as responders in a drug trial (odds ratio 6.14, P = 0.006); however, this association was primarily attributable to a greater change in pain scores in individuals receiving placebo (r = 0.460, P = 0.02) rather than active drug (r = 0.09, P > 0.10).

Conclusion

Among individuals with FM, there were large between‐subject differences in real‐time pain reports. Pain variability was relatively constant over time within individuals. Perhaps the most important finding is that individuals with larger pain fluctuations were more likely to respond to placebo. It is not clear whether these findings are applicable only to patients with FM or whether they may also be seen in patients with other chronic pain conditions.
MEFV analysis is of particularly weak diagnostic value for recurrent fevers in Western European Caucasian patients
Authors: Tchernitchko D. , Moutereau S. , Legendre M. , Delahaye A. , Cazeneuve C. , Lacombe C. , Grateau G. , Amselem S.
Published: October 2005

Objective

Familial Mediterranean fever (FMF) is an autosomal‐recessive disorder characterized by recurrent attacks of fever, with abdominal, thoracic, or articular pain. FMF is particularly common in Mediterranean populations, while other populations are rarely affected. MEFV gene analysis provides the only objective diagnostic criterion for FMF. However, the spectrum of MEFV mutations, which was first established in classically affected populations, remains insufficiently studied in other populations. The purpose of this study was to assess involvement of MEFV in the phenotype of western European Caucasian patients with a clinical diagnosis of FMF.

Methods

Mutation analysis was performed in 208 Caucasian patients from western Europe, by screening for the most common MEFV mutations in exons 2, 3, 5, and 10, and by sequencing the promoter region and the whole MEFV coding sequence in 21 of these patients.

Results

None of the patients carried 2 mutated alleles. Only 2 patients carried 1 mutated allele.

Conclusion

FMF‐like syndromes in western European Caucasian populations cannot be explained by MEFV mutations. These results should be helpful in avoiding laborious and costly MEFV molecular analyses that, at the population level, seem to be of poor diagnostic value in the case of western European Caucasian patients, and rather should prompt a search for other causes in those patients.
Cat‐scratch disease–associated arthropathy
Authors: Giladi Michael , Maman Eran , Paran Daphna , Bickels Jacob , Comaneshter Doron , Avidor Boaz , Varon‐Graidy Merav , Ephros Moshe , Wientroub Shlomo
Published: October 2005

Objective

To characterize the articular manifestations of cat‐scratch disease (CSD) and to evaluate the long‐term clinical outcome of those manifestations.

Methods

A community‐ and hospital‐based surveillance study of CSD was conducted in Israel between 1991 and 2002. CSD was defined as present in a patient when a compatible clinical syndrome and a positive confirmatory finding of Bartonella henselae (by serology and/or polymerase chain reaction) were identified. CSD patients with arthropathy (arthritis/arthralgia) that limited or precluded usual activities of daily living constituted the study group. Patients were followed up until ≥6 weeks after resolution of symptoms, or if symptoms persisted, for ≥12 months. CSD patients without arthropathy served as controls.

Results

Among 841 CSD patients, 24 (2.9%) had rheumatoid factor–negative arthropathy that was often severe and disabling. Both univariate and multivariate analyses identified female sex (67% of arthropathy patients versus 40% of controls; relative risk [RR] 2.5, P = 0.047), age older than 20 years (100% of arthropathy patients versus 43% of controls; RR 4.9, P = 0.001), and erythema nodosum (21% of arthropathy patients versus 2% of controls; RR 7.9, P = 0.001) as variables significantly associated with arthropathy. Knee, wrist, ankle, and elbow joints were most frequently affected. Ten patients (42%) had severe arthropathy in the weight‐bearing joints, which substantially limited their ability to walk, and 4 of these patients were hospitalized. All of the patients had regional lymphadenopathy, 37.5% had nocturnal joint pain, and 25% had morning stiffness. Nineteen patients (79.2%) recovered after a median duration of 6 weeks (range 1–24 weeks), whereas 5 patients (20.8%) developed chronic disease persisting 16–53 months (median 30 months) after the onset of arthropathy.

Conclusion

This is the first comprehensive study of arthropathy in CSD. CSD‐associated arthropathy is an uncommon syndrome affecting mostly young and middle‐age women. It is often severe and disabling, and may take a chronic course.
Positive effects of moderate exercise on glycosaminoglycan content in knee cartilage: A four‐month, randomized, controlled trial in patients at risk of osteoarthritis
Authors: Roos Ewa M. , Dahlberg Leif
Published: October 2005

Objective

To evaluate the effects of moderate exercise on glycosaminoglycan (GAG) content in knee cartilage in subjects at high risk of knee osteoarthritis (OA).

Methods

Forty‐five subjects (16 women, mean age 46 years, mean body mass index 26.6 kg/m2) who underwent partial medial meniscus resection 3–5 years previously were randomized to undergo a regimen of supervised exercise 3 times weekly for 4 months or to a nonintervention control group. Cartilage GAG content, an important aspect of the biomechanical properties of cartilage, was estimated by delayed gadolinium‐enhanced magnetic resonance imaging of cartilage (dGEMRIC), with results expressed as the change in the T1 relaxation time in the presence of Gd‐DTPA (T1[Gd]).

Results

Thirty of 45 patients were examined by dGEMRIC at baseline and followup. The exercise group (n = 16) showed an improvement in the T1(Gd) compared with the control group (n = 14) (15 msec versus −15 msec; P = 0.036). To study the dose response, change in the T1(Gd) was assessed for correlation with self‐reported change in physical activity level, and a strong correlation was found in the exercise group (n = 16, rS = 0.70, 95% confidence interval [95% CI] 0.31–0.89) and in the pooled group of all subjects (n = 30, rS = 0.74, 95% CI 0.52–0.87).

Conclusion

This in vivo cartilage monitoring study in patients at risk of knee OA who begin exercising indicates that adult human articular cartilage has a potential to adapt to loading change. Moderate exercise may be a good treatment not only to improve joint symptoms and function, but also to improve the knee cartilage GAG content in patients at high risk of developing OA.
Assessing bone loss on radiographs of the knee in osteoarthritis: A cross‐sectional study
Authors: Dieppe Paul A. , Reichenbach Stephan , Williams Susan , Gregg Paul , Watt Iain , Jüni Peter
Published: October 2005

Objective

The only established system to grade subchondral bone attrition in knee osteoarthritis (OA) has low interobserver reliability. In this study, our aim was to convert this system into a reliable tool for the assessment of subchondral bone loss in knee OA.

Methods

Templates that were designed to outline the normal contours of the knee were overlaid onto conventional radiographs of a random sample of 100 knees of OA patients who were awaiting total knee replacement (TKR). Seventy‐five films from individuals with chronic knee pain who were not awaiting TKR and 75 films from asymptomatic control subjects were also assessed. Bone loss was graded from 0 (no attrition) to 3 (severe attrition of >10 mm); other established radiologic features were also graded. Spearman's rho was used to determine the correlation of attrition scores with other features, and logistic regression was used to explore whether definite bone attrition was associated with night pain.

Results

The inter‐ and intraobserver reliability values were high for attrition scores and for the presence of definite attrition (score ≥2). Bone attrition was evident in 62% of films from patients awaiting TKR, in 9% of films from individuals with chronic knee pain who were not awaiting TKR, and in 1% of films from controls. In all groups, the correlation between attrition and other features was weak to moderate. There was a nonsignificant association between definite bone attrition and night pain.

Conclusion

Bone attrition is an additional dimension of knee OA that can be measured reliably. Definite attrition may be associated with night pain.
Determination of the baculovirus transducing titer in mammalian cells
Authors: Chan Zun‐Ren , Lai Chia‐Wei , Lee Hsiao‐Ping , Chen Huang‐Chi , Hu Yu‐Chen
Published: October 2005

Baculovirus has emerged as a promising vector for in vivo or ex vivo gene therapy. To date, the infectious titer and multiplicity of infection (MOI) based on the ability of baculovirus to infect insect cells are commonly adopted to indicate the virus dosage. However, the infectious titer and MOI do not reliably represent the baculovirus transducing ability, making the comparison of baculovirus‐mediated gene transfer difficult. To determine the baculovirus transducing ability more rapidly and reliably, we developed a protocol to evaluate the transducing titers of baculovirus stocks. The virus was diluted twofold serially and used to transduce HeLa cells. The resultant transduction efficiencies were measured by flow cytometry for the calculation of transducing titers. Compared to the infectious titer, the determination of transducing titer is more reproducible as the standard deviations among measurements are smaller. Also, the transducing titers can be obtained in 24 h, which is significantly faster as opposed to 4–7 days to obtain the infectious titer. More importantly, we demonstrated that baculoviruses with higher transducing titers could transduce cells at higher efficiency and yield stronger and longer transgene expression, confirming that the transducing titer was representative of the baculovirus transducing ability. This finding is particularly significant for ex vivo gene delivery whereby unconcentrated viruses are used for transduction and long‐term transgene expression is desired. In this regard, our titration protocol provides a simple, fast, and reliable measure to evaluate the quality of virus stocks during virus production and purification, and is helpful to predict the performance of vector supernatants and ensure reproducible gene delivery experiments. © 2005 Wiley Periodicals, Inc.
Neurenteric cyst: Case report and a review of the potential dysembryology
Authors: Tubbs R. Shane , Salter E. George , Oakes W. Jerry
Published: October 2005

We report a 13‐year‐old female who presented to an outside emergency room following blunt trauma to the head. As part of her evaluation, an unenhanced CT of the face and radiographs of the cervical spine were performed. She was referred to our clinic with “abnormal” imaging. Radiographs revealed dysmorphic cervical spine and ventral clefting of the vertebral bodies from C7‐T2. A subsequent MRI was obtained that demonstrated a large spinal cord mass. MRI demonstrated an unenhanced intramedullary mass of the cervicothoracic spinal cord measuring approximately 1.5 cm in greatest axial diameter. Surgical exploration of her intraspinal mass revealed a neurenteric cyst. Spinal neurenteric cysts are categorized in the spectra of occult spinal dysraphism and most likely arise from incomplete separation of the developing notochord and foregut in the embryo. We discuss potential etiologies for the formation of such cysts. The clinician should consider neurenteric cysts in their differential diagnosis of patients with spinal dysraphism and/or intraspinal masses. Clin Anat. 19:669–672, 2006 © 2005 Wiley‐Liss, Inc.
The molecular genetics of gastroenteropancreatic neuroendocrine tumors
Authors: Zikusoka Michelle N. , Kidd Mark , Eick Geeta , Latich Igor , Modlin Irvin M.
Published: October 2005

The pathobiology of neuroendocrine tumors (NETs) is hampered by the lack of scientific tools that define their mechanisms of secretion, proliferation, and metastasis; and, currently, there are no accurate means to assess tumor behavior and disease prognosis. Molecular biologic techniques and genetic analysis may facilitate the delineation of the molecular pathology of NETs and provide novel insights into their cellular mechanisms. The current status and recent advances in assessment of the molecular basis of tumorigenesis of gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) were reviewed (1981–2004). The objectives of this retrospective study were to provide a cohesive overview of the current state of knowledge and to develop a molecular understanding of these rare tumor entities to facilitate the establishment of therapeutic targets and rational management strategies. Multiple differences in chromosomal aberration patterns were noted between gastrointestinal (GI) neuroendocrine and pancreatic endocrine tumors (PETs). Divergence in gene expression patterns in the development of GI carcinoids and PETs was identified, whereas examination of the PET and GI carcinoid data demonstrated only few areas of overlap in the accumulation of genetic aberrations. These data suggest that the recent World Health Organization classification of GEP‐NETs may require updating. In addition, previous assumptions of tumor similarity (pancreatic vs. GI) may be unfounded when they are examined at a molecular level. On the basis of the evolution of genetic information, enteric neuroendocrine lesions (carcinoids) and PETs may need to be classified as two distinct entities rather than grouped together as the single entity “GEP‐NETs.” Cancer 2005. © 2005 American Cancer Society.
Phase II study of pemetrexed in combination with carboplatin in the first‐line treatment of advanced nonsmall cell lung cancer
Authors: Zinner Ralph G. , Fossella Frank V. , Gladish Gregory W. , Glisson Bonnie S. , Blumenschein George R. , Papadimitrakopoulou Vassiliki A. , Pisters Katherine M.W. , Kim Edward S. , Oh Yun W. , Peeples Beverly O. , Ye Zhishen , Curiel Rafael E. , Obasaju Coleman K. , Hong Waun K. , Herbst Roy S.
Published: October 2005

BACKGROUND

The primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed‐carboplatin combination as first‐line therapy in patients with advanced nonsmall cell lung cancer.

METHODS

Eligibility criteria included Zubrod performance status of 0 or 1, Stage IIIB (malignant effusion) or IV disease, and no prior chemotherapy. Treatment was pemetrexed 500 mg/m2 given intravenously and carboplatin area under the serum concentration–time curve = 6 given intravenously on Day 1 every 3 weeks for six cycles; patients could receive additional cycles at the discretion of the treating physician and patient. All patients received folic acid, vitamin B12, and dexamethasone prophylaxis.

RESULTS

Fifty patients (31 men and 19 women) were treated. The median age was 62 years. Ninety‐six percent of patients had Stage IV disease, and 88% had a performance status of 1. The median number of cycles was 6; 15 patients received 8 or more cycles. There was Grade 3/4 neutropenia in 11 (22%) and 2 (4%) patients, respectively; Grade 3/4 thrombocytopenia in 1 (2%) and 0 patients, respectively. Three patients (6%) experienced Grade 3 nonhematologic side effects (diarrhea, neutropenic pneumonia, and fatigue). No patients had sensory neuropathy or alopecia >Grade 1. The partial response rate was 24%, median time to progression 5.4 months, 1‐year survival 56.0%, and median survival 13.5 months.

CONCLUSIONS

This is an active, very well‐tolerated regimen. Trials focused on how to integrate this doublet with novel agents are warranted. Cancer 2005. © 2005 American Cancer Society.