bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate
Authors: Kane David , Gogarty Martina , O'Leary John , Silva Ivan , Bermingham Niamh , Bresnihan Barry , FitzGerald Oliver
Published: October 2004

Objective

Methotrexate is one of the most commonly used disease‐modifying antirheumatic drugs in the management of psoriatic arthritis (PsA). Despite the differences between the inflammation in PsA and rheumatoid arthritis (RA), the effects of methotrexate on the synovium have been described solely in RA. In this study, we sought to determine the effects of methotrexate on the inflammatory infiltrate and on cytokine and metalloproteinase gene expression in the synovium of PsA patients.

Methods

Ten patients with PsA (median duration 18 months) underwent arthroscopy and synovial biopsy of an inflamed knee before and after clinical improvement induced by methotrexate. Immunohistologic analysis was performed using antibodies to CD3, CD4, CD8, CD68, factor VIII, vascular cell adhesion molecule, E‐selectin, and intercellular adhesion molecule (ICAM). Matrix metalloproteinase 3 (MMP‐3) and tissue inhibitor of metalloproteinases 1 (TIMP‐1) messenger RNA (mRNA) were quantified by competitive reverse transcription–polymerase chain reaction (RT‐PCR). Interleukin‐1α (IL‐1α), IL‐1β, IL‐2, IL‐4, IL‐5, IL‐8, IL‐10, IL‐12p35, IL‐12p40, IL‐15, interferon‐γ (IFNγ), and tumor necrosis factor α (TNFα) mRNA expression was quantified by real‐time PCR.

Results

Patients received a median methotrexate dosage of 13.75 mg/week (range 7.5–15) for a median of 11.5 months (range 7–14 months). The Ritchie Articular Index, swollen joint count, and Disease Activity Score were significantly reduced. There was a decrease in all immunohistologic staining, although this was statistically significant only for CD3, CD4, CD8, CD68, E‐selectin, and ICAM. Despite clinical improvement in all patients, there was a residual T cell infiltrate in all synovial biopsy tissues. The synovial lining layer thickness, but not hypervascularity, was significantly reduced. There was also a significant reduction in MMP‐3, but not TIMP‐1, expression. Before treatment, PsA synovium was characterized by a predominant expression of the proinflammatory cytokines IL‐15, IFNγ, IL‐1β, and TNFα and the antiinflammatory cytokine IL‐10. Methotrexate reduced synovial IL‐1α, IL‐1β, IL‐8, IL‐10, IL‐15, IFNγ, and TNFα mRNA expression, but the effect was significant only for IL‐8.

Conclusion

Methotrexate produced a clinical response in PsA by reducing, but not abolishing, the inflammatory infiltrate, adhesion molecule expression, and MMP‐3 and proinflammatory cytokine gene expression, particularly IL‐8, in the synovium. Methotrexate did not reduce hypervascularity, which is a prominent differentiating feature of PsA synovium.
Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus
Authors: Hutloff Andreas , Büchner Kerstin , Reiter Karin , Baelde Hans J. , Odendahl Marcus , Jacobi Annett , Dörner Thomas , Kroczek Richard A.
Published: October 2004

Objective

In systemic lupus erythematosus (SLE), the increased generation of memory B cells and plasma cells leads to autoimmune hypergammaglobulinemia and destructive immunoglobulin deposits in the kidneys. We undertook this study to determine the biologic mechanism driving this overactivation of the B cell compartment, which is the central issue in SLE.

Methods

We used flow cytometry to analyze expression of the T cell–specific inducible costimulator (ICOS) and its ligand (ICOS‐L) on B cells obtained from the peripheral blood of SLE patients. We correlated ICOS‐L expression with the differentiation status of the B cells using a large panel of surface antigens. In addition, SLE kidneys were analyzed by immunohistology.

Results

We found an increased expression of ICOS on CD4+ as well as CD8+ T cells in SLE. At the same time, we documented a down‐regulation of ICOS‐L on a high proportion of peripheral blood memory B cells. Based on in vitro experiments, we inferred that this ICOS‐L down‐regulation on B cells was a signature of recent interaction with ICOS+ T cells in vivo. In the kidneys of SLE patients, we found clusters of B cells and plasma cells in close contact with ICOS+ T cells.

Conclusion

Detailed analysis of B cells with down‐regulated ICOS‐L suggests that ICOS is one of the forces driving the formation of memory B cells and plasma cells in SLE. Furthermore, our identification of plasma cells in areas of T cell–B cell interaction in kidneys suggests that components of a T cell–driven B cell activation process may take place in peripheral tissues in SLE.
Thrombotic thrombocytopenic purpura with severe ADAMTS‐13 deficiency in two patients with primary antiphospholipid syndrome
Authors: Amoura Zahir , Costedoat‐Chalumeau Nathalie , Veyradier Agnès , Wolf Martine , Ghillani‐Dalbin Pascale , Cacoub Patrice , Meyer Dominique , Piette Jean‐Charles
Published: October 2004

Arterial thrombotic events, thrombocytopenia, and hemolytic anemia with schistocytes may be encountered in the setting of both thrombotic thrombocytopenic purpura (TTP) and primary antiphospholipid syndrome (APS). We report 2 cases of TTP occurring in patients with definite primary APS. We also describe the results of tests for ADAMTS‐13 activity in 20 consecutive patients with primary APS, as well as tests for antiphospholipid antibodies in 26 patients who had TTP, severe ADAMTS‐13 deficiency, and ADAMTS‐13–inhibiting antibodies. In both of the patients with primary APS and TTP, ADAMTS‐13 activity was undetectable, and ADAMTS‐13–inhibiting antibodies were present. None of the 26 patients with TTP and severe ADAMTS‐13 deficiency was positive for the lupus anticoagulant. One of these patients had a low level of anticardiolipin antibodies (22 IgG phospholipid units). In the 20 patients with primary APS, mean ADAMTS‐13 activity was 116% (range 44–250%), and no severe deficiency (<5%) was observed. Our findings suggest that primary APS must be added to the list of autoimmune disorders that can be complicated by TTP.
A human COL2A1 gene with an Arg519Cys mutation causes osteochondrodysplasia in transgenic mice
Authors: Sahlman Janne , Pitkänen Marja T. , Prockop Darwin J. , Arita Machiko , Li Shi‐Wu , Helminen Heikki J. , Långsjö Teemu K. , Puustjärvi Kaija , Lammi Mikko J.
Published: October 2004

Objective

An arginine‐to‐cysteine substitution at position 519 of the COL2A1 gene causes early generalized osteoarthritis with mild chondrodysplasia in humans. In this study, a human COL2A1 gene with the same mutation was introduced into a murine genome having 1 or no alleles of the murine Col2a1 gene, and the skeletal phenotypes of the transgenic mice were compared with those of control mice.

Methods

Mice with 1 allele of the normal murine Col2a1 gene and 1 allele of the mutated human COL2A1 gene (n = 10), those with no murine Col2a1 gene and 2 alleles of the mutated human COL2A1 gene (n = 13), those with no murine Col2a1 gene and only 1 allele of the mutated COL2A1 gene (n = 9), and normal control mice (n = 11) were studied for skeletal abnormalities, using radiographic imaging and light microscopic analyses of histologic sections. The collagen network of cartilage was also investigated with transmission electron microscopy.

Results

At 2 months of age, all transgenic mice had dysplastic changes in their long bones, flattened vertebral bodies, and osteoarthritic changes in their joints. The intervertebral discs of the transgenic animals were degenerated, and their histologic structure was disturbed. The changes were more severe in mice with no murine Col2a1 allele.

Conclusion

The human COL2A1 gene with the Arg519Cys mutation causes osteochondrodysplasia in mice, as it does in humans.
Outcome of pregnancies in patients with anti‐SSA/Ro antibodies: A study of 165 pregnancies, with special focus on electrocardiographic variations in the children and comparison with a control group
Authors: Costedoat‐Chalumeau Nathalie , Amoura Zahir , Lupoglazoff Jean‐Marc , Thi Huong Du Le , Denjoy Isabelle , Vauthier Danièle , Sebbouh Djamel , Fain Olivier , Georgin‐Lavialle Sophie , Ghillani Pascale , Musset Lucile , Wechsler Bertrand , Duhaut Pierre , Piette Jean‐Charles
Published: October 2004

Objective

Aside from congenital heart block (CHB), sinus bradycardia and prolongation of the corrected QT (QTc) interval have been reported in infants born to mothers with anti‐SSA antibodies. To assess the pathologic nature of these manifestations, this study focused on electrocardiographic (EKG) variations in these children, comparing them with findings in a control group.

Methods

We studied 165 consecutive pregnancies in 106 anti‐SSA–positive women with connective tissue diseases (CTDs). EKGs obtained on 58 children of this group were compared with those obtained on 85 infants born to mothers with CTD who were negative for both anti‐SSA and anti‐SSB.

Results

No statistically significant difference was seen between the 2 study groups with regard to gestational age, prematurity, birth weight, age of the children at the time of EKG, age of the mothers, or treatments received by the mothers during their pregnancies. Seven of 137 children developed cutaneous neonatal lupus syndrome; 1 child developed CHB (CHB risk of 1 in 99 [1%] if only the first prospectively observed pregnancy in women without a history of CHB is included in the analysis). For EKGs recorded during the first 2 months of life, the mean ± SD PR interval was 96 ± 16 msec in the anti‐SSA–positive group and 96 ± 13 msec in the anti‐SSA–negative group (P = 0.84), with mean QTc values of 397 ± 27 and 395 ± 25 msec (P = 0.57) and mean heart rates of 141 ± 23 and 137 ± 21 beats per minute (P = 0.20), respectively. No difference in the PR interval, QTc interval, or heart rate was observed for EKGs obtained between 2 and 4 months of life. When EKGs obtained at 0–2 months were compared with those obtained at 2–4 months, a physiologic prolongation of the QTc interval was observed in both study groups. No sudden infant death or symptomatic arrhythmia occurred during the first year of life.

Conclusion

The EKG findings in children of anti‐SSA–positive and anti‐SSA–negative mothers were not significantly different. Our results suggest that the prolongation of the QTc interval and sinus bradycardia that have recently been reported in children of mothers with anti‐SSA antibodies occur independently of the anti‐SSA antibodies. The pathologic nature of these EKG variations was not confirmed by our controlled study.
Interaction between RANKL and HLA–DRB1 genotypes may contribute to younger age at onset of seropositive rheumatoid arthritis in an inception cohort
Authors: Wu Hui , Khanna Dinesh , Park Grace , Gersuk Vivian , Nepom Gerald T. , Wong Weng Kee , Paulus Harold E. , Tsao Betty P.
Published: October 2004

Objective

To determine whether the RANKL and HLA–DRB1 “shared epitope” (SE) genotypes contribute to the development of rheumatoid arthritis (RA).

Methods

We studied 237 patients with early RA (within 15 months of symptom onset) who were seropositive for rheumatoid factor. HLA–DRB1 genotyping was performed using the polymerase chain reaction (PCR)–based oligonucleotide probe assay. RANKL polymorphisms were analyzed using PCR pyrosequencing for SNP1 and fluorescence‐based PCR for the presence or absence of the TAAA insertion.

Results

The presence of SE‐containing DRB1*04 alleles was associated with an earlier age at RA onset (mean ± SD 47 ± 12.7 years versus 53 ± 12.5 years in SE– patients; P = 0.0004). The 2 novel RANKL polymorphisms were in strong linkage disequilibrium (P < 0.0001) and were associated with earlier ages at disease onset (e.g., for the CC versus CT/TT genotypes, 44 ± 13.5 years versus 51 ± 12.7 years; P = 0.0080). The mean age at disease onset in SE+ patients with the RANKL‐CC genotype (35 ± 7.2 years) was a mean of 18 years younger than in SE– patients with RANKL‐CT/TT (53 ± 12.5 years; P < 0.0001) and was 17 years younger than in SE– patients with RANKL‐CC (52 ± 13.2 years; P = 0.0005). The proportion of patients with both the SE and RANKL risk alleles was highest (23%) in those who developed RA during their third decade of life (ages 20–30 years), with a declining trend among those who developed RA during their fourth (16%), fifth (5%), and sixth or later (0%) decades. Interestingly, 92% of the patients diagnosed as having RA between ages 20 and 30 years carried at least 1 of the RA‐associated DRB1*04 alleles, suggesting a strong influence of the SE in the early onset of RA. The majority of patients who developed RA symptoms in their third to fifth decades (74 of 119 [62%]) carried at least 1 copy of the DRB1*04 alleles; in contrast, fewer than half of the patients who developed RA in their sixth decade or later (50 of 118 [42%]) had DRB1*04 alleles. RANKL genotypes were not associated with erosive disease at baseline or with the yearly progression rate of radiographic joint damage.

Conclusion

This study provides the first evidence that novel RANKL polymorphisms were associated with an earlier age at RA onset in SE+, but not SE–, patients and that an interaction between SE‐containing HLA–DRB1 and RANKL polymorphisms increased the disease penetrance, resulting in a mean age at RA onset that was 18–20 years younger. Our results also suggested genetic differences between patients with early‐onset and those with late‐onset RA.
Quantification of cortical bone loss and repair for therapeutic evaluation in collagen‐induced arthritis, by micro–computed tomography and automated image analysis
Authors: Barck Kai H. , Lee Wyne P. , Diehl Lauri J. , Ross Jed , Gribling Peter , Zhang Yifan , Nguyen Kathy , van Bruggen Nicholas , Hurst Stephen , Carano Richard A. D.
Published: October 2004

Objective

Ex vivo and in vivo micro–computed tomography (micro‐CT) combined with a novel image analysis algorithm were used to quantify cortical bone loss and periosteal new bone formation for therapeutic evaluation in a murine model of collagen‐induced arthritis.

Methods

An automated algorithm was created to locate 5 metatarsophalangeal and 3 metacarpophalangeal joints in 3‐dimensional micro‐CT images of mouse paws for evaluation of joint cortical bone volume (JCBV) within close proximity of the joints as well as cortical bone mineral density and periosteal new bone formation within the paws. For validation, automated estimates of JCBV were compared with radiographic visual scores (RVS) in 4 treatment groups (n = 9 per group): rat anti‐mouse CD11a monoclonal antibody, methotrexate (MTX), anti‐CD11a plus MTX, and saline only. In a separate study, serial images of hind limbs were evaluated in 2 treatment groups: murine tumor necrosis factor receptor II–Fc fusion protein (mTNFRII; n = 10) and control antibody (n = 7).

Results

Automated estimates of the JCBV were significantly correlated with the RVS (hind paws R = −0.94, front paws R = −0.81, combined R = −0.87). The anti‐CD11a group had significantly higher JCBV compared with controls. In the serial study, the automated estimate of JCBV detected significant treatment effects in the mTNFRII‐Fc group compared with controls. Cortical bone mineral density was significantly higher in all treatment groups compared with controls.

Conclusion

Micro‐CT combined with a novel image analysis technique (estimation of JCBV) provides a fully automated means to quantify bone destruction in a mouse model of rheumatoid arthritis.
Induction of endothelial cell apoptosis by heat‐shock protein 60–reactive antibodies from anti–endothelial cell autoantibody–positive systemic lupus erythematosus patients
Authors: Dieudé Mélanie , Senécal Jean‐Luc , Raymond Yves
Published: October 2004

Objective

To determine whether anti–endothelial cell autoantibodies (AECAs) from systemic lupus erythematosus (SLE) patients with the antiphospholipid syndrome are involved in the initial endothelial cell (EC) membrane perturbation effect that is postulated to provide a target for antiphospholipid antibody (aPL) binding and, hence, to trigger the thrombotic cascade. To identify the AECA antigenic target on ECs and to determine the mechanism whereby the EC membrane is disrupted.

Methods

AECAs from SLE patients were assayed for binding to ECs by flow cytometry. Positive AECAs were assayed by immunoblotting, and a consensus antigen was identified by mass spectrometry. This candidate antigen was tested in recombinant form for AECA recognition. AECAs were affinity‐purified on this antigen and incubated with ECs to determine their physiologic effects. Anti‐Hsp60 antibody titers were determined by enzyme‐linked immunosorbent assay. The relationship of anti‐Hsp60 status and lupus anticoagulant (LAC) status to thrombotic manifestations between disease onset and the last followup visit were analyzed.

Results

Most of the SLE sera (73%) possessed IgG that bound to the surface of ECs. These positive IgG shared reactivity against a 60‐kd EC surface polypeptide that was identified as human Hsp60. The presence of Hsp60 at the EC surface was established using anti‐Hsp60 antibodies from commercial sources or affinity‐purified from SLE sera that bound ECs. Incubation of ECs with these anti‐Hsp60 antibodies induced apoptosis in a time‐ and dose‐dependent manner, as determined by Hoechst 33342 dye staining of condensed nuclei and by annexin V binding to surface phosphatidylserine. Anti‐Hsp60 antibodies were not restricted to SLE patients, but were found in patients with other autoimmune diseases. However, anti‐Hsp60 antibodies were significantly associated with an increased frequency of thrombosis when present in combination with LAC in the SLE patients.

Conclusion

The presence of Hsp60 at the surface of ECs serves as a target for the anti‐Hsp60 antibodies in SLE sera. These anti‐Hsp60 antibodies bind to ECs and induce apoptosis, particularly phosphatidylserine exposure, thus providing a target for the binding of aPL and inducing the subsequent thrombotic cascade.
The “enthesis organ” concept: Why enthesopathies may not present as focal insertional disorders
Authors: Benjamin M. , Moriggl B. , Brenner E. , Emery P. , McGonagle D. , Redman S.
Published: October 2004

Objective

The Achilles tendon insertion is associated with a complex of adjacent fibrocartilages, a bursa, and a fat‐pad, and is functionally much more than a focal insertion. This has important implications for a better understanding of the spondylarthropathies (SpA). However, the degree to which other insertions form comparable “enthesis organs” has not been established. The aim of this study was to demonstrate the applicability of the enthesis organ concept to other insertion sites.

Methods

Both joint‐related (articular) and extraarticular entheses were removed from 28 sites in the limbs of formalin‐fixed cadavers (age at death 70–101 years) that had been donated for anatomic study. The samples were prepared for paraffin histologic analysis and sectioned longitudinally. The presence and extent of enthesis organs was evaluated at each site in serial sections stained with Masson's trichrome and toluidine blue.

Results

Articular enthesis organs were found at 14 entheses, including the attachments of the digital extensor tendons and collateral ligaments, the cruciate ligaments, tibialis anterior, the lateral collateral ligament of the knee, and the popliteal tendon. Extraarticular enthesis organs were seen at 2 sites, the biceps brachii and patellar tendon insertions. In all enthesis organs, sesamoid and/or periosteal fibrocartilage was present in close association with synovium.

Conclusion

The concept of an enthesis organ is of general significance in understanding attachment sites and may explain the diverse pathologic changes, including synovitis, bursitis, and extracapsular changes, seen adjacent to tendon/ligament entheses in SpA. These findings may provide insight into the reason the target tissues in SpA are apparently so diverse.
Association of increased expression of macrophage elastase (matrix metalloproteinase 12) with rheumatoid arthritis
Authors: Liu Mozhen , Sun Huijun , Wang Xiaofei , Koike Tomonari , Mishima Hajime , Ikeda Kotaro , Watanabe Teruo , Ochiai Naoyuki , Fan Jianglin
Published: October 2004

Objective

Increased enzymatic activity of matrix metalloproteinases (MMPs) may promote the progression of rheumatoid arthritis (RA). We undertook this study to investigate the expression and localization of human macrophage elastase (MMP‐12) in synovial tissue from RA patients and to compare MMP‐12 levels in the synovial tissue and synovial fluid of RA patients with the corresponding levels in patients with osteoarthritis (OA).

Methods

We obtained synovial tissues from 23 RA patients and 29 OA patients and analyzed MMP‐12 expression using immunohistochemistry, Western and Northern blotting analyses, and zymography. Furthermore, we quantified MMP‐12 levels in synovial fluid by Western blotting and zymography.

Results

Northern blotting analysis demonstrated that RA synovial tissue contained higher levels of MMP‐12 messenger RNA than did OA synovial tissue. Western blotting revealed that MMP‐12 proteins were consistently and markedly increased in RA synovial tissue compared with OA synovial tissue. A greater amount of immunoreactive proteins corresponding to catalytic forms of MMP‐12 was present in RA synovial tissue and synovial fluid, and the MMP‐12 proteins exhibited caseinolytic activity in vitro. Immunohistochemical staining showed that the major cells expressing MMP‐12 were synovial lining cells, many of which were inflammatory macrophages.

Conclusion

These results establish a possible mechanism by which macrophage‐derived MMP‐12 may play an important role in the destructive process in RA. Inhibition of MMP‐12 may be a potential modality for the treatment of RA.
Safety and efficacy of tumor necrosis factor α blockade in systemic lupus erythematosus: An open‐label study
Authors: Aringer Martin , Graninger Winfried B. , Steiner Günter , Smolen Josef S.
Published: October 2004

Objective

To investigate the safety of therapeutic tumor necrosis factor α (TNFα) blockade in patients with systemic lupus erythematosus (SLE), in whom this proinflammatory cytokine is significantly increased and may be involved in the disease pathogenesis.

Methods

In an open‐label study, 6 patients with moderately active SLE (4 with nephritis and 3 with arthritis refractory to other therapies) were given 4 300‐mg doses of infliximab, a chimeric anti‐TNFα antibody, in addition to immunosuppression with azathioprine or methotrexate.

Results

The only significant adverse events observed were urinary tract infection in 3 patients, 1 of which was accompanied by Escherichia coli bacteremia, and a prolonged febrile episode of putatively viral origin in 1 of them. These patients had similar infectious conditions in the past. In none of the patients was it necessary to terminate the treatment prematurely. Levels of antibodies to double‐stranded DNA and cardiolipin increased in 4 patients each, but this was not associated with a decrease in serum complement levels, with vascular events, or with flares. In contrast, disease activity declined during therapy. All 3 patients with joint involvement experienced remission of arthritis, which relapsed 8–11 weeks after the last infliximab infusion. In the 4 patients with lupus nephritis, proteinuria decreased significantly within 1 week after initiation of therapy and was diminished by ≥60% within 8 weeks, remaining at low levels until the end of the observation period (at least several months).

Conclusion

Infliximab did not lead to adverse events related to an increase in SLE activity, although autoantibodies to double‐stranded DNA and cardiolipin increased, as expected. This finding, coupled with the clinical improvement in the inflammatory manifestations of the disease, indicates that further study in larger controlled trials is warranted.
Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXII. Predictors of time to the occurrence of initial damage
Authors: Toloza Sergio M. A. , Roseman Jeffrey M. , Alarcón Graciela S. , McGwin Gerald , Uribe América G. , Fessler Barri J. , Bastian Holly M. , Vilá Luis M. , Reveille John D.
Published: October 2004

Objective

To examine the factors predisposing to initial damage in patients in the LUMINA (lupus in minorities: nature versus nurture) cohort, a multiethnic cohort of patients with systemic lupus erythematosus (SLE) in the US.

Methods

One hundred fifty‐eight LUMINA patients with no damage at baseline (time 0) according to the Systemic Lupus International Collaborating Clinics Damage Index (SDI) and with disease duration >6 months were followed up for a median of 24 months (range 5–112 months). Damage was assessed from time 0 to the last visit. Predictors of time to initial damage were examined by univariable and multivariable Cox proportional hazard regression models. Results were reported as hazard ratios (HRs); HR values ≥1 indicated a shorter time to initial damage, and values <1 indicated a longer time.

Results

Initial damage occurred in 54 patients (34%), of whom 21 were Hispanics from Texas (39%), 2 were Hispanics from Puerto Rico (4%), 21 were African Americans (39%), and 10 were Caucasians (19%). The most frequently observed initially involved SDI domains (and items) were as follows: renal (primarily proteinuria) in Hispanics from Texas and African Americans, integument (primarily scarring alopecia) in Hispanics from Puerto Rico, and ocular (primarily cataracts) in Caucasians. By multivariable analyses, independent predictors of a shorter time to initial damage were Hispanic ethnicity from Texas (HR 2.11, 95% confidence interval [95% CI] 1.15–3.88), greater disease activity according to the Systemic Lupus Activity Measure (HR 1.09, 95% CI 1.04–1.15), the occurrence of thrombotic events in visceral and/or peripheral veins or arteries (HR 7.66, 95% CI 2.13–27.51), and prednisone at a dosage of <10 mg/day (HR 2.53, 95% CI 1.15–5.55). Prednisone at a dosage of 10–30 mg/day was found to be protective against the occurrence of initial damage (HR 0.46, 95% CI 0.22–0.96).

Conclusion

Given that damage is a predictor of further damage, identifying the factors that may herald the occurrence of initial damage has very practical implications for the management of patients with SLE. These results need to be considered when evaluating therapies for SLE.
Amelioration of symptoms by enhancement of proprioception in patients with joint hypermobility syndrome
Authors: Ferrell William R. , Tennant Nicola , Sturrock Roger D. , Ashton Linda , Creed Gisela , Brydson Gillian , Rafferty Daniel
Published: October 2004

Objective

Joint hypermobility syndrome (JHS) is characterized by an association between joint hypermobility and musculoskeletal pains, the latter occurring in the absence of any objective indicator of rheumatic disease. The lack of a recognizable disease marker makes this condition difficult to identify and manage. We previously observed that patients with JHS have impaired proprioception compared with that of a matched control group. The purpose of this study was to investigate whether a home‐based exercise program could produce objective enhancement of proprioception as well as alleviate symptoms in JHS.

Methods

A threshold detection paradigm was used to assess knee joint proprioception, balance was assessed using a balance board, and quadriceps and hamstring strength were measured by an isokinetic dynamometer. A visual analog scale was used to assess musculoskeletal pain, and quality of life was evaluated by a Short Form 36 questionnaire. Assessments were performed before and after an 8‐week program of progressive closed kinetic chain exercises.

Results

Following the exercise program, proprioceptive acuity increased in 16 of 18 subjects and was very significantly improved overall (P < 0.001). There was a comparable improvement in performance on the balance board (P < 0.001), and quadriceps and hamstring strength also increased significantly. Symptomatic improvement also occurred, in terms of both pain (P = 0.003) and quality‐of‐life (P = 0.029 for physical functioning; P = 0.008 for mental health) scores.

Conclusion

Appropriate exercises lead not only to symptomatic improvement, but also to demonstrable enhancement of objective parameters such as proprioception.
High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury
Authors: Lohmander L. S. , Östenberg A. , Englund M. , Roos H.
Published: October 2004

Objective

To determine the prevalence of radiographic knee osteoarthritis (OA) as well as knee‐related symptoms and functional limitations in female soccer players 12 years after an anterior cruciate ligament (ACL) injury.

Methods

Female soccer players who sustained an ACL injury 12 years earlier were examined with standardized weight‐bearing knee radiography and 2 self‐administered patient questionnaires, the Knee Injury and Osteoarthritis Outcome Score questionnaire and the Short Form 36‐item health survey. Joint space narrowing and osteophytes were graded according to the radiographic atlas of the Osteoarthritis Research Society International. The cutoff value to define radiographic knee OA approximated a Kellgren/Lawrence grade of 2.

Results

Of the available cohort of 103 female soccer players, 84 (82%) answered the questionnaires and 67 (65%) consented to undergo knee radiography. The mean age at assessment was 31 years (range 26–40 years) and mean body mass index was 23 kg/m2 (range 18–40 kg/m2). Fifty‐five women (82%) had radiographic changes in their index knee, and 34 (51%) fulfilled the criterion for radiographic knee OA. Of the subjects answering the questionnaires, 63 (75%) reported having symptoms affecting their knee‐related quality of life, and 28 (42%) were considered to have symptomatic radiographic knee OA. Slightly more than 60% of the players had undergone reconstructive surgery of the ACL. Using multivariate analyses, surgical reconstruction was found to have no significant influence on knee symptoms.

Conclusion

A very high prevalence of radiographic knee OA, pain, and functional limitations was observed in young women who sustained an ACL tear during soccer play 12 years earlier. These findings constitute a strong rationale to direct increased efforts toward prevention and better treatment of knee injury.
Crystal and Magnetic Structure of the System Li0.5+0.5xFe2.5−1.5xTixO4 (x=0.16, 0.44, and 0.72)
Authors: Arillo María Angeles , Cuello Gabriel , López María Luisa , Pico Carlos , Veiga María Luisa
Published: October 2004

The influence of thermal treatment on the structure of lithium titanium ferrite spinels of general formula Li0.5+0.5xFe2.5−1.5xTixO4 (x=0.16, 0.44, and 0.72) has been studied by X‐ray and neutron diffraction and analysed by the Rietveld method. The results allow us to conclude the presence of an ordered phase (space group P4332) at room temperature for the sample with x=0.16; this phase does not appear for the remaining compositions. The magnetic properties evidence a ferrimagnetic ordering in the structures when a random cation distribution (space group Fd3 m) is obtained. An exhaustive study carried out by neutron diffraction measurements on these samples shows a different behaviour when the titanium content is increased, concluding that the lower substituted phase (x=0.16) exhibits a Néel's collinear ferrimagnetic structure, with the higher substituted structures being noncollinear (x=0.44 and 0.72).
Synthesis, Structure, and Bonding of the Nonclassical Zintl Phase K5As3Pb3.
Authors: Klem Michael T. , Corbett John D.
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Bi7‐xAs1+xMo3O21 (0 ≤ x ≤ 1) a New Pillar Structure Type: Synthesis, Crystal Structure and Conductivity.
Authors: Duc F. , Rozier P. , Millet P. , Galy J.
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
New Chiral 1,2‐Diamines and Their Use in Zinc‐Catalyzed Asymmetric Hydrosilylation of Acetophenone.
Authors: Bette Virginie , Mortreux Andre , Ferioli Federico , Martelli Gianluca , Savoia Diego , Carpentier Jean‐Francois
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Ionic Liquid‐Immobilized Catalytic System for Biomimetic Dihydroxylation of Olefins.
Authors: Closson Adam , Johansson Mikael , Baeckvall Jan‐E.
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
“Polysiloxane‐Pd” Nanocomposites as Recyclable Chemoselective Hydrogenation Catalysts.
Authors: Chauhan Bhanu P. S. , Rathore Jitendra S. , Bandoo Tariq
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Novel Bromination Method for Anilines and Anisoles Using NH4Br/H2O2 in CH3COOH.
Authors: Mohan K. V. V. Krishna , Narender N. , Srinivasu P. , Kulkarni S. J. , Raghavan K. V.
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
A Convenient Scalable One‐Pot Conversion of Esters and Weinreb Amides to Terminal Alkynes.
Authors: Dickson Hamilton D. , Smith Stephon C. , Hinkle Kevin W.
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Buffer‐Induced, Selective Mono‐C‐Alkylation of Phloroglucinol: Application to the Synthesis of an Advanced Intermediate of Catechin.
Authors: Gissot Arnaud , Wagner Alain , Mioskowski Charles
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Phosphine‐Free Cationic Rhodium(I) Complex‐Catalyzed Disulfide Exchange Reaction: Convenient Synthesis of Unsymmetrical Disulfides.
Authors: Tanaka Ken , Ajiki Kaori
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Fluorescent Hydrophobic Probes Based on Intramolecular Charge Transfer State for Sensitive Protein Detection in Solution.
Authors: Jun Hyunsook , Hong Soo Yeon , Yoon Seung Soo , Kang Chulhun , Suh Myungkoo
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Concomitant Ring Contraction Cyclization Strategy for the Synthesis of Novel 4‐Oxo‐4,5‐dihydro‐pyrroloquinolines.
Authors: Manh Gabriel Thia , Bakkali Hicham , Maingot Lucie , Pipelier Muriel , Joshi Uday , Pradere Jean Paul , Sabelle Stephane , Tuloup Remy , Dubreuil Didier
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Synthesis and Antileukemic Activity of New 3‐(5‐Methylisoxazol‐3‐yl) and 3‐(Pyrimidin‐2‐yl)‐2‐styrylquinazolin‐4(3H)‐ones.
Authors: Raffa Demetrio , Daidone Giuseppe , Maggio Benedetta , Cascioferro Stella , Plescia Fabiana , Schillaci Domenico
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
IMDA Cycloadditions of 3‐Alkynyl Tethered 2‐Pyrones for the Synthesis of Medium‐Sized Macrocycles.
Authors: Shin Jeong‐Taek , Shin Seunghoon , Cho Cheon‐Gyu
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Synthesis and Antibacterial Evaluation of 1β‐Methyl‐2‐(5‐substituted heterocyclic carbamoyl‐pyrrolidin‐3‐ylthio)carbapenem Derivatives.
Authors: Lee Joo‐Shin , Cho Jung‐Hyuck Cho Jung‐Hyuck , Cho Heeyeong , Oh Chang‐Hyun
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Enhanced Mesostructural Order and Changes to Optical and Electrochemical Properties Induced by the Addition of Cerium(III) to Mesoporous Titania Thin Films.
Authors: Frindell Karen L. , Tang Jing , Harreld John H. , Stucky Galen D.
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Synthesis of Metal Chalcogenide Nanoparticles
Authors: Zhu Jun‐Jie , Wang Hui
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Fluorocarbon Oxy and Peroxy Radicals
Authors: von Ahsen Stefan , Willner Helge , Argueello Gustavo A.
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Fluoride Ion Transfer and Stabilization of Reactive Ions
Authors: Borrmann Tobias , Lork Enno , Mews Ruediger , Stohrer Wolf‐Dieter
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Basic Studies for the Development of Anticancer, Antidementia, and Taste Modifier Drugs
Authors: Nakaya Kazuyasu
Published: October 2004

For Abstract see ChemInform Abstract in Full Text.
Dynamics of endocytic traffic of Entamoeba histolytica revealed by confocal microscopy and flow cytometry
Authors: Meza Isaura , Clarke Margaret
Published: October 2004

Entamoeba histolytica, the protozoan parasite of humans, manifests constitutive endocytosis to obtain nutrients and, when induced to express invasive behavior, as a means of ingesting and processing host cells and tissue debris. E. histolytica trophozoites were grown in liquid axenic medium that contained fluorescently labeled fluid‐phase markers, so that the kinetics of uptake, the transit of loaded endosomes through the cytoplasm, and the time of release of the markers could be monitored by flow cytometry. Confocal microscopy of live trophozoites revealed uptake of fluid by avid macropinocytosis and the occurrence of fusion between young and older endosomes, as well as between pinosomes and phagosomes containing bacteria. Endosomes were rapidly acidified, then gradually neutralized; finally, indigestible material was released. Transit of endosomes containing fluid‐phase markers required about 2 h. Uptake and release of fluid‐phase markers were impaired by drugs that inhibited actin dynamics and actin‐myosin interaction; uptake was also impaired by inhibition of PI 3‐kinase. A striking feature of the trophozoites was the great heterogeneity of their endocytic behavior. Cell Motil. Cytoskeleton 59:215–226, 2004. © 2004 Wiley‐Liss, Inc.
Nuclear factor‐κB and IκB kinase are constitutively active in human pancreatic cells, and their down‐regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis
Authors: Li Lan , Aggarwal Bharat B. , Shishodia Shishir , Abbruzzese James , Kurzrock Razelle
Published: October 2004

BACKGROUND

Pancreatic carcinoma is a lethal malignancy, with the best available therapeutic option—gemcitabine—yielding response rates of < 10%. Because nuclear factor‐κB (NF‐κB) has been determined to play a role in cell survival/proliferation in human pancreatic carcinoma, this transcription factor is a potential therapeutic target.

METHODS

The authors investigated the ability of curcumin (diferuloylmethane), an agent that is pharmacologically safe in humans, to modulate NF‐κB activity.

RESULTS

NF‐κB and IκB kinase (IKK) were constitutively active in all human pancreatic carcinoma cell lines examined, and curcumin consistently suppressed NF‐κB binding (as assessed using an electrophoretic mobility gel‐shift assay) and IKK activity. Curcumin decreased the expression of NF‐κB–regulated gene products, including cyclooxygenase‐2 (as assessed using immunoblot analysis), prostaglandin E2, and interleukin‐8 (as assessed using an enzyme‐linked immunoassay), all of which have been implicated in the growth and invasiveness of pancreatic carcinoma. These changes were associated with concentration‐ and time‐dependent antiproliferative activity (as assessed using a 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide [MTT] assay) and proapoptotic effects (as assessed via annexin V/propidium iodide staining [fluorescence‐activated cell sorting, as well as with the induction of polyadenosine‐5′‐diphosphate‐ribose polymerase cleavage).

CONCLUSIONS

Curcumin down‐regulated NF‐κB and growth control molecules induced by NF‐κB in human pancreatic cells. These effects were accompanied by marked growth inhibition and apoptosis. Through these findings, the authors provided a biologic rationale for the treatment of patients with pancreatic carcinoma using this nontoxic phytochemical. Cancer 2004. © 2004 American Cancer Society.
Pancreatic carcinoma cells express neuropilins and vascular endothelial growth factor, but not vascular endothelial growth factor receptors
Authors: Li Min , Yang Hui , Chai Hong , Fisher William E. , Wang Xiaoping , Brunicardi F. Charles , Yao Qizhi , Chen Changyi
Published: October 2004

BACKGROUND

Neuropilins (NRPs) are characterized as coreceptors of vascular endothelial growth factor (VEGF). In the current study, the authors assessed the expression of NRPs, VEGF, and vascular endothelial growth factor receptors (VEGFRs), as well as VEGF‐induced cell proliferation, in pancreatic carcinoma cell lines and tissue specimens.

METHODS

Human pancreatic carcinoma cell lines (Panc‐1 and MIA PaCa‐2), normal human pancreatic ductal epithelial cells (HPDE), and human umbilical vein endothelial cells (HUVECs) were cultured. Human pancreatic adenocarcinoma tissue specimens were also studied. Expression levels of NRPs, VEGFRs, and VEGF were determined by real‐time polymerase chain reaction analysis and immunostaining. Cell proliferation was examined using a [3H]thymidine incorporation assay.

RESULTS

Both NRP‐1 and NRP‐2 were expressed in Panc‐1 cells, HPDE cells, and HUVECs but were expressed minimally in MIA PaCa‐2 cells. Panc‐1 expressed 30 times more NRP‐1 mRNA than NRP‐2 mRNA. NRP‐1 levels in Panc‐1 cells were 5.3 times higher than in HPDE cells but were similar to NRP‐1 levels in HUVECs. NRP‐2 levels in Panc‐1 cells were similar to NRP‐2 levels in HPDE cells but lower than NRP‐2 levels in HUVECs. Expression of all three VEGFRs was observed only in HUVECs. However, VEGF mRNA was detected in all cell types except for HUVECs. NRP‐1 immunoreactivity levels were much higher than NRP‐2 immunoreactivity levels in Panc‐1 and human pancreatic adenocarcinoma tissue specimens, whereas VEGFRs were not detected in either of these two settings. In response to VEGF165, [3H]thymidine incorporation in Panc‐1 cells increased significantly (by 61%; P < 0.01). A monoclonal antibody against human NRP‐1 significantly blocked VEGF‐induced cell proliferation in Panc‐1 cells.

CONCLUSIONS

The pancreatic carcinoma cell line Panc‐1 and adenocarcinoma tissue specimens expressed high levels of NRP‐1 and VEGF, but not VEGFRs, and exogenous VEGF significantly increased NRP‐1‐mediated, but not VEGFR‐mediated, Panc‐1 cell proliferation. These data suggested that NRP‐1 may be involved in the pathogenesis of pancreatic carcinoma. Cancer 2004. © 2004 American Cancer Society.
Preclinical evaluation of antisense bcl‐2 as a chemosensitizer for patients with gastric carcinoma
Authors: Kim Ryungsa , Emi Manabu , Tanabe Kazuaki , Toge Tetsuya
Published: October 2004

BACKGROUND

Because bcl‐2 is a critical factor for anticancer drug‐induced apoptosis, the authors conducted a preclinical evaluation of antisense (AS) bcl‐2 as an enhancer of the chemotherapeutic effect in the treatment of patietns with gastric carcinoma.

METHODS

AS bcl‐2 was used with 18‐mer phosphorothiated oligonucleotides in the MKN‐45 gastric carcinoma cell line. Drug sensitivity in vitro was evaluated using the methyl‐thiazoldiphenyl tetrazolium assay, and antitumor effects in vivo were evaluated using the nude mouse xenograft. Apoptosis was determined with the terminal deoxyuridine triphosphate nick‐end labeling assay. AS bcl‐2 in vitro was treated with lipofectin, whereas it was administered intraperitoneally for 6 consecutive days twice every 2 weeks in vivo. Anticancer drugs were administered intraperitoneally four times per week.

RESULTS

bcl‐2 was down‐regulated to 60% of its initial value after treatment with 1.0 μM AS bcl‐2 compared with the controls of random and mismatched oligonucleotides. Drug sensitivity to doxorubicin, cisplatin, and paclitaxel (TXL) was increased 3–4‐fold when used in combination with AS bcl‐2, which was determined with 50% inhibitory concentration values, compared with the control group. Increased drug sensitivity was associated with apoptosis, which increased in Bax and poly‐adenosine diphosphate (ADP‐ribose) polymerase and decreased in phosphorylated Akt (pAkt). The antitumor effect of cisplatin and TXL in vivo was enhanced significantly in combination with AS bcl‐2. Down‐regulation of bcl‐2 was observed on Day 4 after the treatment with AS bcl‐2.

CONCLUSIONS

Combination treatment with AS bcl‐2 and anticancer drugs, including cisplatin and TXL, may be a new strategy for enhancing chemotherapeutic effects in the treatment of gastric carcinoma. Cancer 2004. © 2004 American Cancer Society.
Preoperative somatic symptoms are associated with disease progression in patients with bladder carcinoma after cystectomy
Authors: Palapattu Ganesh S. , Bastian Patrick J. , Slavney Phillip R. , Haisfield‐Wolfe Mary Ellen , Walker Joanne M. , BrintzenhofeSzoc Karlynn , Trock Bruce , Zabora James , Schoenberg Mark P.
Published: October 2004

BACKGROUND

A link between patient psychologic factors and bladder carcinoma outcome has not been demonstrated. The purpose of the current study was to assess the association of psychologic factors measured preoperatively with bladder carcinoma progression after cystectomy.

METHODS

The Brief Symptom Inventory (BSI)‐18 was administered prospectively to 65 patients with clinically localized bladder carcinoma before surgery. The BSI‐18 measures distress in three specific domains—depression, anxiety, and somatization (i.e., distress due to somatic symptoms)—as well as general distress. Preoperative BSI‐18 scores, tumor pathologic stage, and certain clinical variables were compared with disease status. Disease progression was defined as the development of either local disease recurrence or distant metastasis. Univariate and multivariate Cox proportional hazards models were constructed for statistical analysis.

RESULTS

Of the 65 patients, 49 (79.4%) had no evidence of disease, 4 (6.2%) had local disease recurrence, and 12 (18.5%) had metastatic disease at last follow‐up. The mean follow‐up time was 1.3 years and did not differ significantly between survival outcomes (P = 0.577). Both tumor pathologic stage and preoperative somatic distress scores were associated with time to disease progression by univariate analysis (P = 0.038 and P = 0.055, respectively). After adjusting for tumor pathologic stage, a somatic distress score of ≥ 2.00 was a significant predictor of disease progression (P = 0.044, hazard ratio = 3.31, 95% confidence interval = 1.03–10.60). Patient age, gender, reconstruction type, and BSI‐18 scores for depression, anxiety, and general distress were not significantly associated with disease outcome.

CONCLUSIONS

The authors found no correlation between psychologic symptoms measured preoperatively (i.e., depression, anxiety, and general distress) and bladder carcinoma progression. However, they reported an association between somatic symptoms and cancer outcome. If confirmed by other studies, these results may have important implications for the diagnosis, staging, and potential treatment of patients with bladder carcinoma. Cancer 2004. © 2004 American Cancer Society.