bluuebunny/crossref_metadata_2025_split huggingface dataset:
Finite element analysis of the mouse tibia: Estimating endocortical strain during three‐point bending in SAMP6 osteoporotic mice
Authors: Silva Matthew J. , Brodt Michael D. , Hucker William J. 
Published: March 2005

AbstractTo support future studies of tibial bending in a murine model of senile osteoporosis (SAMP6), we sought to determine the relationship between applied external bending force and peak endocortical strain in the tibiae of SAMP6 and control SAMR1 mice. The lower hindlimbs of mice were loaded by three‐point bending in the lateral‐medial plane with a support length of 10 mm. Force‐periosteal strain relations were first determined using standard strain gauge methods. Finite‐element analysis (FEA) models of the tibia‐fibula were generated based on microcomputed tomography images. After choosing appropriate boundary conditions, FEA predictions of periosteal strains were within 15% of measured values. FEA revealed a narrow (3–4 mm) region of the central tibia with well‐developed bending strains (tension medially, compression laterally); outside this region, we observed high shear strains. Both the strain gauge data and the finite‐element simulations indicated that the tibia of the SAMP6 mouse was 20–25% stiffer than the SAMR1 tibia, consistent with a larger moment of inertia and higher cortical bone modulus. Thus, higher levels of force are required to produce the same target values of strain in the SAMP6 tibia. The ratio of periosteal to endocortical strain in the region of interest was similar for the two mouse strains (1.5–1.6). Based on these ratios, we scaled the strain gauge data to estimate the force‐endocortical strain relations for the two mouse strains. In conclusion, FEA, with supporting strain gauge measurements, has provided unique insight regarding the strain environment throughout the tibia during three‐point bending in mice. © 2005 Wiley‐Liss, Inc.
Australopithecus anamensis: A finite‐element approach to studying the functional adaptations of extinct hominins
Authors: Macho Gabriele A. , Shimizu Daisuke , Jiang Yong , Spears Iain R. 
Published: March 2005

AbstractAustralopithecus anamensis is the stem species of all later hominins and exhibits the suite of characters traditionally associated with hominins, i.e., bipedal locomotion when on the ground, canine reduction, and thick‐enameled teeth. The functional consequences of its thick enamel are, however, unclear. Without appropriate structural reinforcement, these thick‐enameled teeth may be prone to failure. This article investigates the mechanical behavior of A. anamensis enamel and represents the first in a series that will attempt to determine the functional adaptations of hominin teeth. First, the microstructural arrangement of enamel prisms in A. anamensis teeth was reconstructed using recently developed software and was compared with that of extant hominoids. Second, a finite‐element model of a block of enamel containing one cycle of prism deviation was reconstructed for Homo, Pan, Gorilla, and A. anamensis and the behavior of these tissues under compressive stress was determined. Despite similarities in enamel microstructure between A. anamensis and the African great apes, the structural arrangement of prismatic enamel in A. anamensis appears to be more effective in load dissipation under these compressive loads. The findings may imply that this hominin species was well adapted to puncture crushing and are in some respects contrary to expectations based on macromorphology of teeth. Taking together, information obtained from both finite‐element analyses and dental macroanatomy leads us to suggest that A. anamensis was probably adapted for habitually consuming a hard‐tough diet. However, additional tests are needed to understand the functional adaptations of A. anamensis teeth fully. © 2005 Wiley‐Liss, Inc.
Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox20‐binding enhancer
Authors: Leclerc Nathalie , Noh Tommy , Khokhar Arvinder , Smith Elisheva , Frenkel Baruch 
Published: March 2005

AbstractObjectiveGlucocorticoids are widely used for the management of rheumatoid arthritis. Osteoporosis is a major side effect of glucocorticoid therapy and is attributable to inhibition of bone formation. We developed an osteoblast culture system in which glucocorticoids strongly inhibit development of the osteoblast phenotype, including expression of the bone‐specific osteocalcin (OC) gene. Using this gene as a model, the goal of this study was to discover glucocorticoid‐sensitive transcriptional mechanisms in osteoblasts.MethodsDexamethasone (DEX; 1 μM) was administered to murine MC3T3‐E1 osteoblastic cultures under conditions that inhibit mineralized extracellular matrix formation and OC messenger RNA levels by >10‐fold. Because standard (short‐term) transient transfection assays with OC promoter‐reporter constructs did not recapitulate the strong DEX‐mediated repression, mapping of OC negative glucocorticoid response elements (GREs) was performed initially by stable transfection and then with long‐term transient transfection assays. Transcription factor binding to the OC negative GRE was studied by electrophoretic mobility shift assays.ResultsSeveral‐fold repression of OC–luciferase constructs was recapitulated in stable and long‐term transient transfection assays, in which the transfected cells were allowed to progress to a sufficiently advanced developmental stage. Analysis of a 5′ promoter deletion series mapped an OC negative GRE to a 15‐bp G/C‐rich motif (−161/−147) located just upstream of the binding site for the osteoblast master transcription factor Runx2. Oligonucleotides encompassing this element and MC3T3‐E1 cell extracts formed a protein–DNA complex that contained an Egr/Krox family member(s). Complex formation was competed by either an oligonucleotide containing 2 consensus Egr motifs or by anti‐Egr2/Krox20 antibodies. Three copies of this Krox‐binding element conferred 20‐fold transcriptional activation on the 147‐bp basal OC promoter in osteoblasts, and the enhancer activity was inhibited by DEX. Enhancer activity was not observed in 10T1/2 fibroblasts unless these cells were cotransfected with Runx2.ConclusionAn Egr2/Krox20‐binding site located immediately upstream of the Runx2 site of the mouse OC promoter was identified as an enhancer in osteoblasts, whose activity is repressed by glucocorticoids. Sequence similarity suggests that such a mechanism is likely operative in both murine and human cells. Because glucocorticoids inhibit Egr2/Krox20 expression in osteoblasts, and because trabecular bone formation is arrested in Egr2/Krox20‐knockout mice, the inhibition of Egr2/Krox20 activity likely contributes to glucocorticoid‐induced osteoporosis.
Joint inflammation and chondrocyte death become independent of Fcγ receptor type III by local overexpression of interferon‐γ during immune complex–mediated arthritis
Authors: Nabbe K. C. A. M. , Boross P. , Holthuysen A. E. M. , Sloëtjes A. W. , Kolls J. K. , Verbeek S. , Van Lent P. L. E. M. , Van Den Berg W. B. 
Published: March 2005

AbstractObjectiveIt has previously been shown that the onset and the degree of joint inflammation during immune complex (IC)–mediated arthritis depend on Fcγ receptor type III (FcγRIII). Local adenoviral overexpression of interferon‐γ (IFNγ) in the knee joint prior to onset of IC‐mediated arthritis aggravated severe cartilage destruction. In FcγRI−/− mice, however, chondrocyte death was not enhanced by IFNγ, whereas matrix metalloproteinase (MMP)–mediated aggrecan breakdown was markedly elevated, suggesting a role for the activating FcγRIII in the latter process. We undertook this study to determine the role of FcγRIII in joint inflammation and severe cartilage destruction in IFNγ‐stimulated IC‐mediated arthritis, using FcγRIII−/− mice.MethodsFcγRIII−/− and wild‐type (WT) mice were injected in the knee joint with recombinant adenovirus encoding murine IFNγ (AdIFNγ) or with adenovirus encoding enhanced green fluorescent protein 1 day prior to induction of IC‐mediated arthritis. Histologic sections were obtained 3 days after arthritis onset to study inflammation and cartilage damage. MMP‐mediated expression of the VDIPEN neoepitope was detected by immunolocalization. Chemokine and FcγR expression levels were determined in synovial washouts and synovium, respectively.ResultsInjection of AdIFNγ in naive knee joints markedly increased levels of messenger RNA for FcγRI, FcγRII, and FcγRIII. Upon IFNγ overexpression prior to induction of IC‐mediated arthritis, joint inflammation was similar in FcγRIII−/− and WT mice. The percentage of macrophages in the knee joint was increased, which correlated with high concentrations of the macrophage attractant macrophage inflammatory protein 1α. Furthermore, IFNγ induced 2‐fold and 3‐fold increases in chondrocyte death in WT controls and FcγRIII−/− mice, respectively. Notably, VDIPEN expression also remained high in FcγRIII−/− mice.ConclusionIFNγ bypasses the dependence on FcγRIII in the development of IC‐mediated arthritis. Furthermore, both FcγRI and FcγRIII can mediate MMP‐dependent cartilage matrix destruction.
Expression of interleukin‐21 receptor in epidermis from patients with systemic sclerosis
Authors: Distler Jörg H. W. , Jüngel Astrid , Kowal‐Bielecka Otylia , Michel Beat A. , Gay Renate E. , Sprott Haiko , Matucci‐Cerinic Marco , Chilla Meike , Reich Kristian , Kalden Joachim R. , Müller‐Ladner Ulf , Lorenz Hanns M. , Gay Steffen , Distler Oliver 
Published: March 2005

AbstractObjectiveTo examine the expression and regulation of interleukin‐21 (IL‐21) and IL‐21 receptor (IL‐21R) in patients with systemic sclerosis (SSc; scleroderma).MethodsSkin biopsy specimens were obtained from 23 patients with SSc and 15 healthy controls. IL‐21/IL‐21R messenger RNA (mRNA) was quantified using real‐time polymerase chain reaction (PCR). The expression pattern of IL‐21/IL‐21R was analyzed by in situ hybridization and Western blotting. Stimulation experiments were performed with cultured dermal fibroblasts from patients with SSc and healthy controls as well as with keratinocytes, using IL‐1β, platelet‐derived growth factor BB, monocyte chemoattractant protein 1, transforming growth factor β, and IL‐21. The SCID‐hu skin mouse model was used for in vivo experiments.ResultsIL‐21R mRNA was detected in all biopsy specimens from patients with SSc and controls, with a 4.7‐fold increase observed in SSc samples. In situ hybridization and immunohistochemical analysis showed an up‐regulation of IL‐21R in samples of epidermis from SSc patients, whereas no signal was detected in skin specimens from healthy controls. These results were confirmed in vitro, in that cultured keratinocytes expressed significant levels of IL‐21R, whereas no signal was observed in fibroblasts. Interestingly, mRNA for IL‐21 could not be detected by real‐time PCR and in situ hybridization. Various concentrations of key cytokines in the pathogenesis of SSc did not stimulate the expression of IL‐21R mRNA in cultured keratinocytes and dermal fibroblasts. In the SCID mouse transplantation model, the overexpression of IL‐21R mRNA in SSc keratinocytes remained unchanged after transplantation.ConclusionThe up‐regulation of IL‐21R in keratinocytes indicates that, similar to fibroblasts and endothelial cells, the expression pattern is altered in SSc. Moreover, the expression of IL‐21R appears to be independent of key cytokines that are operant in SSc.
Induction of cartilage damage by overexpression of T cell interleukin‐17A in experimental arthritis in mice deficient in interleukin‐1
Authors: Koenders Marije I. , Lubberts Erik , Oppers‐Walgreen Birgitte , van den Bersselaar Liduine , Helsen Monique M. , Kolls Jay K. , Joosten Leo A. B. , van den Berg Wim B. 
Published: March 2005

AbstractObjectiveTo examine the capacity of T cell interleukin‐17A (IL‐17A; referred to hereinafter as IL‐17) to induce cartilage damage during experimental arthritis in the absence of IL‐1.MethodsLocal IL‐17 gene transfer was performed in the knee joint of IL‐1–deficient mice and wild‐type controls during streptococcal cell wall (SCW)–induced arthritis. Knee joints were isolated at various time points for histologic analysis of cartilage proteoglycan (PG) depletion. Expression of messenger RNA for inducible nitric oxide synthase, matrix metalloproteinases (MMPs) 3, 9, and 13, and ADAMTS‐4 was determined by quantitative polymerase chain reaction analysis. VDIPEN staining was analyzed to study MMP‐mediated cartilage damage. In addition, systemic anti–IL‐1α/β antibody treatment was performed in mice immunized with type II collagen and injected locally with an adenoviral vector expressing IL‐17 or with control adenovirus. Knee joints were isolated and analyzed for cartilage PG depletion, chondrocyte death, and cartilage surface erosion.ResultsDuring SCW‐induced arthritis, local T cell IL‐17 gene transfer turned this acute, macrophage‐driven joint inflammation into a severe, chronic arthritis accompanied by aggravated cartilage damage. Of high interest, the IL‐1 dependency of cartilage PG depletion was fully abrogated when IL‐17 was locally overexpressed in the joint. Moreover, local IL‐17 gene transfer increased MMP expression without the need for IL‐1, although IL‐1 remained essential for part of the cartilage VDIPEN expression. Furthermore, when IL‐17 was overexpressed in the knee joints of mice with collagen‐induced arthritis, anti–IL‐1 treatment did not reduce the degree of chondrocyte death or cartilage surface erosion.ConclusionThese data show the capacity of IL‐17 to replace the catabolic function of IL‐1 in cartilage damage during experimental arthritis.
Acetabular dysplasia predicts incident osteoarthritis of the hip: The Rotterdam study
Authors: Reijman M. , Hazes J. M. W. , Pols H. A. P. , Koes B. W. , Bierma‐Zeinstra S. M. A. 
Published: March 2005

AbstractObjectiveTo investigate the association between acetabular dysplasia and the incidence of radiographic osteoarthritis (OA) of the hip in a population‐based sample of elderly subjects.MethodsRadiographs of the hip at baseline and at followup (mean followup time 6.6 years) were evaluated in 835 men and women (age ≥55 years) from the Rotterdam Study. Subjects with a baseline Kellgren/Lawrence grade of 0 or 1 in both hips were included in the study. Incident radiographic OA of the hip was defined as a decrease of joint space width of the hip (≥1.0 mm) at followup. Acetabular dysplasia was assessed using the center‐edge angle and the acetabular depth. The association between acetabular dysplasia and incident radiographic hip OA was assessed by calculating odds ratios using multivariate regression analysis.ResultsIn this study population with a mean ± SD age of 65.6 ± 6.5 years, 9.3% developed incident radiographic hip OA. Subjects with acetabular dysplasia (center‐edge angle <25°) had a 4.3‐fold increased risk for incident radiographic OA of the hip (95% confidence interval 2.2–8.7) compared with subjects without acetabular dysplasia. These associations were independent of known determinants of hip OA such as age, sex, and body mass index (BMI), but tended to be enhanced by female sex, heavy mechanical load, and low BMI.ConclusionIn a study population age ≥55 years, acetabular dysplasia is still a strong independent determinant of incident radiographic hip OA.
A serum proteomic approach to gauging the state of remission in Wegener's granulomatosis
Authors: Stone John H. , Rajapakse Vinodh N. , Hoffman Gary S. , Specks Ulrich , Merkel Peter A. , Spiera Robert F. , Davis John C. , St.Clair E. William , McCune Joseph , Ross Sally , Hitt Ben A. , Veenstra Timothy D. , Conrads Thomas P. , Liotta Lance A. , Petricoin Emanuel F. ,   Wegener's Granulomatosis Etanercept Trial (WGET) Research Group
Published: March 2005

AbstractObjectiveTo identify serum ion patterns that distinguish remission from active disease in patients with Wegener's granulomatosis (WG).MethodsUsing sera collected in the WG Etanercept Trial, we selected samples from patients who either were undergoing a period of extended disease remission or had recent flares of active WG. Unfractionated samples were randomized into sets for training and testing, such that remission sera and active disease sera could be analyzed without batch bias. Molecular species within the sera were ionized by high‐resolution, matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry. We then used a bioinformatics pattern‐recognition tool to identify optimal combinations of ions. During the training stage, the clinical data (remission versus active disease) were provided in association with the spectral data from each sample. In the testing stage, we performed blinded testing on a previously unexamined set of samples.ResultsThe most robust model, trained on a total of 82 samples (42 remission, 40 active disease), included 7 key ions with mass:charge ratios of 803.239, 2,171.672, 2,790.574, 3,085.237, 5,051.726, 5,833.989, and 6,630.465. The combined relative amplitudes of these 7 ions identified 5 distinct clusters of either remission or active disease samples during the training stage. In the testing stage, this model segregated 72 samples into the same 5 clusters, including 1 large remission cluster (n = 28) and another large active disease cluster (n = 32). Three smaller clusters of active disease or remission samples were also identified, with remission clusters populated by 2 samples in one cluster and 8 in another, and an active disease cluster populated by 2 samples. The model categorized 35 of 37 remission samples correctly (sensitivity 95%, 95% confidence interval [95% CI] 82.1–99.4) and 32 of 35 active disease samples correctly (specificity 91%, 95% CI 78.1–98.1).ConclusionThis serum proteomic profiling approach appears to be useful in distinguishing between states of stable clinical remission and active disease. Further validation and refinement of this strategy may help clinicians apply immunosuppressive therapies more judiciously among their patients, thereby avoiding morbidity and mortality from excessive treatment. Identification of the most robust and clinically useful combinations of ions will permit the rational selection of molecules for sequencing and analysis.
Electroencephalography in the assessment of neuropsychiatric manifestations in antiphospholipid syndrome and systemic lupus erythematosus
Authors: Lampropoulos Christos E. , Koutroumanidis Michael , Reynolds Piero P. M. , Manidakis Ioannis , Hughes Graham R. V. , D'Cruz David P. 
Published: March 2005

AbstractObjectiveTo describe the prevalence and clinical associations of abnormalities on electroencephalography (EEG) in patients with antiphospholipid syndrome (APS) and/or systemic lupus erythematosus (SLE) who have neuropsychiatric symptoms.MethodsThe study group comprised 57 patients (age ≤50 years) with manifestations of neuropsychiatric illness. Patients with stroke, epilepsy, or other encephalopathies were excluded. Fourteen patients had APS, 24 patients were positive for antiphospholipid antibodies (aPL), and 19 patients had SLE without aPL. All patients underwent EEG and brain magnetic resonance imaging (MRI) while they were awake.ResultsAbnormal EEG findings (showing mainly bitemporal slow activity) were recorded in 37 of 57 patients (65%). Abnormal EEG findings were observed in all patients with APS and in 17 of 24 aPL‐positive patients (71%), compared with 6 of 19 patients with SLE (32%) (P < 0.001 and P < 0.05, respectively). There was an association between abnormal EEG findings and the frequency of aPL positivity (at least 2 positive results) (P = 0.002). Three EEG recordings showed potentially epileptiform activity. Results of brain MRI were abnormal in 18 (31.6%) of 57 patients: 8 in the APS group (57.1%), 7 in the aPL‐positive group (29.2%), and 3 in the SLE group (15.8%). None of the patients with normal EEG findings had abnormal MRI results. Thus, brain MRI findings were normal in the majority of patients. Patients with abnormal EEG results were more likely to report memory problems (P < 0.001).ConclusionOur findings suggest that EEG abnormalities are common and correlate with the presence of aPL even in the absence of brain abnormalities on MRI. EEG should be considered in aPL‐positive patients with neuropsychiatric symptoms, because use of antiaggregants or anticoagulation may need to be considered.
PEGylated interferon alfa‐2b and ribavirin treatment in patients with hepatitis C virus–related systemic vasculitis
Authors: Cacoub Patrice , Saadoun David , Limal Nicolas , Sene Damien , Lidove Olivier , Piette Jean‐Charles 
Published: March 2005

AbstractObjectiveType II mixed cryoglobulinemia (MC) is a systemic vasculitis usually associated with hepatitis C virus (HCV), which may involve the skin, kidneys, and nervous system. Molecular evidence of antigen‐driven B cell proliferation is definitively provided in HCV‐associated type II MC, and HCV appears to be the key trigger. The present trial was established to investigate the efficacy of therapy with PEGylated interferon alfa‐2b (PEG–IFN alfa‐2b) plus ribavirin in patients with HCV‐related MC vasculitis.MethodsNine consecutive patients with HCV‐related MC received PEG–IFN alfa‐2b (1.5 μg/kg/week) subcutaneously plus oral ribavirin (800–1,200 mg/day) for at least 6 months. The response to treatment was analyzed by comparing clinical, immunologic, and virologic parameters at the initial evaluation with those observed during followup.ResultsThe mean ± SD duration of therapy with PEG–IFN alfa‐2b plus ribavirin was 13.5 ± 2.8 months. After a mean period of 18.6 months following discontinuation of treatment, all 9 patients are alive. Seven patients (78%) had a sustained virologic response and were complete clinical responders. Serum cryoglobulin disappeared in 5 of 9 patients (56%), and complement levels normalized in 80% of the patients. One patient had a partial virologic response with a complete clinical response. In another patient, a clinical relapse of MC vasculitis occurred in association with the reappearance of HCV RNA. Treatment was well tolerated, and no patient had side effects for which discontinuation of therapy was required.ConclusionTreatment with PEG–IFN alfa‐2b plus ribavirin can achieve a complete clinical response in most patients with HCV‐related MC vasculitis. Complete clinical response correlates with the eradication of HCV and requires a shorter treatment period than that previously reported for IFNα plus ribavirin.
Amelioration of acute inflammation by systemic administration of a cell‐permeable peptide inhibitor of NF‐κB activation
Authors: di Meglio Paola , Ianaro Angela , Ghosh Sankar 
Published: March 2005

AbstractObjectiveWe used an experimental model of inflammation in mice, carrageenan‐induced paw edema, to study the antiinflammatory effects of the NEMO‐binding domain (NBD) peptide, which blocks activation of the inducible transcription factor NF‐κB.MethodsPaw edema was induced by subplantar injection of 1% λ‐carrageenan into the mouse left hind paw. Test agents were given intraperitoneally immediately after carrageenan injection. The increase in footpad thickness was considered to be edema. In some experiments, the mice were killed and the paws were removed for histologic and molecular biology analysis. NF‐κB DNA binding activity was evaluated in nuclear extracts by electrophoretic mobility shift assays. The expression levels of NF‐κB–regulated cyclooxygenase 2 (COX‐2) protein and tumor necrosis factor α (TNFα) messenger RNA (mRNA) were evaluated by immunoblot analysis and polymerase chain reaction amplification of reverse‐transcribed mRNA, respectively.ResultsWe found that systemically administered NBD peptide significantly inhibited edema formation and cellular infiltration in inflamed mouse paws. This antiinflammatory activity was most likely due to inhibition of expression of proinflammatory mediators, such as TNFα and COX‐2, in inflamed tissues.ConclusionThese studies further establish NF‐κB as a target for antiinflammatory therapy and provide support for the use of the NBD peptide as a possible therapeutic agent for inflammatory diseases.