bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthesis and pp60c‐Src Tyrosine Kinase Inhibitory Activities of Novel Indole‐3‐Imine and Amine Derivatives Substituted at N1 and C5
Authors: Kiliç Zuhal , Isgör Yasemin G. , Ölgen Süreyya 
Published: May 2009

AbstractA series of novel 1,3,5‐trisubstituted indole derivatives, namely, N‐benzyl 5‐phenyl indole‐3‐imine, N‐benzyl‐5‐(p‐fluorophenyl)indole‐3‐imine and their corresponding amine congeners, were designed and synthesized as pp60c‐Src tyrosine kinase inhibitors, and their inhibitory activities toward pp60c‐Src tyrosine kinase were evaluated by in‐vitro kinase assay. Pre‐screening at two doses of compounds against kinase target revealed that, except for the N‐benzyl‐5‐phenyl indole imine derivatives 7a–7d, all indole derivatives show the target inhibition at varying levels. Consequently, the compounds, 8c, 8f, 8g, and 8h, were selected for prescreening tests. The dose‐response curves for up to six concentrations (250 to 7.8 μM) of the active compounds were obtained by tyrosine kinase assay and the four‐parameter logistic analysis of these data resulted in the IC50s of 4.69, 74.79, 75.06, and 84.23 μM for compounds 8c, 8f, 8g, and 8h, respectively. Therefore, compound 8c, 1‐(1‐benzyl‐5‐phenyl‐1H‐indole‐3‐yl)‐N‐(4‐fluorobenzyl)methanamine·HCl, was the promising inhibitor for pp60c‐Src, followed by compounds 8g and 8h. Under the same conditions, compound 8f did not provide any reasonable inhibition pattern to be considered as active compound. Therefore, among all four active compounds, compound 8f was not found suitable for further analysis.
Development of a radiographic scoring tool for ankylosing spondylitis only based on bone formation: Addition of the thoracic spine improves sensitivity to change
Authors: Baraliakos X. , Listing J. , Rudwaleit M. , Sieper J. , Braun J. 
Published: May 2009

AbstractObjectiveThe modified Stokes Ankylosing Spondylitis Spinal Score (mSASSS) quantifies radiographic changes in the cervical spine (C‐spine) and the lumbar spine (L‐spine), but not in the thoracic spine (T‐spine). Our objective was to study the contribution of the lower part of the T‐spine to structural damage in patients with ankylosing spondylitis (AS).MethodsRadiographs of 80 AS patients obtained at baseline and after 2 years were scored by 2 readers using the mSASSS. In addition, changes in the lower T‐spine (T10–T12) were quantified. On this basis, a new scoring tool was developed: the Radiographic Ankylosing Spondylitis Spinal Score (RASSS). The RASSS includes 2 changes: no scoring of erosions in order to confine the scoring to new bone formation, and no scoring of squaring in the C‐spine for anatomic and feasibility reasons.ResultsThe mean ± SD change was 0.9 ± 2.5 units using the mSASSS and 1.6 ± 2.8 units using the RASSS (P < 0.001). Although the mSASSS identified new syndesmophytes in mean ± SD 1.4 ± 2.9 vertebral edges over 2 years, an additional 0.6 ± 1.2 vertebral edges were seen in the lower T‐spine. New syndesmophytes or ankylosis were found in 15 patients (21.4%; 95% confidence interval [95% CI] 13.1–32.4%) in the C‐spine/L‐spine and in 6 patients (8.6%; 95% CI 3.8–17.2%) in the T‐spine alone. The reliability of the RASSS and the agreement between readers was excellent.ConclusionThe lower T‐spine improves the sensitivity to change of scoring radiographic progression in AS. The tool developed in this study, the RASSS, showed better face and content validity than the mSASSS and was proven to be superior in the quantification of new bone formation in AS.
Prolactin alters the mechanisms of B cell tolerance induction
Authors: Saha Subhrajit , Gonzalez Juana , Rosenfeld Gabriel , Keiser Harold , Peeva Elena 
Published: May 2009

AbstractObjectiveAutoimmune diseases predominantly affect women, suggesting that female sex hormones may play a role in the pathogenesis of such diseases. We have previously shown that persistent mild‐to‐moderate elevations in serum prolactin levels induce a break in self tolerance in mice with a BALB/c genetic background. The aim of this study was to evaluate the effects of hyperprolactinemia on the mechanisms of B cell tolerance induction.MethodsEffects of prolactin on splenic B cell subsets were studied in female BALB/c mice. B cell receptor (BCR)–mediated apoptosis and proliferation of transitional B cells were analyzed by flow cytometry. Expression of apoptotic genes was examined by microarrays and real‐time polymerase chain reaction analysis. B cells coexpressing κ/λ light chains were assessed by flow cytometry and immunohistochemistry. Activation status of transitional type 3 (T3) B cells was evaluated by BCR‐induced calcium influx studies.ResultsBCR‐mediated apoptosis of the T1 B cell subset, a major checkpoint for negative selection of autoreactive specificities, was decreased in prolactin‐treated mice. Microarray studies indicated that this event may be mediated by the prolactin‐induced up‐regulation of the antiapoptotic gene interferon‐γ receptor type II and down‐regulation of the proapoptotic gene Trp63. Prolactin treatment also altered the amount of receptor editing, as indicated by the increased number of transitional B cells coexpressing κ/λ light chains. Additionally, hyperprolactinemia modified the level of B cell anergy by increasing the degree of BCR‐induced calcium influx in the T3 B cells.ConclusionPersistently elevated serum prolactin levels interfere with B cell tolerance induction by impairing BCR‐mediated clonal deletion, deregulating receptor editing, and decreasing the threshold for activation of anergic B cells, thereby promoting autoreactivity.
Improved endothelial function after endothelin receptor blockade in patients with systemic sclerosis
Authors: Cardillo Carmine , Schinzari Francesca , Melina Domenico , Mores Nadia , Bosello Silvia , Peluso Giusy , Zoli Angelo , Ferraccioli Gianfranco 
Published: May 2009

AbstractObjectiveImpaired endothelium‐dependent vasodilator function may contribute to vascular damage in patients with systemic sclerosis (SSc). This study was undertaken to investigate whether increased activity of the endothelin 1 (ET‐1) system plays a role in the occurrence of endothelial dysfunction in patients with SSc.MethodsIn 12 patients with SSc (6 with diffuse cutaneous SSc [dcSSc] and 6 with limited cutaneous SSc [lcSSc]), forearm blood flow responses to graded doses of acetylcholine (ACh) and sodium nitroprusside (SNP) given intraarterially were assessed by plethysmography, during infusion of saline and following selective blockade of ETA receptors with BQ‐123 (10 nmoles/minute).ResultsDuring saline infusion, the vasodilator response to ACh was blunted in patients with SSc as compared with that in healthy controls (P < 0.001), whereas the response to SNP was not different between groups (P = 0.27). The vasodilator effect of ETA receptor antagonism was higher in patients than in controls (P < 0.001), indicating enhanced ET‐1–mediated vasoconstriction in SSc. In patients, ETA receptor blockade resulted in a potentiation of the vasodilator response to ACh (P < 0.001 versus saline), but did not affect the response to SNP (P = 0.31). Notably, both the vasodilator effect of ETA receptor antagonism and the improvement in the responsiveness to ACh following BQ‐123 infusion were higher in patients with dcSSc than in those with lcSSc (P < 0.01).ConclusionET‐1–dependent vasoconstrictor tone is increased predominantly in the subgroup of SSc patients with dcSSc, in whom acute blockade of ETA receptors was able to improve impaired endothelium‐dependent vasodilator function. Our results suggest novel vasculoprotective effects of ETA receptor antagonism and support further exploration of strategies that target the ET‐1 pathway in SSc.
Single‐center series and systematic review of randomized controlled trials of malignancies in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis receiving anti–tumor necrosis factor α therapy: Is there a need for more comprehensive screening procedures?
Authors: Nannini Carlotta , Cantini Fabrizio , Niccoli Laura , CassarÀ Emanuele , Salvarani Carlo , Olivieri Ignazio , Lally Edward V. 
Published: May 2009

AbstractObjectiveTo systematically review the occurrence of malignancies among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) treated with anti–tumor necrosis factor α (anti‐TNFα) therapy in randomized controlled trials (RCTs), and to report a retrospective personal case series evaluating the frequency of malignancies in patients with RA, PsA, and AS requiring anti‐TNF therapy selected with more comprehensive cancer screening procedures compared with patients screened according to previously published procedures.MethodsThe primary outcome was the report of frequency of malignancies in RCTs and the latency between the therapy introduction and the occurrence of the neoplasm. A total of 363 consecutive RA, PsA, and AS patients requiring anti‐TNF therapy from 2002 to 2006 observed at the Rheumatology Unit in Prato, Italy, underwent extensive cancer screening procedures. An historical controlled group of 73 patients treated between January 1999 and December 2001 underwent the screening procedures accepted for the RCT procedures.ResultsThirty‐six RCTs were included for analysis. Malignancies occurred in 60 (0.75%) of 8,015 patients randomized to the active treatment arm and in 21 (0.52%) of 3,991 patients in the placebo arms (P = 0.15). In the personal retrospective case series, 1 study patient (0.27%) and 3 controls (4.1%) developed cancer over the followup period (P = 0.017). Mean ± SD followup duration was 40.9 ± 16.7 months in study patients and 50.6 ± 18.1 months in controls.ConclusionThe results of RCTs and our data showing 26% of malignancies occurring within 12 weeks from enrollment suggest the need for a revision of current cancer screening procedures in RCTs and in clinical practice.
The effectiveness of Tai Chi for chronic musculoskeletal pain conditions: A systematic review and meta‐analysis
Authors: Hall Amanda , Maher Chris , Latimer Jane , Ferreira Manuela 
Published: May 2009

AbstractObjectiveTo determine whether Tai Chi improves pain, disability, physical performance, and/or health‐related quality of life (HRQOL) in people with chronic musculoskeletal pain.MethodsEight databases were searched for randomized controlled trials (RCTs). Two independent reviewers rated trial quality and extracted trial data. Effect sizes and 95% confidence intervals were calculated for individual trials, and pooled effect sizes were calculated using a random‐effects model.ResultsSeven RCTs were selected for inclusion in the review. Of these, 6 studied people with chronic arthritis and 1 studied people with chronic tension headaches. The trials were typically small and of low methodologic quality. The pooled effect size for arthritic populations on a 0–100 scale was 10.1 (range 6.3–13.9) points for pain reduction, and was 9.6 (range 5.2–14.0) points for disability reduction. Additionally, physical performance and HRQOL outcomes favored the Tai Chi intervention, but of these outcomes, only the level of tension and satisfaction with general health were statistically significant.ConclusionThe available data on the effect of Tai Chi are sparse and derived principally from low‐quality studies. These data suggest that Tai Chi has a small positive effect on pain and disability in people with arthritis. The extent to which it benefits other forms of musculoskeletal pain is unclear.
Expression and modulation of ghrelin O‐acyltransferase in cultured chondrocytes
Authors: Gómez Rodolfo , Lago Francisca , Gómez‐Reino Juan J. , Dieguez Carlos , Gualillo Oreste 
Published: May 2009

AbstractObjectiveTo use reverse transcription–polymerase chain reaction to detect ghrelin O‐acyltransferase (GOAT) transcripts in both murine and human chondrocytes, to evaluate the effect of pharmacologic in vitro treatments with lipopolysaccharide (LPS), growth hormone, ghrelin, and dexamethasone on GOAT messenger RNA (mRNA) expression, and to study the GOAT mRNA profile during chondrocyte differentiation.MethodsMurine and human GOAT and ghrelin mRNA levels were determined by the SYBR Green–based quantitative real‐time polymerase chain reaction method.ResultsGOAT mRNA was expressed in murine cartilage explants as well as in the cultured murine chondrogenic ATDC‐5 cell line. GOAT was also expressed in human immortalized chondrocyte cell lines and in human cultured primary chondrocytes. In addition, GOAT mRNA expression in differentiating ATDC‐5 cells was lower at the early stage of differentiation (days 3–7), whereas GOAT mRNA levels increased progressively at the late stages. Finally, among the drugs and hormones tested, only LPS was able to strongly decrease GOAT mRNA expression.ConclusionThese data indicate that chondrocytes are equipped with biochemical machinery for the synthesis of acylated ghrelin and suggest a novel role of the ghrelin axis in prehypertrophic and hypertrophic chondrocyte differentiation during endochondral ossification.
The three‐year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France
Authors: Hachulla Eric , de Groote Pascal , Gressin Virginie , Sibilia Jean , Diot Elisabeth , Carpentier Patrick , Mouthon Luc , Hatron Pierre‐Yves , Jego Patrick , Allanore Yannick , Tiev Kiet Phong , Agard Christian , Cosnes Anne , Cirstea Daniela , Constans Joël , Farge Dominique , Viallard Jean‐François , Harle Jean‐Robert , Patat Frédéric , Imbert Bernard , Kahan André , Cabane Jean , Clerson Pierre , Guillevin Loïc , Humbert Marc 
Published: May 2009

AbstractObjectiveAn algorithm for the detection of pulmonary arterial hypertension (PAH), based on the presence of dyspnea and the findings of Doppler echocardiographic evaluation of the velocity of tricuspid regurgitation (VTR) and right‐sided heart catheterization (RHC), which was applied in a large multicenter systemic sclerosis (SSc) population, estimated the prevalence of PAH to be 7.85%. The aim of this observational study was to investigate the incidence of PAH and pulmonary hypertension (PH) during a 3‐year followup of patients from the same cohort (the ItinérAIR‐Sclérodermie Study).MethodsPatients with SSc and without evidence of PAH underwent evaluation for dyspnea and VTR at study entry and during subsequent visits. Patients in whom PAH was suspected because of a VTR of 2.8–3.0 meters/second and unexplained dyspnea or a VTR of >3.0 meters/second underwent RHC to confirm the diagnosis.ResultsA total of 384 patients were followed up for a mean ± SD of 41.03 ± 5.66 months (median 40.92 months). At baseline, 86.7% of the patients were women, and the mean ± SD age of the patients was 53.1 ± 12.0 years. The mean ± SD duration of SSc at study entry was 8.7 ± 7.6 years. After RHC, PAH was diagnosed in 8 patients, postcapillary PH in 8 patients, and PH associated with severe pulmonary fibrosis in 2 patients. The incidence of PAH was estimated to be 0.61 cases per 100 patient‐years. Two patients who exhibited a mean pulmonary artery pressure of 20–25 mm Hg at baseline subsequently developed PAH.ConclusionThe estimated incidence of PAH among patients with SSc was 0.61 cases per 100 patient‐years. The high incidence of postcapillary PH highlights the value of RHC in investigating suspected PAH.
Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort
Authors: Pons‐Estel Guillermo J. , Alarcón Graciela S. , McGwin Gerald , Danila Maria I. , Zhang Jie , Bastian Holly M. , Reveille John D. , Vilá Luis M. 
Published: May 2009

AbstractObjectiveTo assess whether hydroxychloroquine can delay renal damage development in lupus nephritis patients.MethodsLupus nephritis patients (n = 256) from the LUpus in MInorities, NAture versus nurture study (n = 635), a multiethnic cohort of African Americans, Hispanics, and Caucasians, age ≥16 years with disease duration ≤5 years at baseline (T0) were studied. Renal damage was defined using the Systemic Lupus International Collaborating Clinics Damage Index (≥1 of the following lasting at least 6 months: estimated/measured glomerular filtration rate <50%, 24‐hour proteinuria ≥3.5 gm and/or end‐stage renal disease, regardless of dialysis or transplantation). Patients with renal damage before T0 were excluded (n = 53). The association between hydroxychloroquine use and renal damage (as defined, or omitting proteinuria) was estimated using Cox proportional regression analyses adjusting for potential confounders. Kaplan‐Meier survival curves based on hydroxychloroquine intake or the World Health Organization (WHO) class glomerulonephritis were also derived.ResultsSixty‐three (31.0%) of the 203 patients included developed renal damage over a mean ± SD disease duration of 5.2 ± 3.5 years. The most frequent renal damage domain item was proteinuria. Patients who received hydroxychloroquine (79.3%) exhibited a lower frequency of WHO class IV glomerulonephritis, had lower disease activity, and received lower glucocorticoid doses than those who did not take hydroxychloroquine. After adjusting for confounders, hydroxychloroquine was protective of renal damage occurrence in full (hazard ratio [HR] 0.12, 95% confidence interval [95% CI] 0.02–0.97, P = 0.0464) and reduced (HR 0.29, 95% CI 0.13–0.68, P = 0.0043) models. Omitting proteinuria provided comparable results. The cumulative probability of renal damage occurrence was higher in those who did not take hydroxychloroquine and those classified as WHO class IV glomerulonephritis (P < 0.0001).ConclusionAfter adjusting for possible confounding factors, the protective effect of hydroxychloroquine in retarding renal damage occurrence in systemic lupus erythematosus is still evident.
Long‐term medical costs and resource utilization in systemic lupus erythematosus and lupus nephritis: A five‐year analysis of a large medicaid population
Authors: Li Tracy , Carls Ginger Smith , Panopalis Pantelis , Wang Sara , Gibson Teresa B. , Goetzel Ron Z. 
Published: May 2009

AbstractObjectiveTo estimate the long‐term direct medical costs and health care utilization for patients with systemic lupus erythematosus (SLE) and a subset of SLE patients with nephritis.MethodsPatients with newly active SLE were found in the MarketScan Medicaid Database (1999–2005), which includes all inpatient, outpatient, emergency department, and pharmaceutical claims for more than 10 million Medicaid beneficiaries. The date a patient became newly active was defined as the earliest observed SLE diagnosis code, with a 6‐month clean period prior to the diagnosis. This method identified 2,298 patients with a consecutive followup of 5 years. A reference group of patients without SLE was constructed using propensity score matching. Nephritis was assessed based on diagnosis and procedure codes involving the kidney.ResultsMean annual medical costs for SLE patients totaled $16,089 at year 1, which is significantly greater (by $6,831) than that for reference patients. Costs decreased slightly at year 2 but then increased yearly at an average rate of 16% through year 5, to $23,860. SLE patients without nephritis (n = 1,809) had costs $967–3,756 higher than the reference patients. SLE patients with nephritis (n = 489) had costs $13,228–34,907 greater than the reference group. Inpatient visits for the nephritis subgroup were 0.6–1.0 per capita, which are approximately twice the rate for all SLE patients and 3 to 4 times higher than the reference group.ConclusionSLE is a costly condition to treat. Medical expenses incurred by SLE patients increase steadily over time, particularly for patients with nephritis.
Elevated serum interferon‐α activity in juvenile dermatomyositis: Associations with disease activity at diagnosis and after thirty‐six months of therapy
Authors: Niewold Timothy B. , Kariuki Silvia N. , Morgan Gabrielle A. , Shrestha Sheela , Pachman Lauren M. 
Published: May 2009

AbstractObjectiveInterferon‐α (IFNα) has been implicated in the pathogenesis of juvenile dermatomyositis (DM). The aim of this study was to examine serum IFNα activity in a cohort of children with juvenile DM to determine relationships between IFNα and indicators of disease activity and severity.MethodsThirty‐nine children with definite/probable juvenile DM were included in the study. Serum samples were obtained at the time of diagnosis from 18 untreated patients with juvenile DM. Second samples from 11 of these patients were obtained at 24 months, while they were receiving treatment, and third samples were obtained from 7 of these patients at 36 months. The remaining 21 children were studied 36 months after their initial diagnosis. Serum IFNα activity was measured using a functional reporter cell assay.ResultsPatients with juvenile DM had higher serum IFNα activity than both pediatric and adult healthy control subjects. In untreated patients, serum IFNα activity was positively correlated with serum muscle enzyme levels (P < 0.05 for creatine kinase, aspartate aminotransferase, and aldolase) and inversely correlated with the duration of untreated disease (P = 0.017). The tumor necrosis factor α −308A allele was associated with higher serum IFNα levels only in untreated patients (P = 0.030). At 36 months, serum IFNα levels were inversely correlated with muscle enzyme levels in those patients still requiring therapy and with the skin Disease Activity Score in those patients who had completed therapy (P = 0.002).ConclusionSerum IFNα activity was associated with higher serum levels of muscle‐derived enzymes and a shorter duration of untreated disease in patients with newly diagnosed juvenile DM and was inversely correlated with measures of chronic disease activity at 36 months postdiagnosis. These data suggest that IFNα could play a role in disease initiation in juvenile DM.
Neutralization of interferon‐α/β–inducible genes and downstream effect in a phase I trial of an anti–interferon‐α monoclonal antibody in systemic lupus erythematosus
Authors: Yao Yihong , Richman Laura , Higgs Brandon W. , Morehouse Christopher A. , de los Reyes Melissa , Brohawn Philip , Zhang Jianliang , White Barbara , Coyle Anthony J. , Kiener Peter A. , Jallal Bahija 
Published: May 2009

AbstractObjectiveType I interferons (IFNs) play an important role in the pathogenesis of systemic lupus erythematosus (SLE). This phase Ia trial was undertaken to evaluate the safety, pharmacokinetics, and immunogenicity of anti‐IFNα monoclonal antibody (mAb) therapy in SLE. During the trial, we also examined whether overexpression of an IFNα/β‐inducible gene signature in whole blood could serve as a pharmacodynamic biomarker to evaluate IFNα neutralization and investigated downstream effects of neutralizing IFNα on BAFF and other key signaling pathways, i.e., granulocyte–macrophage colony‐stimulating factor (GM‐CSF), interleukin‐10 (IL‐10), tumor necrosis factor α (TNFα), and IL‐1β, in SLE.MethodsAffymetrix Human Genome U133 Plus 2.0 microarrays were used to profile whole blood and lesional skin of patients receiving standard therapy for mild to moderate SLE. Selected IFNα/β‐inducible proteins were analyzed by immunohistochemistry.ResultsWith the study treatment, we observed anti‐IFNα mAb–specific and dose‐dependent inhibition of overexpression of IFNα/β‐inducible genes in whole blood and skin lesions from SLE patients, at both the transcript and the protein levels. In SLE patients with overexpression of messenger RNA for BAFF, TNFα, IL‐10, IL‐1β, GM‐CSF, and their respective inducible gene signatures in whole blood and/or skin lesions, we observed a general trend toward suppression of the expression of these genes and/or gene signatures upon treatment with anti‐IFNα mAb.ConclusionIFNα/β‐inducible gene signatures in whole blood are effective pharmacodynamic biomarkers to evaluate anti‐IFNα mAb therapy in SLE. Anti‐IFNα mAb can neutralize overexpression of IFNα/β‐inducible genes in whole blood and lesional skin from SLE patients and has profound effects on signaling pathways that may be downstream of IFNα in SLE.