Steven Abramson, M.D.

Clinical guidelines: Expert recommendations for NSAID use: a user-friendly model?
Abramson SB
2011 Mar;7(3):133-134, Nature reviews. Rheumatology
— id: 121306, year: 2011, vol: 7, page: 133, stat: Journal Article,

Introduction to OARSI FDA initiative OAC special edition
Abramson, S B; Berenbaum, F; Hochberg, M C; Moskowitz, R W
2011 May;19(5):475-477, Osteoarthritis & cartilage
— id: 132571, year: 2011, vol: 19, page: 475, stat: Journal Article,

THERAPIES IN OSTEOARTHRITIS
Abramson, S. B.
2011 JUN ;60(6):20-20, Inflammation research
— id: 134494, year: 2011, vol: 60, page: 20, stat: Journal Article,

Differing opinion, not misconduct
Abramson, Steven B
2011 Feb 24;470(7335):465-465, Nature
— id: 141614, year: 2011, vol: 470, page: 465, stat: Journal Article,

Glatiramer acetate (GA), the immunomodulatory drug, inhibits inflammatory mediators and collagen degradation in osteoarthritis (OA) cartilage
Attur, M; Millman, J S; Dave, M N; Al-Mussawir, H E; Patel, J; Palmer, G; Abramson, S B
2011 Sep;19(9):1158-1164, Osteoarthritis & cartilage
OBJECTIVE: Glatiramer acetate (GA), the generic name for Copaxone, an immunomodulatory agent, has been shown to induce interleukin-1 receptor antagonist (IL-1Ra) production in macrophages. We therefore tested the effects of GA on the catabolic activities of osteoarthritis (OA) chondrocytes. DESIGN: Primary human chondrocytes and OA cartilage explants were utilized in this study. IL-1Ra, pro-matrix metalloproteinase-13 (proMMP-13) and prostaglandin E(2) (PGE(2)) were estimated in the cell culture supernatants and in vitro MMP-13 activity was measured using fluorogenic substrate. TaqMan Real-Time quantitative polymerase chain reaction (RT-qPCR) was performed to estimate relative expression levels of genes. RESULTS: GA treatment significantly increased transcription and production of sIL-1Ra (P=0.001) in both culture models. Furthermore, addition of GA (100mug) inhibited: (1) spontaneous collagen degradation as assayed by CTX II enzyme-linked immunosorbent assay (ELISA) [mean CTX II (ng/g cartilage)] in control was 7.79 [95% confidence interval (CI) 2.57-13.02]-3.415 (95% CI 0.81-6.02) (P=0.0286); (2) spontaneous proMMP-13 secretion [mean MMP-13 (ng/g cartilage)] in control was 16.98 (95% CI 7.739-26.23)-6.973 (95% CI 1.632-12.31) (P=0.0286); (3) production of IL-1beta-induced inflammatory mediators such as nitric oxide (NO) [mean NO (muM)] in IL-1 cultures was 11.47 (95% CI 7.10-15.83)-0.87 (95% CI 0.18-1.56) (P=0.0022); and (4) recombinant MMP-13 in vitro activity (15-25%; P=0.004). CONCLUSIONS: These data suggest that GA effects may be due to upregulation of IL-1Ra as well as direct inhibition of MMP-13 activity. Based on these studies, we propose that GA has potential for disease modifying properties in OA and should be evaluated in vivo in animal studies
— id: 136941, year: 2011, vol: 19, page: 1158, stat: Journal Article,

Increased interleukin-1beta gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis
Attur, Mukundan; Belitskaya-Levy, Ilana; Oh, Cheongeun; Krasnokutsky, Svetlana; Greenberg, Jeffrey; Samuels, Jonathan; Smiles, Stephen; Lee, Sicy; Patel, Jyoti; Al-Mussawir, Hayf; McDaniel, Gary; Kraus, Virginia Byers; Abramson, Steven B
2011 Jul;63(7):1908-1917, Arthritis & rheumatism
OBJECTIVE: To evaluate whether gene expression profiles could serve as biomarkers of symptomatic knee osteoarthritis (OA) by examining gene expression profiles in peripheral blood leukocytes (PBLs) from patients with OA compared with those from non-OA controls, and to determine whether candidate genomic biomarkers (PBL expression of inflammatory genes) predict an increased risk of disease progression in patients with symptomatic radiographic knee OA. METHODS: Three independent cohorts of patients with knee OA and non-OA control subjects were studied. Two cohorts (a learning cohort and a validation cohort) were recruited at New York University Hospital for Joint Diseases (NYUHJD), and 1 cohort (a validation cohort) was recruited at Duke University Medical Center. PBL gene expression was assessed using Affymetrix microarray and was confirmed by quantitative polymerase chain reaction (qPCR). Radiographic progression at 2 years was assessed in 86 patients. RESULTS: We identified 173 genes that were significantly up-regulated or down-regulated (>/=1.5-fold change) in OA PBLs, at a false discovery rate of 5%. Cluster analysis revealed 2 distinct subgroups among the patients with OA: those in whom the expression of interleukin-1beta (IL-1beta) was increased >/=2-fold compared with controls, and those in whom the expression of IL-1beta was comparable with that in controls. Overexpression of IL-1beta in these OA subclasses was validated using qPCR in all 3 cohorts. Patients with the inflammatory 'IL-1beta signature' had higher pain scores and decreased function and were at higher risk of radiographic progression of OA. CONCLUSION: PBLs from patients with symptomatic knee OA display a characteristic transcriptome profile. Moreover, increased expression of IL-1beta identifies a subset of patients with OA who have increased pain and are at higher risk of radiographic progression of OA
— id: 134740, year: 2011, vol: 63, page: 1908, stat: Journal Article,

Large-scale meta-analysis of interleukin-1 beta and interleukin-1 receptor antagonist polymorphisms on risk of radiographic hip and knee osteoarthritis and severity of knee osteoarthritis
Kerkhof, H J M; Doherty, M; Arden, N K; Abramson, S B; Attur, M; Bos, S D; Cooper, C; Dennison, E M; Doherty, S A; Evangelou, E; Hart, D J; Hofman, A; Javaid, K; Kerna, I; Kisand, K; Kloppenburg, M; Krasnokutsky, S; Maciewicz, R A; Meulenbelt, I; Muir, K R; Rivadeneira, F; Samuels, J; Sezgin, M; Slagboom, E; Smith, A J P; Spector, T D; Tamm, A; Tamm, A; Uitterlinden, A G; Wheeler, M; Zhai, G; Zhang, W; van Meurs, J B J; Valdes, A M
2011 Mar;19(3):265-271, Osteoarthritis & cartilage
OBJECTIVE: To clarify the role of common genetic variation in the Interleukin-1beta (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. METHODS: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. RESULTS: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I(2)=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). CONCLUSION: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA
— id: 133192, year: 2011, vol: 19, page: 265, stat: Journal Article,

Quantitative magnetic resonance imaging evidence of synovial proliferation is associated with radiographic severity of knee osteoarthritis
Krasnokutsky, Svetlana; Belitskaya-Levy, Ilana; Bencardino, Jenny; Samuels, Jonathan; Attur, Mukundan; Regatte, Ravinder; Rosenthal, Pamela; Greenberg, Jeffrey; Schweitzer, Mark; Abramson, Steven B; Rybak, Leon
2011 Oct;63(10):2983-2991, Arthritis & rheumatism
OBJECTIVE: To evaluate the relationships between both quantitative and semiquantitative assessments of the degree of knee synovitis on 3T magnetic resonance imaging (MRI) and the severity of knee osteoarthritis (OA) on radiography. METHODS: Fifty-eight patients with knee OA underwent nonfluoroscopic fixed-flexion knee radiography. In addition, dynamic contrast-enhanced 3T MRI of the knees was performed, before and after gadolinium administration, to quantify synovial membrane volume (SV) as a measure of synovial proliferation (expressed as the quantitative SV), and semiquantitative measures of synovitis were also applied using both contrast-enhanced and unenhanced images. Two radiologists scored the knee radiographs using the Osteoarthritis Research Society International atlas; interreader agreement was assessed using kappa statistics and concordance correlation coefficients. Multiple linear and logistic regression analyses were used to assess associations among variables, while controlling for the effects of age, body mass index, sex, and meniscal extrusion. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for measures of disease activity. RESULTS: The Kellgren/Lawrence (K/L) grade of radiographic knee OA severity (beta = 0.78), the diseased compartment joint space width (dcJSW) (beta = -0.22), and the diseased compartment joint space narrowing (dcJSN) score (beta = 0.53) were each significantly associated with the quantitative SV (P = 0.0001, P = 0.0003, and P = 0.0001, respectively). Furthermore, the quantitative SV strongly correlated with the total volume of subchondral bone marrow lesions (BMLs) (beta = 0.22, P = 0.0003). The K/L grade, dcJSW, and dcJSN score were each significantly associated with the semiquantitative Boston Leeds Osteoarthritis Knee Score (BLOKS) for the extent of infrapatellar synovitis (OR 9.05 [95% CI 1.94, 42.3] for K/L grade; OR 0.75 [95% CI 0.54, 1.03] for dcJSW; and OR 2.22 [95% CI 1.15, 4.31] for dcJSN score) and extent of joint effusion (OR 5.75 [95% CI 1.23, 26.8] for K/L grade; OR 0.70 [95% CI 0.50, 0.98] for dcJSW; and OR 1.96 [95% CI 1.02, 3.74] for dcJSN score). In addition, the semiquantitative synovitis grade on contrast-enhanced MRI was significantly associated with the K/L grade (beta = 0.036, P = 0.0040) and dcJSN score (beta = 0.015, P = 0.0266), and also significantly associated with the BLOKS synovitis score. CONCLUSION: Synovitis is a characteristic feature of advancing knee OA and is significantly associated with the K/L grade, JSW, JSN score, and total volume of BMLs on radiographs. Furthermore, BLOKS scoring of synovitis on unenhanced MRI is associated with measurements of synovitis on contrast-enhanced MRI
— id: 137878, year: 2011, vol: 63, page: 2983, stat: Journal Article,

Rheumatic diseases
Lee, Sicy H; Abramson, Steven B
Medical aspects of disability : a handbook for the rehabilitation professional New York : Springer, c2011,
— id: 5795, year: 2011, vol: , page: ?, stat: Chapter,

The microbiome and rheumatoid arthritis
Scher, Jose U; Abramson, Steven B
2011 ;7(10):569-578, Nature reviews. Rheumatology
Humans are not (and have never been) alone. From the moment we are born, millions of micro-organisms populate our bodies and coexist with us rather peacefully for the rest of our lives. This microbiome represents the totality of micro-organisms (and their genomes) that we necessarily acquire from the environment. Micro-organisms living in or on us have evolved to extract the energy they require to survive, and in exchange they support the physiological, metabolic and immune capacities that have contributed to our evolutionary success. Although currently categorized as an autoimmune disorder and regarded as a complex genetic disease, the ultimate cause of rheumatoid arthritis (RA) remains elusive. It seems that interplay between predisposing genetic factors and environmental triggers is required for disease manifestation. New insights from DNA sequence-based analyses of gut microbial communities and a renewed interest in mucosal immunology suggest that the microbiome represents an important environmental factor that can influence autoimmune disease manifestation. This Review summarizes the historical clues that suggest a possible role for the microbiota in the pathogenesis of RA, and will focus on new technologies that might provide scientific evidence to support this hypothesis
— id: 138111, year: 2011, vol: 7, page: 569, stat: Journal Article,

The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice
Tang W; Lu Y; Tian QY; Zhang Y; Guo FJ; Liu GY; Syed NM; Lai Y; Lin EA; Kong L; Su J; Yin F; Ding AH; Zanin-Zhorov A; Dustin ML; Tao J; Craft J; Yin Z; Feng JQ; Abramson SB; Yu XP; Liu CJ
2011 Apr 22;332(6028):478-484, Science
The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFR) and disturbed the TNFalpha/TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFalpha-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFalpha signaling and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFalpha-mediated pathologies and conditions, including rheumatoid arthritis
— id: 126500, year: 2011, vol: 332, page: 478, stat: Journal Article,

T1rho MRI of menisci and cartilage in patients with osteoarthritis at 3T
Wang L; Chang G; Xu J; Vieira RL; Krasnokutsky S; Abramson S; Regatte RR
2011 Sep 9;:?-? #, European journal of radiology
OBJECTIVE: To assess and compare subregional and whole T1rho values (median+/-interquartile range) of femorotibial cartilage and menisci in patients with doubtful (Kellgren-Lawrence (KL) grade 1) to severe (KL4) osteoarthritis (OA) at 3T. MATERIALS AND METHODS: 30 subjects with varying degrees of OA (KL1-4, 13 females, 17 males, mean age+/-SD=63.9+/-13.1 years) were evaluated on a 3T MR scanner using a spin-lock-based 3D GRE sequence for T1rho mapping. Clinical proton density (PD)-weighted fast spin echo (FSE) images in sagittal (without fat saturation), axial, and coronal (fat-saturated) planes were acquired for cartilage and meniscus Whole-organ MR imaging score (WORMS) grading. Wilcoxon rank sum test was performed to determine whether there were any statistically significant differences between subregional and whole T1rho values of femorotibial cartilage and menisci in subjects with doubtful to severe OA. RESULTS: Lateral (72+/-10ms, median+/-interquartile range) and medial (65+/-10ms) femoral anterior cartilage subregions in moderate-severe OA subjects had significantly higher T1rho values (P<0.05) than cartilage subregions and whole femorotibial cartilage in doubtful-minimal OA subjects. There were statistically significant differences in meniscus T1rho values of the medial posterior subregion of subjects with moderate-severe OA and T1rho values of all subregions and the whole meniscus in subjects with doubtful-minimal OA. When evaluated based on WORMS, statistically significant differences were identified in T1rho values between the lateral femoral anterior cartilage subregion in patients with WORMS5-6 (advanced degeneration) and whole femorotibial cartilage and all cartilage subregions in patients with WORMS0-1 (normal). CONCLUSION: T1rho values are higher in specific meniscus and femorotibial cartilage subregions. These findings suggest that regional damage of both femorotibial hyaline cartilage and menisci may be associated with osteoarthritis
— id: 139810, year: 2011, vol: , page: ?, stat: Journal Article,

Assessment of subchondral bone marrow lipids in healthy controls and mild osteoarthritis patients at 3T
Wang L; Salibi N; Chang G; Vieira RL; Babb JS; Krasnokutsky S; Abramson S; Regatte RR
2011 Aug 18;:?-?, NMR in biomedicine
The compartment-specific lipid changes in femoral-tibial bone of healthy controls and mild osteoarthritis (OA) patients were quantified at 3.0 T. Healthy volunteers [Kellgren-Lawrence (KL) grade = 0; n = 15, 4 females, 11 males, mean age 39 +/- 16 years, age range = 24-78 years] and mild OA patients (KL = 1, 2; n = 26, 12 females, 14 males, mean age 61 +/- 14 years, age range = 27-80 years) were scanned on a 3 T scanner. Clinical proton density (PD)-weighted fast spin echo (FSE) images in the sagittal (without fat-saturation), axial and coronal (fat-saturation) planes were acquired for cartilage Whole-Organ MR Imaging Score (WORMS) grading. A voxel of 10 x 10 x 10 mm(3) was positioned in the medial and lateral compartments of the tibia [medial tibial (MT) and lateral tibial (LT)] and femur [medial femoral (MF) and lateral femoral (LF)] for MRS measurements using the single voxel-stimulated echo acquisition mode (STEAM) pulse sequence. All MRS data were processed with Java-based Magnetic Resonance User Interface (JMRUI). Wilcoxon's rank sum test and mixed model two-way analysis of variance (anova) were performed to determine significant differences between different compartments as well as examine the effect of OA grade and compartment, and their interactions. Generally, the MF compartment index of unsaturation was increased in healthy subjects compared with OA subjects (whether graded by KL or WORMS score). Differences between MF at KL0 and all other compartments at KL1 except LF approached statistical significance (p < 0.05). Differences in saturated lipids signals could be observed predominantly in the 2.03 p.p.m. frequency shift. Healthy controls in the MF compartment had the lowest saturated lipid signals, and mild OA patients with KL2 and WORMS5-6 in the MF compartment had the highest saturated lipid signals compared with other compartments at 2.03 p.p.m. (p < 0.05).
— id: 139811, year: 2011, vol: , page: ?, stat: Journal Article,

Inhibitory effects of iron on bone morphogenetic protein 2-induced osteoblastogenesis
Yang, Qing; Jian, Jinlong; Abramson, Steven B; Huang, Xi
2011 Jun;26(6):1188-1196, Journal of bone & mineral research
Postmenopausal osteoporosis is characterized by an imbalance of bone resorption exceeding bone formation, resulting in a net loss of bone mineral density (BMD). Estrogen deficiency is known to promote bone resorption. However, the causative factors that impair bone formation have not been identified. Women after menopause experience not only estrogen deficiency but also iron accumulation as a result of cessation of menstruation. In this study we investigated whether increased iron plays a role in osteoporosis. By growing primary mouse osteoclast and osteoblast progenitor cells as well as immortalized cell lines in the presence of iron, we found that increased iron had minimal effects on osteoclast cell differentiation. Interestingly, iron, particularly in its inorganic form, and to a lesser extent ferritin and transferrin all suppressed alkaline phosphatase (ALP) activities in osteoblasts. Moreover, iron downregulated mRNA levels of several other osteoblastogenic markers such as Runx2, osterix, osteopontin, and osteocalcin. To further show that this in vitro finding is relevant to the in vivo condition, we demonstrated that iron-accumulated mice with intact ovaries exhibited a significant decrease in BMD. Although iron inhibited preosteoblast cell differentiation, it did enhance preosteoblast cell proliferation, as evidenced by increased cell growth and expression of cell cycle regulator genes such as CDK4, CDK6, cyclin D1, and cyclin D3 and G(2) /M phase cell population. Taken together, our results suggest that increased iron could be a factor that slows down bone formation in postmenopausal women. (c) 2011 American Society for Bone and Mineral Research
— id: 132876, year: 2011, vol: 26, page: 1188, stat: Journal Article,

New York University School of Medicine
Abramson, Steven B; Rosenfeld, Mel
2010 Sep;85(9 Suppl):S380-S386, Academic medicine
— id: 141615, year: 2010, vol: 85, page: S380, stat: Journal Article,

ASSOCIATION OF INTERLEUKIN-1 RECEPTOR ANTAGONIST (IL-1RN) TTG HAPLOTYPE WITH RADIOGRAPHIC KNEE OA SEVERITY IN META-ANALYSIS
Attur, M.; Kerkhof, H.; Oh, C.; Krasnokutsky, S.; Samuels, J.; Uitterlinden, A. G.; Hofman, A.; Rivadeneira, F.; Valdes, A.; Spector, T. D.; van Meurs, J.; Abramson, S. B.
2010 OCT ;18(12):S172-S172, Osteoarthritis & cartilage
— id: 120556, year: 2010, vol: 18, page: S172, stat: Journal Article,

INTERLEUKIN-1 RECEPTOR ANTAGONIST GENE VARIATIONS PREDICT THE SEVERITY AND PROGRESSION OF KNEE OSTEOARTHRITIS
Attur, M.; Oh, C.; Krasnokutsky, S.; Samuels, J.; Rybak, L.; Bencardino, J.; Kraus, V.; Kornman, K.; Abramson, S. B.
2010 OCT ;18(12):S172-S172, Osteoarthritis & cartilage
— id: 120557, year: 2010, vol: 18, page: S172, stat: Journal Article,

Targeting the synovial tissue for treating osteoarthritis (OA): where is the evidence?
Attur, Mukundan; Samuels, Jonathan; Krasnokutsky, Svetlana; Abramson, Steven B
2010 Feb;24(1):71-79, Bailliere's best practice & research. Clinical rheumatology
Osteoarthritis (OA) is often a progressive and disabling disease, which occurs in the setting of a variety of risk factors--such as advancing age, obesity and trauma--that collude to incite a cascade of pathophysiological events within joint tissues. An important emerging theme in OA is a broadening of focus from a disease of cartilage to one of the 'whole joint.' The synovium, bone and cartilage are each involved in pathological processes that lead to progressive joint degeneration. Additional themes that have emerged over the past decade are novel mechanisms of cartilage degradation and repair, the relationship between biomechanics and biochemical pathways, the importance of inflammation and the role of genetics. In this article, we review the molecular, clinical and imaging evidence that synovitis is not an 'incidental finding of OA', but plays a significant role in disease pathogenesis, and could therefore represent a target for future treatments
— id: 107276, year: 2010, vol: 24, page: 71, stat: Journal Article,

Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations
Attur, Mukundan; Wang, Hwa-Ying; Kraus, Virginia Byers; Bukowski, Jack F; Aziz, Nazneen; Krasnokutsky, Svetlana; Samuels, Jonathan; Greenberg, Jeffrey; McDaniel, Gary; Abramson, Steven B; Kornman, Kenneth S
2010 May;69(5):856-861, Annals of rheumatic diseases
BACKGROUND: A lack of biomarkers that identify patients at risk for severe osteoarthritis (OA) complicates development of disease-modifying OA drugs. OBJECTIVE: To determine whether inflammatory genetic markers could stratify patients with knee OA into high and low risk for destructive disease. METHODS: Genotype associations with knee OA severity were assessed in two Caucasian populations. Fifteen single nucleotide polymorphisms (SNPs) in six inflammatory genes were evaluated for association with radiographic severity and with synovial fluid mediators in a subset of the patients. RESULTS: Interleukin 1 receptor antagonist (IL1RN) SNPs (rs419598, rs315952 and rs9005) predicted Kellgren-Lawrence scores independently in each population. One IL1RN haplotype was associated with lower odds of radiographic severity (OR=0.15; 95% CI 0.065 to 0.349; p<0.0001), greater joint space width and lower synovial fluid cytokine levels. Carriage of the IL1RN haplotype influenced the age relationship with severity. CONCLUSION: IL1RN polymorphisms reproducibly contribute to disease severity in knee OA and may be useful biomarkers for patient selection in disease-modifying OA drug trials
— id: 109509, year: 2010, vol: 69, page: 856, stat: Journal Article,

Effects of NSAIDs and the Cyclooxygenase-Inhibiting Nitric Oxide Donator (CINOD) NCX 429 on human chondrocytes and cartilage from OA patients
Bolla M.; Viappiani S.; Dave M.; Patel J.; Abramson S.B.; Attur M.
2010 ;62:1477-1477, Arthritis & rheumatism
Background: The role of nitric oxide (NO) in osteoarthritis (OA) is controversial. NO, particularly when metabolized to peroxynitrite, is a recognized mediator of inflammation, which induces catabolic effects and promotes chondrocyte apoptosis. Conversely, NO delivered at low concentrations by NO donors exerts anti-inflammatory effects. Cyclooxygenase-Inhibiting Nitric Oxide Donators (CINODs) are anti-inflammatory compounds designed to inhibit both COX-1 and COX-2 while releasing nitric oxide, an important modulator of vascular tone. We studied the effect of naproxen and the CINOD NCX 429 in human chondrocytes and cartilage tissues from OA patients, to understand whether NO donation from CINODs may modulate the inflammatory/metabolic response. Methods: The experiments were performed with human cartilage and chondrocytes isolated from OA cartilage. Isolated chondrocytes stimulated with IL-1beta to induce inflammation, followed by measurement of inflammatory and matrix parameters, such as iNOS, COX-2, MMP1 and 13, PGE2, NO, matrix metalloproteinases, collagen degradation and NF-B nuclear translocation. Reference NSAIDs naproxen and celecoxib were used in comparison to NCX 429 (10 and 50 muM), and incubated 16 h before IL-1beta challenge. Cartilage explants culture supernatants (untreated and treated with modulators) were harvested at 24 and 72 hours post-treatment. RNA was extracted from chondrocytes and estimated by qPCR. NF-B binding was assessed using Marligen Bioscience kit and both cytoplasm and nuclear p65 subunit of NF-B was also assessed by Western blot. Results: The reference NSAIDs and the CINOD similarly upregulated MMP1 but inhibited MMP13, showing comparable net effect on collagen degradation as assayed by CTX-II ELISA. They similarly inhibited ADAMTS4, but only 50 muM NCX 429 downregulated COX-2 expression. In isolated OA chondrocytes, NCX 429 (10 and 50 muM) significantly and completely inhibited IL-1beta-induced PGE2 production, and both the constitutive and IL-1beta-stimulated induction of NF-B activity. Western blot analysis of p65 subunit isolated from nuclear fraction showed that the cells treated with CINOD (both in unstimulated and IL-1beta stimulated cells) had increased p65 accumulation although decreased NF-B binding and also inhibited NF-B promoter mediated luciferase reporter assay. Conclusions: Reference NSAIDs and the CINOD NCX 429 appear to similarly modulate human OA chondrocytes, both in unstimulated and stimulated conditions. NO has been considered detrimental for chondrocytes; however, donation of low concentrations of NO is recognized to be beneficial in a variety of conditions. Here, the CINOD NCX 429 does not differ from reference NSAIDs, indicating that CINODs do not adversely affect chondrocytes via NO donation. In addition, NCX 429 showed inhibition of the NF-B signalling, therefore presenting interesting anti-inflammatory features to be further explored
— id: 130933, year: 2010, vol: 62, page: 1477, stat: Journal Article,

The role of microRNA in rheumatoid arthritis and other autoimmune diseases
Furer, Victoria; Greenberg, Jeffrey D; Attur, Mukundan; Abramson, Steven B; Pillinger, Michael H
2010 Jul;136(1):1-15, Clinical immunology
MicroRNAs (miRNAs) represent a class of non-coding RNA molecules playing pivotal roles in cellular and developmental processes. miRNAs modulate the expression of multiple target genes at the post-transcriptional level and are predicted to affect up to one-third of all human protein-encoding genes. Recently, miRNA involvement in the adaptive and innate immune systems has been recognized. Rheumatoid arthritis serves an example of a chronic inflammatory disorder in which miRNAs modulate the inflammatory process in the joints, with the potential to serve as biomarkers for both the inflammatory process and the potential for therapeutic response. This review discusses the investigations that led to miRNA discovery, miRNA biogenesis and mode of action, and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We conclude with a discussion of the implications of miRNA biology in rheumatoid arthritis and other autoimmune disorders
— id: 110075, year: 2010, vol: 136, page: 1, stat: Journal Article,

LARGE SCALE META-ANALYSIS OF INTERLEUKIN-1 BETA AND INTERLEUKIN-1 RECEPTOR ANTAGONIST POLYMORPHISMS ON RISK OF RADIOGRAPHIC HIP AND KNEE OSTEOARTHRITIS AND SEVERITY OF KNEE OSTEOARTHRITIS
Kerkhof, H. J.; Doherty, M.; Abramson, S. B.; Arden, N. K.; Attur, M.; Bos, S.; Cooper, C.; Doherty, S. A.; Evangelou, E.; Kerna, I.; Kisand, K.; Kloppenburg, M.; Maciewicz, R. A.; Meulenbelt, I.; Sezgin, M.; Slagboom, E.; Smith, A.; Spector, T. D.; Tamm, A.; Tamm, A.; Uitterlinden, A. G.; Wheeler, M.; Zhang, W.; van Meurs, J. B.; Valdes, A. M.
2010 OCT ;18(12):S166-S166, Osteoarthritis & cartilage
— id: 120555, year: 2010, vol: 18, page: S166, stat: Journal Article,

miR-7 and miR-130b are differentially regulated during Mesenchymal Stem Cell commitment
Palmer G.; Danielson L.S.; Attur M.; Abramson S.B.; Hernando E.
2010 ;62:1490-1490, Arthritis & rheumatism
Purpose: Stem cell-based therapies aimed at introducing progenitor cells into cartilage lesions hold great promise for the restoration of damaged articular surfaces following joint injury or osteoarthritis. Key to the generation of a functional repair tissue is the controlled differentiation into the desired phenotype. To this end microRNAs (miRNAs) may be important molecules that regulate this process. By acting as transcriptional repressors, their modulation during differentiation may enable commitment to a specific lineage by suppressing the expression of other lineage markers. In this study we profiled MSCs for miRNA expression following induction into the chondrocyte (C), osteoblast (O) and smooth muscle (SM) lineages. Results: Human bone marrow-derived Mesenchymal Stem Cells (MSCs) were obtained from NIH, or from the discarded hips of patients undergoing joint replacement surgery. SM differentiation was induced by treating monolayer cultures with 1 mM thromboxane-A2 [DP1] in the presence of 0.25% serum. C differentiation was induced by seeding MSCs in aggregate cultures in the presence of dexamethasone and TGF-b1 (10 ng/ml). O differentiation was induced by treatment of monolayer cultures with dexamethasone, ascorbate and beta-glycerolphosphate. Profiling of miRNAs by microarray (Agilent) or QPCR (SA Biosciences) revealed differential regulation of miR-7 and miR-130b, among 376 probes. Following SM and C differentiation, miR-7 expression was down-regulated up to 6.9-fold and 3-fold respectively. Conversely, during O differentiation, its expression was induced approximately 7-fold. Analysis of theoretical mRNA targets using TargetScan online software (www.targetscan.org) identified conserved sites in several genes associated with chondrocyte and myoblast lineages. Putative chondrogenic targets were found to include COL2A1, IGFR1, and GDF5, while potential smooth muscle modulators included EGFR1, PIK3CD, IRS1/IRS2, KLF4, CNN3 and IGF1R. Following a similar trend to miR-7, miR-130b was down-regulated up to 3.2-fold and 3.1-fold in C and SM differentiation respectively, while O differentiation induced its expression 2-fold. TargetScan analysis identified putative chondrogenic targets, TGF-BRII, Sox5, BMP-2 and IGF1; Potential smooth muscle regulators included ESR1, TGF-BRII, MBLN1, TGFBR1 and IGF2BP1. Together these observations suggest that miR-7 and miR-130b act to negatively regulate myogenic and chondrogenic cell fates via regulation of lineage specific genes. Conclusion: Our findings suggest that miR-7 and miR-130b, via the targeting of lineage specific molecules, regulate cell fate in adult human MSCs by inhibiting smooth muscle and chondrocyte differentiation, thereby promoting 'default' differentiation into the osteoblast lineage. [DP1]0.25% FBS 24 hours prior to addition of 1.0mM of the TxA2 chemical analog U46619
— id: 130943, year: 2010, vol: 62, page: 1490, stat: Journal Article,

MIR-7 AND MIR-130B ARE DIFFERENTIALLY REGULATED DURING MESENCHYMAL STEM CELL COMMITMENT
Palmer, G.; Danielson, L.; Attur, M.; Abramson, S. B.; Hernando, E.
2010 OCT ;18(12):S39-S39, Osteoarthritis & cartilage
— id: 120554, year: 2010, vol: 18, page: S39, stat: Journal Article,

F-spondin regulates chondrocyte terminal differentiation and endochondral bone formation
Palmer, Glyn D; Piton, Alejandro H; Thant, Lwin Mon; Oliveira, Serafim M; D'Angelo, Marina; Attur, Mukundan G; Abramson, Steven B; Teixeira, Cristina C
2010 Oct;28(10):1323-1329, Journal of orthopaedic research
This study examines the role of F-spondin, an extracellular matrix protein of osteoarthritic cartilage, during chondrocyte maturation in embryonic growth plate cartilage. In chick tibia, F-spondin expression localized to the hypertrophic and calcified zones of the growth plate. Functional studies using tibial organ cultures indicated that F-spondin inhibited ( approximately 35%, p = 0.02), and antibodies to F-spondin increased ( approximately 30%, p < 0.1) longitudinal limb growth relative to untreated controls. In cell cultures, induction of chondrocyte maturation, by retinoic acid (RA) or transforming growth factor (TGF)-beta treatment led to a significant upregulation of F-spondin (p < 0.05). F-spondin transfection increased mineral deposition, alkaline phosphatase (AP) and matrix metalloproteinase (MMP)-13 mRNA levels (p < 0.05), and AP activity following RA stimulation, compared to mock transfected controls. Using AP as a differentiation marker we then investigated the mechanism of F-spondin promaturation effects. Blocking endogenous F-spondin via its thrombospondin (TSR) domain inhibited RA induced AP activity 40% compared to controls (p < 0.05). The stimulatory effect of F-spondin on AP expression was also inhibited following depletion of TGF-beta from culture supernatants. Our findings indicate that F-spondin is expressed in embryonic cartilage, where it has the capacity to enhance chondrocyte terminal differentiation and mineralization via interactions in its TSR domain and TGF-beta dependent pathways. Published by Wiley Periodicals, Inc. J Orthop Res 28:1323-1329, 2010
— id: 112436, year: 2010, vol: 28, page: 1323, stat: Journal Article,

The use of musculoskeletal ultrasound by rheumatologists in the United States
Samuels, Jonathan; Abramson, Steven B; Kaeley, Gurjit S
2010 ;68(4):292-298, Bulletin of the NYU Hospital for Joint Diseases
Fewer United States rheumatologists perform or utilize musculoskeletal ultrasound (MSUS) than those in Europe, though this disparity is narrowing. To document perceptions and use of MSUS in the U.S. rheumatology community, we sent an anonymous electronic survey to American College of Rheumatology (ACR) physicians and tailored versions to fellows and program directors. A separately-conducted survey was sent to a smaller group of rheumatologists already utilizing MSUS. Acknowledging survey bias, we found that 20% of rheumatologists and fellows who responded are utilizing MSUS, and those using it primarily do so for diagnosis and injection guidance. Many rheumatologists across the country think that ultrasound should become a standard tool in rheumatology training, practice, and research. Despite an inherent survey bias likely overstating interest in MSUS, this study is valuable as the first to document this trend among U.S. rheumatologists
— id: 117346, year: 2010, vol: 68, page: 292, stat: Journal Article,

Protein kinase C-theta mediates negative feedback on regulatory T cell function
Zanin-Zhorov, Alexandra; Ding, Yi; Kumari, Sudha; Attur, Mukundan; Hippen, Keli L; Brown, Maryanne; Blazar, Bruce R; Abramson, Steven B; Lafaille, Juan J; Dustin, Michael L
2010 Apr 16;328(5976):372-376, Science
T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Protein kinase C-theta (PKC-theta) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-theta was sequestered away from the Treg immunological synapse. Furthermore, PKC-theta blockade enhanced Treg function, demonstrating PKC-theta inhibits Treg-mediated suppression. Inhibition of PKC-theta protected Treg from inactivation by TNF-alpha, restored activity of defective Treg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-theta-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases
— id: 109214, year: 2010, vol: 328, page: 372, stat: Journal Article,

Developments in the scientific understanding of osteoarthritis
Abramson, Steven B; Attur, Mukundan
2009 ;11(3):227-227, Arthritis research & therapy
Osteoarthritis is often a progressive and disabling disease, which occurs in the setting of a variety of risk factors--such as advancing age, obesity, and trauma--that conspire to incite a cascade of pathophysiologic events within joint tissues. An important emerging theme in osteoarthritis is a broadening of focus from a disease of cartilage to one of the 'whole joint'. The synovium, bone, and cartilage are each involved in pathologic processes that lead to progressive joint degeneration. Additional themes that have emerged over the past decade are novel mechanisms of cartilage degradation and repair, the relationship between biomechanics and biochemical pathways, the importance of inflammation, and the role played by genetics. In this review we summarize current scientific understanding of osteoarthritis and examine the pathobiologic mechanisms that contribute to progressive disease
— id: 101117, year: 2009, vol: 11, page: 227, stat: Journal Article,

Variable X-ray beam angulation improves quality of medial tibial plateau alignment in fixed-flexion knee radiographs of osteoarthritis (OA) patients
Alapati K.; Belitskaya-Levy I.; Schweitzer M.; Shabshin N.; Samuels J.; Abramson S.B.; Krasnokutsky S.
2009 ;60:1180-1180, Arthritis & rheumatism
Purpose: To assess whether variability in caudal X-ray beam angulation (CBA) improves alignment of the medial tibial plateau (MTP) versus a fixed 10degree CBA, using non-fluoroscopic fixed-flexion knee radiographs. Methods: 133 subjects with knee OA underwent fixed-flexion AP X-ray examinations as part of a longitudinal study. We performed a cross sectional substudy in which 90 subjects were imaged with a 10degree CBA (Method 1) and 43 subjects were imaged using different CBAs (choosing from 5degree, 10degree, 15degree) determined by a trained radiology technician, depending on MTP alignment assessed in real time (Method 2). After reading a blinded training set of radiographs, an experienced radiologist, who was blinded to patients and method used, read the x-rays for MTP alignment quality using a 1-5 scale (1, 2=good, 3=acceptable, 4= poor, 5= unacceptable), and for Kellgren-Lawrence (KL) grade. Results: Method 1 subjects (10degree angulation): MTP alignment quality was scored as good or acceptable 62% and 69% of the time for the right and left knees, respectively. Method 2 subjects (variable angulation): Variable angulation resulted in good or acceptable MTP alignment quality on at least one x-ray 86% and 88% of the time for right and left knees, respectively. When CBA was changed, MTP alignment quality changed 84% of the time for the right knee and 77% of the time for the left knee in subjects who had at least 2 radiographs (n=43). The KL grade changed 28% and 46% of the time in the right and left knees, respectively, when MTP alignment quality changed in the same knee. The KL grade changed 38% and 36% of the time in the right and left knees, respectively, when there was no change in MTP alignment quality but there was a change in CBA. A change in CBA resulted in MTP alignment quality change in bilateral knees 66% of the time, of which this change was in the same direction (improved vs worsened) 86% of the time. Using a CBA of 10degree resulted in improved (over other angulations) MTP alignment quality 53% and 50% of the time for the right and left knees, respectively. Using a CBA of 10degree resulted in worsened MTP alignment 33% and 22% of the time for right and left knees, respectively. Conclusion: While fixed 10degree CBA in fixed-flexion radiographs results in acceptable or good MTP alignment quality the majority of the time, variable CBA improves this frequency in knee OA subjects. Changes in CBA often change the MTP alignment quality, usually in the same direction in both knees, and sometimes change the KL grade. More studies are needed to determine the optimal CBA for non-fluoroscopic fixed-flexion protocols and all radiographic knee OA studies should report the specific techniques used, including CBA
— id: 130350, year: 2009, vol: 60, page: 1180, stat: Journal Article,

F-spondin, a neuroregulatory protein, is up-regulated in osteoarthritis and regulates cartilage metabolism via TGF-beta activation
Attur, Mukundan G; Palmer, Glyn D; Al-Mussawir, Hayf E; Dave, Mandar; Teixeira, Cristina C; Rifkin, Daniel B; Appleton, C Thomas G; Beier, Frank; Abramson, Steven B
2009 Jan;23(1):79-89, FASEB journal
In osteoarthritis (OA) articular chondrocytes undergo phenotypic changes culminating in the progressive loss of cartilage from the joint surface. The molecular mechanisms underlying these changes are poorly understood. Here we report enhanced (approximately 7-fold) expression of F-spondin, a neuronal extracellular matrix glycoprotein, in human OA cartilage (P<0.005). OA-specific up-regulation of F-spondin was also demonstrated in rat knee cartilage following surgical menisectomy. F-spondin treatment of OA cartilage explants caused a 2-fold increase in levels of the active form of TGF-beta1 (P<0.01) and a 10-fold induction of PGE2 (P<0.005) in culture supernatants. PGE2 induction was found to be dependent on TGF-beta and the thrombospondin domain of the F-spondin molecule. F-spondin addition to cartilage explant cultures also caused a 4-fold increase in collagen degradation (P<0.05) and a modest reduction in proteoglycan synthesis (approximately 20%; P<0.05), which were both TGF-beta and PGE2 dependent. F-spondin treatment also led to increased secretion and activation of MMP-13 (P<0.05). Together these studies identify F-spondin as a novel protein in OA cartilage, where it may act in situ at lesional areas to activate latent TGF-beta and induce cartilage degradation via pathways that involve production of PGE2
— id: 92153, year: 2009, vol: 23, page: 79, stat: Journal Article,

Reply
Desai, Sonali P; Solomon, Daniel H; Abramson, Steven B; Buckley, Lenore; Crofford, Leslie J; Cush, John J; Lovell, Daniel J; Saag, Kenneth G
2009 Feb 15;61(2):285-286, Arthritis & rheumatism
— id: 93875, year: 2009, vol: 61, page: 285, stat: Journal Article,

Pathogenesis of osteoarthritis
Di Cesare PE; Samuels J; Abramson SB
Kelley's textbook of rheumatology Philadelphia, PA : Saunders/Elsevier, 2009,
— id: 4812, year: 2009, vol: , page: ?, stat: Chapter,

The COX-2 inhibitor market withdrawals and prescribing patterns by rheumatologists in patients with gastrointestinal and cardiovascular risk
Greenberg, J D; Fisher, M C; Kremer, J; Chang, H; Rosenstein, E D; Kishimoto, M; Lee, S; Yazici, Y; Kavanaugh, A; Abramson, S B
2009 May-Jun;27(3):395-401, Clinical & experimental rheumatology
OBJECTIVE:To examine effects of the COX-2 inhibitor market withdrawals on NSAID utilization among patients at increased risk of gastrointestinal (GI) and cardiovascular (CV) toxicities. METHODS:A prospective cohort study was conducted using patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) Registry. The study population included rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients prescribed NSAIDs by rheumatologists from 1/1/2003 to 12/31/2005. Three cohorts were defined based on calendar year. The primary outcome assessed whether or not an NSAID gastroprotective strategy was prescribed. Secondary outcomes included rates of COX-2 inhibitor utilization and gastroprotective co-therapy utilization, stratified by the presence of cardiac and GI risk factors. RESULTS:NSAID gastroprotection utilization decreased from 65.1% in 2003 to 47.7% (p<0.001) in 2005. COX-2 inhibitor use decreased from 55.1% to 29.2% (p<0.001), whereas nonselective NSAIDs (nsNSAIDs) use increased from 50.2% to 73.9% (p=<0.01). Among patients with two or more risk factors for NSAID related GI bleeding, gastroprotection decreased from 74.4% in 2003 to 60.9% (p<0.01). For patients with two or more CV risk factors from 2003 to 2005, COX-2 inhibitor utilization decreased significantly, whereas nsNSAID utilization increased significantly.CONCLUSIONS:The COX-2 inhibitor withdrawals resulted in a rapid decline in NSAID gastroprotection prescribed by participating U.S. rheumatologists despite the availability of other gastroprotective options. Channeling toward nsNSAID use was widespread, including among patients at increased CV risk. Longer term follow-up is required to determine the clinical significance of these changes in NSAID prescribing, particularly for NSAID-related GI and CV-related toxicities
— id: 100676, year: 2009, vol: 27, page: 395, stat: Journal Article,

PGE2 differentially regulates expression of chondrocyte markers during chondrogenesis of human bone marrow derived MSCs
Palmer G.; Al-Mussawir H.; Attur M.; Abramson S.B.
2009 ;60:1309-1309, Arthritis & rheumatism
Purpose: A necessary step for the successful regeneration of cartilage lesions using stem cell-based therapies is the controlled differentiation of progenitor cells into a stable articular chondrocyte phenotype. Prostaglandin E2 (PGE2) has been shown to have an important role in both fracture healing and chondrocyte maturation during endochondral bone formation. This study investigates the effects of PGE2 on chondrocyte differentiation of adult, human mesenchymal stem cells (MSCs). Methods: Bone marrow-derived MSCs were isolated from the discarded tissues of patients undergoing hip replacement surgery. Chondrogenesis was induced by seeding MSCs in serum-free aggregate cultures supplemented with dexamethasone (10-7 M) and TGF-b1 (10 ng/ml). At various time points, RNA was extracted for gene expression analysis by semi-quantitative RT-PCR. PGE2 levels were determined by RIA. Results: Gene expression analysis of 4 patient samples revealed an order-of-magnitude increase in chondrogenic markers, col II, col X, MMP-13 and AP. In each case, expression was elevated by day 7 and persisted for the duration of the assay (21 d). To determine the effects of PGE2, aggregates were cocultured in the presence of exogenous PGE2 (10-6 M) and expression of chondrocyte markers determined after 14 d. PGE2 increased expression of col II (65%) and decreased expression of hypertrophic markers, col X (20%), MMP-13 (32 %) and AP (55%). Consistent with these observations, histological examination of treated aggregates after 21 d revealed fewer enlarged, hypertrophic chondrocytes following PGE2 treatment compared to control cultures. In aggregate cultures, PGE2 secretion was inhibited by the selective cox-2 inhibitor, celecoxib, approximately 50%, while cox-1 inhibition by treatment with SC-560 had no effect. Accordingly, celecoxib treatment of chondrogenic aggregates for 7 d decreased expression of sox-9 (80%) and col II (97%) compared non-treated controls. Cox-2 inhibition also increased expression of hypertrophic markers. Celecoxib treatment increased col X (95%) and AP (150%), but had no effect on MMP-13 levels. After 21 d, aggregates treated with celecoxib exhibited greater numbers of hypertrophic chondrocytes, and a modest decrease in proteoglycan staining. These findings suggest that cox-2 derived PGE2 has the capacity modulate chondrocyte differentiation of MSCs via differential regulation of chondrocyte marker genes. Conclusion: PGE2, via upregulation of type II collagen, or inhibition of chondrocyte hypertrophy, has the capacity to regulate chondrocyte phenotype during in vitro chondrogenesis of hMSCs. Further characterization should uncover novel PGE2 pathways that can be exploited to modulate chondrocyte phenotype for tissue regeneration therapies
— id: 130337, year: 2009, vol: 60, page: 1309, stat: Journal Article,

Nitric oxide in inflammation and pain associated with osteoarthritis
Abramson, Steven B
2008 ;10 Suppl 2:S2-S2, Arthritis research & therapy
Osteoarthritis (OA) is a degenerative disease involving chondrocytes, cartilage and other joint tissues, and has a number of underlying causes, including both biochemical and mechanical factors. Although proinflammatory factors including nitric oxide (NO) are associated with OA, there is recent evidence suggesting that NO and its redox derivatives may also play protective roles in the joint. However, the mechanisms that underlie the development and progression of OA are not completely understood. Experiments have demonstrated that NO plays a catabolic role in the development of OA and mediates the inflammatory response, is involved in the degradation of matrix metalloproteinases, inhibits the synthesis of both collagen and proteoglycans, and helps to mediate apoptosis. However, there is also evidence that in cultured chondrocytes the addition of exogenous NO may inhibit proinflammatory activation by preventing the nuclear localization of the transcription factor nuclear factor-kappaB, whereas the presence of peroxynitrite--a redox derivative of NO--appears to enhance the inflammatory response by sustaining the nuclear localization of nuclear factor-kappaB. In addition, under some conditions exogenous NO can stimulate collagen synthesis in cultured rat fibroblasts and human tendon cells. The protective roles of NO in multiple cell types, along with the opposing activities in cultured chondrocytes, suggest that NO may play additional protective roles in chondrocyte function. NO and its derivatives have a similarly complicated involvement in nociception and pain, which may contribute to the functional disability of OA. Further research may help to elucidate a potential role for NO-donating agents in the management of OA
— id: 93876, year: 2008, vol: 10 Suppl 2, page: S2, stat: Journal Article,

Osteoarthritis and nitric oxide
Abramson, Steven B
2008 ;16 Suppl 2:S15-S20, Osteoarthritis & cartilage
Osteoarthritis (OA) is caused by both biochemical and mechanical factors. While the mechanisms that underlie the disease are not completely understood, investigators have characterized a number of catabolic and protective factors that have a role in the disease process. Nitric oxide (NO) and its redox derivatives appear to have a number of different functions in both normal and pathophysiological joint conditions. Until recently, NO was considered a catabolic factor that was responsible for perpetuating the OA disease process by mediating the expression of proinflammatory cytokines, inhibiting the synthesis of collagen and proteoglycans and inducing apoptosis. However, recent studies suggest that NO and its redox derivatives may also have protective effects on cartilage. This review will summarize the literature on the effects of NO on cartilage and chondrocytes as well as discuss some evidence that suggests potential protective effects of NO and/or its derivatives on other cell types. More research is needed to elucidate the role of NO and its derivatives on both normal and osteoarthritis cartilage
— id: 93877, year: 2008, vol: 16 Suppl 2, page: S15, stat: Journal Article,

Are NSAIDs and selective cyclo-oxygenase 2 inhibitors associated with increased risk of myocardial infarction?
Abramson, Steven B; Greenberg, Jeffrey D
2008 Apr;4(4):182-183, Nature clinical practice. Rheumatology
Scott et al. conducted a systematic review to evaluate the risk of myocardial infarction (MI) associated with cyclo-oxygenase-2 (COX2) inhibitors and traditional NSAIDs. The review found a small increased risk of MI associated with COX2 inhibitors, particularly rofecoxib. Although a fixed-effects model of 14 case-control studies suggested a slightly increased risk of MI with NSAID use, a random-effects model of the same data and analysis of 6 cohort studies found no such link. An increased risk of MI was found in four RCTs of NSAID use in colonic adenoma. In an analysis of 14 RCTs that compared COX2 inhibitors with traditional NSAIDs in patients with arthritis, the odds ratio for MI with COX2 inhibitors was 1.6 (95% CI 1.1-2.4), although most of this risk was accounted for by rofecoxib. COX2 inhibitors were, however, associated with a reduced risk of serious gastrointestinal events. An analysis of previous systematic reviews showed increased risks of MI associated with rofecoxib and celecoxib
— id: 79297, year: 2008, vol: 4, page: 182, stat: Journal Article,

F-spondin, a neuroregulatory protein, is upregulated in human and surgically-induced osteoarthritis: Evidence for regulation of cartilage metabolism via latent tgf-b1 activation
Attur, M; Palmer, G; Al-Mussawir, HE; Rifkin, DB; Teixeira, CC; Appleton, CTG; Beier, F; Abramson, SB
2008 SEP ;58(9):S895-S895, Arthritis & rheumatism
— id: 88578, year: 2008, vol: 58, page: S895, stat: Journal Article,

Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: evidence for signaling via the EP4 receptor
Attur, Mukundan; Al-Mussawir, Hayf E; Patel, Jyoti; Kitay, Alison; Dave, Mandar; Palmer, Glyn; Pillinger, Michael H; Abramson, Steven B
2008 Oct 1;181(7):5082-5088, Journal of immunology
Elevated levels of PGE(2) have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE(2) in cartilage metabolism have not previously been studied in detail. To do so, we cultured cartilage explants, obtained from patients undergoing knee replacement surgery for advanced OA, with PGE(2) (0.1-10 muM). PGE(2) inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p < 0.01)). PGE(2) also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE(2) inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE(2) with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE(2) and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE(2), while celecoxib enhanced both spontaneous and IL-1-induced expression. IL-1 induction of aggrecanase 5 (ADAMTS-5), but not ADAMTS-4, was also enhanced by PGE(2) (10 muM) and reversed by celecoxib (2 muM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE(2) receptor EP4 was up-regulated in OA cartilage. Moreover, blocking the EP4 receptor (EP4 antagonist, AH23848) mimicked celecoxib by inhibiting MMP-13, ADAMST-5 expression, and proteoglycan degradation. These results suggest that PGE(2) inhibits proteoglycan synthesis and stimulates matrix degradation in OA chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for OA disease modification
— id: 91441, year: 2008, vol: 181, page: 5082, stat: Journal Article,

The progeria-associated protein lamin a is upregulated in osteoarthritis: Evidence for premature chondrocyte senescence
Ben-Artzi, A; Attur, M; Dave, M; Al-Mussawir, H; Palmer, G; Abramson, SB
2008 SEP ;58(9):S874-S874, Arthritis & rheumatism
— id: 88576, year: 2008, vol: 58, page: S874, stat: Journal Article,

The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production
Dave, Mandar; Attur, Mukundan; Palmer, Glyn; Al-Mussawir, Hayf E; Kennish, Lauren; Patel, Jyoti; Abramson, Steven B
2008 Sep;58(9):2786-2797, Arthritis & rheumatism
OBJECTIVE: To determine the effects of the antioxidant resveratrol on the functions of human chondrocytes in osteoarthritis (OA). METHODS: Chondrocytes and cartilage explants were isolated from OA patients undergoing knee replacement surgery. Effects of resveratrol in the presence or absence of interleukin-1beta (IL-1beta) stimulation were assessed by measurement of prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) synthesis, cyclooxygenase (COX) activity, matrix metalloproteinase (MMP) expression, and proteoglycan production. To explore the mechanisms of action of resveratrol, its effects on mitochondrial function and apoptosis were examined by assessing mitochondrial membrane potential, ATP levels, cytochrome c release, and annexin V staining. RESULTS: Resveratrol inhibited both spontaneous and IL-1beta-induced PGE(2) production by >20% (P < 0.05) and by 80% (P < 0.001), respectively; similarly, LTB(4) production was reduced by >50% (P < 0.05). The production of PGE(2) was inhibited via a 70-90% suppression of COX-2 expression and enzyme activity (P < 0.05). Resveratrol also promoted anabolic effects in OA explant cultures, by elevating proteoglycan synthesis and decreasing production of MMPs 1, 3, and 13. Pretreatment of OA chondrocytes with resveratrol blocked mitochondrial membrane depolarization, loss of mitochondrial biomass, and IL-1beta-induced ATP depletion. Similarly, IL-1beta-mediated induction of the apoptotic markers cytochrome c and annexin V was also inhibited by resveratrol. Exogenous addition of PGE(2) abolished the protective effects of resveratrol on mitochondrial membrane integrity, ATP levels, expression of apoptotic markers, and DNA fragmentation. CONCLUSION: Resveratrol protects against IL-1beta-induced catabolic effects and prevents chondrocyte apoptosis via its inhibition of mitochondrial membrane depolarization and ATP depletion. These beneficial effects of resveratrol are due, in part, to its capacity to inhibit COX-2-derived PGE(2) synthesis. Resveratrol may therefore protect against oxidant injury and apoptosis, which are main features of progressive OA
— id: 93878, year: 2008, vol: 58, page: 2786, stat: Journal Article,

Recommendations for use of selective and nonselective nonsteroidal antiinflammatory drugs: An American College of Rheumatology white paper
Desai, SP; Solomon, DH; Abramson, SB; Buckley, L; Crofford, LJ; Cush, JJ; Lovell, DJ; Saag, KG
2008 AUG 15 ;59(8):1058-1073, Arthritis & rheumatism
— id: 86789, year: 2008, vol: 59, page: 1058, stat: Journal Article,

Comparison of an in vitro tuberculosis interferon-gamma assay with delayed-type hypersensitivity testing for detection of latent Mycobacterium tuberculosis: a pilot study in rheumatoid arthritis
Greenberg, Jeffrey D; Reddy, Soumya M; Schloss, Shari G; Kurucz, Oliver S; Bartlett, Susan J; Abramson, Steven B; Bingham, Clifton O 3rd
2008 May;35(5):770-775, Journal of rheumatology
OBJECTIVE: Recommendations for screening for latent Mycobacterium tuberculosis (MTB) infection have been proposed but are not well studied in patients with rheumatoid arthritis (RA). We estimated the prevalence of anergy in RA and evaluated different methods to detect MTB exposure. METHODS: This was a prospective pilot study of 61 patients with RA and 42 healthy controls. Tuberculin skin test (TST) antigen, Candida, and tetanus toxoid were injected intradermally using the Mantoux method. Subjects negative for TST returned for a second-step test. Whole-blood interferon-gamma (IFN-gamma) release to mycobacterial antigens was evaluated with the first-generation QuantiFeron test (QIFN). RESULTS: Cutaneous anergy in patients with RA was not significantly different than healthy controls (p = 0.154), and was not affected by disease modifying antirheumatic drugs (p = 0.270). In patients with RA, 16.4% had positive TST with 10 mm cutoff vs 11.9% of controls. Using a 5 mm cutoff, 21.3% of patients with RA were positive, and this increased to 29.5% with a second-step TST. QIFN detected MTB exposure in 18% of patients with RA and 19% of controls (p = 0.897). However, indeterminate QIFN tests were higher in RA patients (11.5%) compared to controls (2.4%), demonstrating a lower sensitivity to detect latent MTB. CONCLUSION: Cutaneous anergy may be less common than previously reported in patients with RA. patients. However, the single-step TST and 10 mm cutoff may fail to detect all cases of latent exposure in RA patients. High rates of indeterminate results in QIFN testing suggest that QIFN should not be employed as an alternative, single-screening test in patients with RA. These pilot results require confirmation in larger studies to determine the optimal screening strategy in RA
— id: 81056, year: 2008, vol: 35, page: 770, stat: Journal Article,

Current concepts in the pathogenesis of osteoarthritis
Krasnokutsky, S; Attur, M; Palmer, G; Samuels, J; Abramson, S B
2008 ;16 Suppl 3:S1-S3, Osteoarthritis & cartilage
— id: 86561, year: 2008, vol: 16 Suppl 3, page: S1, stat: Journal Article,

Synovial but not cartilage volumes on MRI predict radiographic severity of knee Osteoarthritis (OA)
Krasnokutsky, S; Samuels, J; Attur, M; Regatte, R; Belitskaya-Levy, I; Babb, J; Rosenthal, P; Al-Mussawir, H; Abellana, V; Greenberg, J; Schweitzer, M; Abramson, SB
2008 SEP ;58(9):S889-S890, Arthritis & rheumatism
— id: 88577, year: 2008, vol: 58, page: S889, stat: Journal Article,

Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin
Luan, Y; Kong, L; Howell, D R; Ilalov, K; Fajardo, M; Bai, X-H; Di Cesare, P E; Goldring, M B; Abramson, S B; Liu, C-J
2008 ;16(11):1413-1420, Osteoarthritis & cartilage
OBJECTIVE: As we previously reported, ADAMTS-7 and ADAMTS-12, two members of ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family, degrade cartilage oligomeric matrix protein (COMP) in vitro and are significantly induced in the cartilage and synovium of arthritic patients [Liu CJ, Kong W, Ilalov K, Yu S, Xu K, Prazak L, et al. ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein. FASEB J 2006;20(7):988-90; Liu CJ, Kong W, Xu K, Luan Y, Ilalov K, Sehgal B, et al. ADAMTS-12 associates with and degrades cartilage oligomeric matrix protein. J Biol Chem 2006;281(23):15800-8]. The purpose of this study was to determine (1) whether cleavage activity of ADAMTS-7 and ADAMTS-12 of COMP are associated with COMP degradation in osteoarthritis (OA); (2) whether alpha-2-macroglobulin (a(2)M) is a novel substrate for ADAMTS-7 and ADAMTS-12; and (3) whether a(2)M inhibits ADAMTS-7 or ADAMTS-12 cleavage of COMP. METHODS: An in vitro digestion assay was used to examine the degradation of COMP by ADAMTS-7 and ADAMTS-12 in the cartilage of OA patients; in cartilage explants incubated with tumor necrosis factor-alpha (TNF-alpha) or interleukin-1-beta (IL-1beta) with or without blocking antibodies; and in human chondrocytes treated with specific small interfering RNA (siRNA) to knockdown ADAMTS-7 or/and ADAMTS-12. Digestion of a(2)M by ADAMTS-7 and ADAMTS-12 in vitro and the inhibition of ADAMTS-7 or ADAMTS-12-mediated digestion of COMP by a(2)M were also analyzed. RESULTS: The molecular mass of the COMP fragments produced by either ADAMTS-7 or ADAMTS-12 were similar to those observed in OA patients. Specific blocking antibodies against ADAMTS-7 and ADAMTS-12 dramatically inhibited TNF-alpha- or IL-1beta-induced COMP degradation in the cultured cartilage explants. The suppression of ADAMTS-7 or ADAMTS-12 expression by siRNA silencing in the human chondrocytes also prevented TNF-alpha- or IL-1beta-induced COMP degradation. Both ADAMTS-7 and ADAMTS-12 were able to cleave a(2)M, giving rise to 180- and 105-kDa cleavage products, respectively. Furthermore, a(2)M inhibited both ADAMTS-7- and ADAMTS-12-mediated COMP degradation in a concentration (or dose)-dependent manner. CONCLUSION: Our observations demonstrate the importance of COMP degradation by ADAMTS-7 and ADAMTS-12 in vivo. Furthermore, a(2)M is a novel substrate for ADAMTS-7 and ADAMTS-12. More significantly, a(2)M represents the first endogenous inhibitor of ADAMTS-7 and ADAMTS-12
— id: 80346, year: 2008, vol: 16, page: 1413, stat: Journal Article,

The use of musculoskeletal ultrasound: Rheumatologists in the US
Samuels, J; Abramson, SB
2008 SEP ;58(9):S470-S471, Arthritis & rheumatism
— id: 88551, year: 2008, vol: 58, page: S470, stat: Journal Article,

Osteoarthritis: a tale of three tissues
Samuels, Jonathan; Krasnokutsky, Svetlana; Abramson, Steven B
2008 ;66(3):244-250, Bulletin of the NYU Hospital for Joint Diseases
While research in osteoarthritis has focused on the events that lead to the destruction of articular cartilage, recent evidence suggests that two other components of the joints-bone and synovium-also play key roles in pathogenesis. All three tissues undergo alterations in concert at the structural levels in response to mechanical stress and joint malalignment. Advanced imaging studies such as MRI support this interdependence, revealing the classical changes of joint space narrowing and cartilage degeneration as well as the more recently appreciated bone marrow lesions and synovitis that may correlate with clinical symptoms. Molecular evidence also points to a coordinated release of cytokines and other inflammatory mediators from each of the three tissues together in progression of disease, although we are still in search of biochemical signatures that will predict the subset of patients who progress more quickly-and who will provide key clues to successful molecular targets in future therapies. At this time we lack definitive evidence pointing to which, if any, of the three tissues should serve as the main target for disease modification or structure protection, although most efforts have focused on cartilage. Thus current therapies focus on controlling symptoms, while research efforts search for reliable imaging and molecular biomarkers to help guide future trials of potential disease-modifying agents
— id: 91488, year: 2008, vol: 66, page: 244, stat: Journal Article,

Annexin-1 mediates TNF-alpha-stimulated matrix metalloproteinase secretion from rheumatoid arthritis synovial fibroblasts
Tagoe, Clement E; Marjanovic, Nada; Park, Jean Y; Chan, Edwin S; Abeles, Aryeh M; Attur, Mukundan; Abramson, Steven B; Pillinger, Michael H
2008 Aug 15;181(4):2813-2820, Journal of immunology
Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-alpha. TNF-alpha induced a biphasic secretion of annexin-1 from RA SF. Early (< or = 60 min), cycloheximide-independent secretion from preformed intracellular pools was followed by late (24 h) cycloheximide-inhibitable secretion requiring new protein synthesis. Exogenous annexin-1 N-terminal peptide Ac2-26 stimulated MMP-1 secretion in a dose- (EC(50) approximately 25 microM) and time- (8-24 h) dependent manner; full-length annexin-1 had a similar effect. Down-regulation of annexin-1 using small interfering RNA resulted in decreased secretion of both annexin-1 and MMP-1, confirming that annexin-1 mediates TNF-alpha-stimulated MMP-1 secretion. Erk, Jnk, and NF-kappaB have been implicated in MMP-1 secretion. Erk, Jnk, and NF-kappaB inhibitors had no effect on annexin-1 secretion stimulated by TNF-alpha but inhibited MMP-1 secretion in response to Ac2-26, indicating that these molecules signal downstream of annexin-1. Annexin-1 stimulation of MMP-1 secretion was inhibited by both a formyl peptide receptor antagonist and pertussis toxin, suggesting that secreted annexin-1 acts via formyl peptide family receptors, most likely FPLR-1. In contrast to its commonly appreciated anti-inflammatory roles, our data indicate that annexin-1 is secreted by RA SF in response to TNF-alpha and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-kappaB, and stimulate MMP-1 secretion
— id: 87806, year: 2008, vol: 181, page: 2813, stat: Journal Article,

Protein isoprenylation regulates secretion of matrix metalloproteinase 1 from rheumatoid synovial fibroblasts: effects of statins and farnesyl and geranylgeranyl transferase inhibitors
Abeles, Aryeh M; Marjanovic, Nada; Park, Jean; Attur, Mukundan; Chan, Edwin S; Al-Mussawir, Hayf E; Dave, Mandar; Fisher, Mark C; Stuchin, Steven A; Abramson, Steven B; Pillinger, Michael H
2007 Sep;56(9):2840-2853, Arthritis & rheumatism
OBJECTIVE: To determine whether protein prenylation (farnesyl/geranylgeranylation) regulates matrix metalloproteinase (MMP) secretion from rheumatoid arthritis (RA) synovial fibroblasts (RASFs), and whether MMP-1 secretion can be regulated by statins or prenyltransferase inhibitors via effects mediated by ERK, JNK, and NF-kappaB. METHODS: RASFs obtained from patients during elective knee replacement surgery were assessed by immunoblotting and/or enzyme-linked immunosorbent assay for secretion of MMP-1 and MMP-13 in the presence of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), statins, the farnesyl transferase (FT) inhibitor FTI-276 and geranylgeranyl transferase inhibitor GGTI-298, and prenyl substrates (farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate [GGPP]). Activities of JNK and ERK were determined by phosphoimmunoblotting, and NF-kappaB activation was determined by nuclear translocation of the p65 component. RESULTS: FTI-276, but not statins, inhibited RASF secretion of MMP-1, but not MMP-13, following induction with TNFalpha (P = 0.0007) or IL-1beta (P = 0.006). Loading RASFs with FPP to promote farnesylation enhanced MMP-1 secretion. FTI-276 inhibited activation of JNK (P < 0.05) and NF-kappaB (P = 0.02), but not ERK. In contrast, GGTI-298 enhanced, while GGPP inhibited, MMP-1 secretion. FTI-276 and GGTI-298 together had no effect on MMP-1 secretion. Stimulation of RASFs with TNFalpha or IL-1beta led to increased expression and activity of FT. CONCLUSION: Protein farnesylation is required for expression and secretion of MMP-1 from RASFs, via effects on JNK and NF-kappaB. The ability of cytokines to stimulate the expression and activity of FT suggests that FT may be increased in the rheumatoid joint. In contrast, geranylgeranylation down-regulates MMP-1 expression. Statins simultaneously inhibit farnesylation and geranylgeranylation, and in consequence do not inhibit MMP-1 secretion. The ability of FTI-276 to inhibit MMP-1 secretion suggests a potential therapeutic strategy in RA
— id: 93879, year: 2007, vol: 56, page: 2840, stat: Journal Article,

Antiresorptive agents and osteoarthritis: more than a bone to pick?
Abramson, Steven B; Honig, Stephen
2007 Aug;56(8):2469-2473, Arthritis & rheumatism
— id: 73873, year: 2007, vol: 56, page: 2469, stat: Journal Article,

Mechanisms of acute inflammation and vascular injury in systemic lupus erythematosus
Belmont, Howard Michael; Abramson, Steven B
Dubois' lupus erythematosus Philadelphia : Lippincott Williams & Wilkins, 2007,
— id: 4871, year: 2007, vol: , page: ?, stat: Chapter,

A subclass of peripheral blood T cells demonstrates increased CD86 expression in patients with rheumatoid arthritis (RA
Ben-Artzi, A; Tse, DB; Attur, M; Greenberg, JD; Nasir, A; Pillinger, MH; Abramson, SB
2007 DEC ;56(12):4305-4306, Arthritis & rheumatism
— id: 87214, year: 2007, vol: 56, page: 4305, stat: Journal Article,

Cardiovascular outcomes in high-risk patients with osteoarthritis treated with Ibuprofen, Naproxen, or Lumiracoxib
Farkouh, M E; Greenberg, J D; Jeger, R V; Ramanathan, K; Verheugt, F W A; Chesebro, J H; Kirshner, H; Hochman, J S; Lay, C L; Ruland, S; Mellein, B; Matchaba, P T; Fuster, V; Abramson, S B
2007 Jun;66(6):764-770, Annals of rheumatic diseases
BACKGROUND: Evidence suggests that both selective cyclooxygenase (COX)-2 inhibitors and non-selective NSAIDs increase the risk of cardiovascular (CV) events. However, evidence from prospective studies of currently available COX-2 inhibitors and non-selective NSAIDs is lacking in high CV risk patients taking aspirin. METHODS: The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18,325 osteoarthritis patients comprised 2 parallel sub- studies, comparing lumiracoxib (COX-2 inhibitor) to either ibuprofen or naproxen. We performed a post hoc analysis stratified by baseline cardiovascular risk, treatment assignment, and low-dose aspirin use. The primary composite endpoint was cardiovascular mortality, nonfatal myocardial infarction, and stroke at 1 year; a secondary endpoint was the development of congestive heart failure (CHF). RESULTS: In high risk patients among aspirin users, patients in the ibuprofen sub-study had more primary events with ibuprofen than lumiracoxib (2.14% vs. 0.25%, p=0.038), whereas in the naproxen sub-study rates were similar for naproxen and lumiracoxib (1.58% vs. 1.48%, p=0.899). High risk patients not taking aspirin had fewer primary events with naproxen versus lumiracoxib (0% vs. 1.57%, p=0.027), but not ibuprofen versus lumiracoxib (0.92% vs. 0.80%, p=0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs. 0.14%; p=0.031), whereas no difference existed between naproxen and lumiracoxib. CONCLUSIONS: These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. Our study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non-aspirin users. Our data should be interpreted as hypothesis-generating
— id: 71979, year: 2007, vol: 66, page: 764, stat: Journal Article,

Osteoarthritis in 2007
Krasnokutsky, Svetlana; Samuels, Jonathan; Abramson, Steven B
2007 ;65(3):222-228, Bulletin of the NYU Hospital for Joint Diseases
Osteoarthritis (OA) is often a progressive and disabling disease resulting from a combination of risk factors, including age, genetics, trauma, and knee alignment, as well as an imbalance of physiologic processes resulting in inflammatory cascades on a molecular level. The synovium, bone, and cartilage are each involved in the pathophysiological mechanisms that lead to progressive joint degeneration, and, thus, also serve as targets for therapies. Efforts to identify disease-modifying osteoarthritis drugs (DMOADs) have been hampered by several factors, but the focus has now shifted toward the validation of chemical and imaging biomarkers that should aid in DMOAD development. In this review, we summarize current pathological mechanisms occurring in the individual but interconnected compartments of OA joints, as well as discuss related therapeutic interventions that are currently available or on the horizon
— id: 75664, year: 2007, vol: 65, page: 222, stat: Journal Article,

Transcriptional repression of matrix metalloproteinase gene expression by the orphan nuclear receptor NURR1 in cartilage
Mix, Kimberlee S; Attur, Mukundan G; Al-Mussawir, Hayf; Abramson, Steven B; Brinckerhoff, Constance E; Murphy, Evelyn P
2007 Mar 30;282(13):9492-9504, Journal of biological chemistry
The NR4A orphan receptors (Nur77, NURR1, and NOR-1) are emerging as key regulators of cytokine and growth factor action in chronic inflammatory diseases. In this study, we address the role of these receptors in cartilage homeostasis during inflammatory joint disease. We document for the first time expression of the NR4A receptors in osteoarthritic cartilage. Relative to Nur77 and NOR-1, NURR1 is expressed at the highest level and correlates with cyclooxygenase-2 levels in cartilage. Consistent with this observation, cyclooxygenase-2-derived prostaglandin E(2) (PGE(2)) rapidly and potently induces NURR1 expression in chondrocytes, suggesting that this receptor may regulate PGE(2)-mediated processes in cartilage. We demonstrate that PGE(2) represses interleukin-1beta-induced matrix metalloproteinase (MMP)-1 and that transient overexpression of NURR1 is sufficient to antagonize expression of this gene. Furthermore, MMP-1 promoter activity is potently suppressed by NURR1, resulting in a significant reduction in endogenous MMP-1 mRNA and secreted pro-MMP-1 protein. In addition, NURR1 selectively antagonizes cytokine-induced MMP-3 and -9 expression with minimal effects on MMP-2 and -13 and tissue inhibitor of matrix metalloproteinases-1 and -2. To explore the molecular mechanisms of NURR1 transrepression, we reveal that this receptor targets a critical region of the MMP-1 promoter (-1772 to -1546 bp) and that repression does not require consensus binding sites for NURR1. We confirm that NURR1 targets a 40-bp promoter sequence that is also positively regulated by ETS transcription factors. Finally, functional studies indicate that transcriptional antagonism exists between NURR1 and ETS1 on the MMP-1 promoter. We propose a protective function for NURR1 in cartilage homeostasis by selectively repressing MMP gene expression during inflammation
— id: 93880, year: 2007, vol: 282, page: 9492, stat: Journal Article,

Coxibs and NSAIDs - Is the air any clearer? Perspectives from the OARSI/International COX-2 Study Group Workshop 2007
Moskowitz, R W; Abramson, S B; Berenbaum, F; Simon, L S; Hochberg, M
2007 Aug;15(8):849-856, Osteoarthritis & cartilage
— id: 73932, year: 2007, vol: 15, page: 849, stat: Journal Article,

Anticancer effects of licofelone (ML-3000) in prostate cancer cells
Narayanan, Narayanan K; Nargi, Dominic; Attur, Mukundan; Abramson, Steven B; Narayanan, Bhagavathi A
2007 Jul-Aug;27(4B):2393-2402, Anticancer research
BACKGROUND: Licofelone, a potent antiinflammatory agent has been reported to interfere with the cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) signaling pathways with few side-effects. However, the underlying mechanism of licofelone against human cancer is not understood. MATERIALS AND METHODS: Human and mouse prostate cancer cells were exposed to licofelone in a time- and dose-dependent manner. Cell growth/cell viability, apoptosis, and expression of COX-2 and 5-LOX at the gene and protein levels were investigated. RESULTS: For the first time, it was demonstrated that licofelone inhibited prostate cancer cell growth and significantly down-regulated COX-2 and 5-LOX expression. A weak inhibitory effect on COX-1 protein was also observed. CONCLUSION: Licofelone inhibited COX-2 and 5-LOX simultaneously and prevented overall cancer cell growth by enhancing apoptosis in both androgen-dependent and androgen-independent prostate cancer cells. Validating the dual role of licofelone in animal models of prostate cancer is critical for promoting its use as a potential chemopreventive or therapeutic agent
— id: 73813, year: 2007, vol: 27, page: 2393, stat: Journal Article,

Helicobacter pylori stimulates gastric epithelial cell MMP-1 secretion via CagA-dependent and -independent ERK activation
Pillinger, Michael H; Marjanovic, Nada; Kim, Seok-Yong; Lee, Yong-Chan; Scher, Jose U; Roper, Jatin; Abeles, Aryeh M; Izmirly, Peter I; Axelrod, Matthew; Pillinger, Mara Y; Tolani, Sonia; Dinsell, Victoria; Abramson, Steven B; Blaser, Martin J
2007 Jun 29;282(26):18722-18731, Journal of biological chemistry
Because the mechanisms of Helicobacter pylori-induced gastric injury are incompletely understood, we examined the hypothesis that H. pylori induces matrix metalloproteinase-1 (MMP-1) secretion, with potential to disrupt gastric stroma. We further tested the role of CagA, an H. pylori virulence factor, in MMP-1 secretion. Co-incubation of AGS cells with Tx30a, an H. pylori strain lacking the cagA virulence gene, stimulated MMP-1 secretion, confirming cagA-independent secretion. Co-incubation with strain 147C (cagA(+)) resulted in CagA translocation into AGS cells and increased MMP-1 secretion relative to Tx30a. Transfection of cells with the recombinant 147C cagA gene also induced MMP-1 secretion, indicating that CagA can independently stimulate MMP-1 secretion. Co-incubation with strain 147A, containing a cagA gene that lacks an EPIYA tyrosine phosphorylation motif, as well as transfection with 147A cagA, yielded an MMP-1 secretion intermediate between no treatment and 147C, indicating that CagA tyrosine phosphorylation regulates cellular signaling in this model system. H. pylori induced activation of the MAP kinase ERK, with CagA-independent (early) and dependent (later) components. MEK inhibitors UO126 and PD98059 inhibited both CagA-independent and -dependent MMP-1 secretion, whereas p38 inhibition enhanced MMP-1 secretion and ERK activation, suggesting p38 negative regulation of MMP-1 and ERK. These data indicate H. pylori effects on host epithelial MMP-1 expression via ERK, with p38 playing a potential regulatory role
— id: 73947, year: 2007, vol: 282, page: 18722, stat: Journal Article,

Disease activity, radiographic features and bone density in psoriatic and rheumatoid arthritis
Reddy, SM; Reed, G; Anandarajah, A; Greenberg, JD; Abramson, SB; Kremer, J; Ritchlin, CT
2007 JUL ;127(7):1821-1821, Journal of investigative dermatology
— id: 73046, year: 2007, vol: 127, page: 1821, stat: Journal Article,

Bone marrow changes (edema and fatty infiltration) on MRI predict radiographic severity of knee OA
Regatte R; Krasnokutsky S; Samuels J; Rosenthal P; Abellana V; Greenberg J; Babb J; Schweitzer M; Attur M; Abramson SB
2007 ;15:C180-C180, Osteoarthritis & cartilage
— id: 86572, year: 2007, vol: 15, page: C180, stat: Journal Article,

Nitric oxide synthases and osteoarthritis
Scher, Jose U; Pillinger, Michael H; Abramson, Steven B
2007 Apr;9(1):9-15, Current rheumatology reports
The production of nitric oxide (NO) by chondrocytes is increased in human osteoarthritis. The excessive production of NO inhibits matrix synthesis and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, NO promotes cellular injury and renders the chondrocyte susceptible to cytokine-induced apoptosis. Thus, NO produced by activated chondrocytes in diseased cartilage may modulate disease progression in osteoarthritis and should therefore be considered a potential target for therapeutic intervention.
— id: 72992, year: 2007, vol: 9, page: 9, stat: Journal Article,

Corticosteroids in preventing severe lupus Hares: do all patients have the same risk? Comment on the article by Tseng et al - Reply
Tseng, CE; Buyon, JP; Kim, M; Belmont, HM; Abramson, SB
2007 JUN ;56(6):2099-2099, Arthritis & rheumatism
— id: 73344, year: 2007, vol: 56, page: 2099, stat: Journal Article,

Rheumatoid arthritis treatment and monitoring of outcomes-where we are in 2007?
Yazici, Yusuf; Abramson, Steven B
2007 ;65(4):300-305, Bulletin of the NYU Hospital for Joint Diseases
Rheumatoid arthritis (RA) treatment has witnessed major advances over the last 10 to 20 years. Methotrexate has emerged as the cornerstone of treatment with new biologic agents being used in addition in severe and resistant patients. New drugs being developed with novel modes of action are promising to expand treatment options and help provide better disease control for RA patients. In addition to medications, equally important is aggressive disease activity monitoring using one of the composite scores available in order to match treatments to disease activity. Disease activity score (DAS), DAS28 (with a 28 joint count), clinical disease activity index (CDAI), simplified disease activity index (SDAI), and routine assessment of patient index data (RAPID) are valuable tools and should be used in routine care to achieve disease control
— id: 76149, year: 2007, vol: 65, page: 300, stat: Journal Article,

Drug delivery in degenerative joint disease: where we are and where to go?
Abramson, Steven
2006 May 20;58(2):125-127, Advanced drug delivery reviews
Drug discovery and delivery to retard the degeneration of joint tissues are challenging. Current treatment is generally inadequate. This commentary places in perspective the inadequacy characteristic of existing therapeutics and the promising developments embodied in the newer therapeutics administered via the oral or intra-auricular routes
— id: 71279, year: 2006, vol: 58, page: 125, stat: Journal Article,

Do nonsteroidal anti-inflammatory drugs accelerate disease progression in osteoarthritis?
Abramson, Steven B
2006 Jun;2(6):302-303, Nature clinical practice. Rheumatology
— id: 68752, year: 2006, vol: 2, page: 302, stat: Journal Article,

Prospects for disease modification in osteoarthritis
Abramson, Steven B; Attur, Mukundan; Yazici, Yusuf
2006 Jun;2(6):304-312, Nature clinical practice. Rheumatology
Osteoarthritis (OA) can be a progressive, disabling disease, leading to diminished quality of life, and, for over 500,000 individuals annually in the US, total joint replacement. The etiology of OA will vary among individuals, with potential roles for systemic factors (such as genetics and obesity) as well as for local biomechanical factors (such as muscle weakness, joint laxity and traumatic injury). Joint deterioration occurs over extended periods of time, and the diverse molecular mechanisms that mediate pathogenic events of early, mid and late disease are not yet fully understood. The success of biologic therapies in the treatment of rheumatoid arthritis has demonstrated that the blockade of a single dominant cytokine or regulatory molecule can prevent cartilage destruction in a complex disease, and has raised expectations that mechanism-based treatments could also be developed for patients with OA. In this review, we will address the biological mechanisms that mediate structural damage in OA and examine current targets that are candidates for disease modification. The challenges to drug development and the obstacles to disease modification strategies will also be addressed
— id: 67863, year: 2006, vol: 2, page: 304, stat: Journal Article,

Biologics in development for rheumatoid arthritis: relevance to osteoarthritis
Abramson, Steven B; Yazici, Yusuf
2006 May 20;58(2):212-225, Advanced drug delivery reviews
The osteoarthritis disease process affects not only the cartilage but also the entire joint structure, including the synovium, bone and periarticular muscles. Characteristically, abnormal biomechanical forces result in an imbalance between chondrocyte anabolic and catabolic pathways, which ultimately leads to progressive joint destruction. Within cartilage and synovium, pro-inflammatory cytokines, particularly IL-1b and TNF-a, auto-catalytically stimulate their own production and induce chondrocytes to produce additional catabolic mediators, including proteases, chemokines, nitric oxide, and prostaglandins. The success of targeted biological therapy in rheumatoid arthritis has taught that the blockade of a single dominant cytokine can lead to remarkable clinical benefit, even in complex disease. The effectiveness of biologicals in inflammatory arthritides as disease modifying agents has increased the likelihood that similar strategies can be developed to target specific molecular mechanisms in osteoarthritis (OA). However, since the clinical development program for disease-modifying OA drugs (DMOADs) is complicated by the slow progression of disease in many patients, the introduction of DMOADs will be greatly enhanced by advances in imaging and biomarkers that serve as validated surrogate endpoints for meaningful clinical outcomes
— id: 68770, year: 2006, vol: 58, page: 212, stat: Journal Article,

Biomarkers in osteoarthritis
Abramson, Steven; Krasnokutsky, Svetlana
2006 ;64(1-2):77-81, Bulletin of the NYU Hospital for Joint Diseases
Osteoarthritis (OA) can be a progressive disabling disease, which results from the pathological imbalance of degradative and reparative processes, with concomitant inflammatory changes. The synovium, bone, and cartilage are each well established sites involved in the pathophysiological mechanisms that lead to progressive joint degeneration. The search for disease-modifying osteoarthritis drugs, DMOADs, has been hampered by several factors, including the variable progression of disease, the lack of specificity and sensitivity of standard radiography, and the fact that the slowing of radiographic progression may not result in corresponding improvement in pain and function. As a result, there is general agreement that development of DMOADs will be facilitated by advances in imaging and the validation of chemical biomarkers. Such biomarkers should be useful tools that will identify patients at risk for disease progression and predict responses to candidate structure-modifying drugs
— id: 71293, year: 2006, vol: 64, page: 77, stat: Journal Article,

NURR1 expression is increased in osteoarthritic cartilage and regulates cytokine and metalloproteinase gene transcription: A downstream action of cyclooxygenase 2-derived PGE2
Attur, M; Al-Mussawir, HE; Pillinger, MH; Mix, K; Tetradis, S; Abramson, SB
2006 SEP ;54(9):S616-S616, Arthritis & rheumatism
— id: 70128, year: 2006, vol: 54, page: S616, stat: Journal Article,

Prostaglandin E2 induces mitochondrial dysfunction in osteoarthritic chondrocytes and exerts catabolic effects aa the EP4 receptor
Attur, M; Dave, M; Patel, J; Al-Mussawir, HE; Pillinger, MH; Abramson, SB
2006 SEP ;54(9):S93-S93, Arthritis & rheumatism
— id: 70104, year: 2006, vol: 54, page: S93, stat: Journal Article,

Classification of osteoarthritis biomarkers: a proposed approach
Bauer, DC; Hunter, DJ; Abramson, SB; Attur, M; Corr, M; Felson, D; Heinegard, D; Jordan, JM; Kepler, TB; Lane, NE; Saxne, T; Tyree, B; Kraus, VB
2006 AUG ;14(8):723-727, Osteoarthritis & cartilage
Objective: Osteoarthritis (OA) biomarkers are needed by researchers and clinicians to assist in disease diagnosis and assessment of disease severity, risk of onset, and progression. As effective agents for CA are developed and tested in clinical studies, biomarkers; that reliably mirror or predict the progression or amelioration of CA will also be needed. Methods: The NIH-funded CA Biomarkers Network is a multidisciplinary group interested in the development and validation of CA biomarkers. This review summarizes our efforts to characterize and classify CA biomarkers. Results: We propose the 'BIPED' biomarker classification (which stands for Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic), and offer suggestions on optimal study design and analytic methods for use in CA investigations. Conclusion. The BIPED classification provides specific biomarker definitions with the goal of improving our ability to develop and analyze OA biomarkers, and to communicate these advances within a common framework. (C) 2006 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved
— id: 67028, year: 2006, vol: 14, page: 723, stat: Journal Article,

The use of the laryngeal mask airway during guidewire dilating forceps tracheostomy
Cattano, Davide; Abramson, Steven; Buzzigoli, Stefano; Zoppi, Candido; Melai, Ettore; Giunta, Francesco; Hagberg, Carin
2006 Aug;103(2):453-7, table of contents, Anesthesia & analgesia
Percutaneous tracheostomy has become a common alternative to the classical open tracheostomy because of its convenience, cost effectiveness, and decreased complication rates. We retrospectively reviewed our intensive care practice using a guidewire dilatating forceps percutaneous tracheostomy technique with an endotracheal tube, as compared with the Classic Laryngeal Mask Airway (LMA) for these procedures. From 1998 to 2004, 274 patients underwent a tracheostomy procedure. Two-hundred-fifty-four (92.7%) of these patients underwent a guidewire dilatating forceps tracheostomy and 20 (7.3%) underwent a surgical tracheostomy. In the guidewire dilatating forceps group, 188 (74%) were performed by endoscopy via LMA-guided bronchoscopy, and 66 (26%) were performed through an endotracheal tube. Endoscopic views obtained via the LMA were subjectively better than those obtained with the endotracheal tube. Acute complications were significantly more frequent when using an endotracheal tube as compared with the LMA (6 of 66 versus 4 of 188; P = 0.022 Fisher's exact test, odds ratio = 4.6). There was a significant difference in terms of acute (10 of 254 versus 6 of 20; P < 0.001, odds ratio = 10.5) and chronic (0 of 254 versus 4 of 20; P < 0.001) complications between the 2 groups. There were no ventilatory complications or reports of gastric aspiration. The LMA provides a safe and effective alternative to an endotracheal tube for airway management during guidewire dilatating forceps tracheostomies in selected patients
— id: 71283, year: 2006, vol: 103, page: 453, stat: Journal Article,

Il-1 promotes mitochondrial dysfunction, increases cytosolic cytochrome C and activates caspases in osteoarthritic chondrocytes
Dave, M; Attur, M; AI-Mussawir, HE; Patel, J; Abramson, SB
2006 SEP ;54(9):S72-S72, Arthritis & rheumatism
— id: 70102, year: 2006, vol: 54, page: S72, stat: Journal Article,

Association of duration of TNF antagonist treatment with reduction in cardiovascular outcomes in RA patients
Greenberg, J; Lin, S; Decktor, D; Dabbous, O; Baumgartner, S; Montgomery, M; Chi, E; Hinkle, K; Reed, G; Hochberg, M; Abramson, S; Kremer, J
2006 SEP ;54(9):S422-S423, Arthritis & rheumatism
— id: 70119, year: 2006, vol: 54, page: S422, stat: Journal Article,

Decline of NSAID gastroprotection in patients treated by rheumatologists in the post-rofecoxib era
Greenberg, J; Yazici, Y; Kremer, JM; Chang, H; Kishimoto, M; Abramson, SB
2006 SEP ;54(9):S110-S110, Arthritis & rheumatism
— id: 70106, year: 2006, vol: 54, page: S110, stat: Journal Article,

Assessment of coxib utilization by rheumatologists for nonsteroidal antiinflammatory drug gastroprotection prior to the coxib market withdrawals
Greenberg, Jeffrey D; Bingham, Clifton O 3rd; Abramson, Steven B; Reed, George; Kishimoto, Mitsumasa; Hinkle, Kim; Kremer, Joel
2006 Aug 15;55(4):543-550, Arthritis & rheumatism
OBJECTIVE: To examine cyclooxygenase 2 inhibitor (coxib) utilization by rheumatologists for patients receiving nonsteroidal antiinflammatory drugs (NSAIDs) prior to the coxib market withdrawals. METHODS: A prospective study of patients with rheumatoid arthritis enrolled in the Consortium of Rheumatology Researchers of North America registry was performed. RESULTS: Of 1,833 patients receiving prescription NSAIDs, 1,380 (75.3%) received gastroprotection, defined as either coxib monotherapy and/or gastroprotective agent (GPA) cotherapy, and 1,207 (65.8%) received coxibs. The distribution of gastroprotective strategies included 860 (46.9%) patients who were prescribed coxib monotherapy, 347 (18.9%) prescribed dual coxib plus GPA cotherapy, 173 (9.4%) prescribed a nonselective NSAID (NS-NSAID) plus GPA cotherapy, and 453 (24.7%) prescribed an NS-NSAID without GPA cotherapy. For patients with 0, 1, and > or =2 identifiable gastrointestinal (GI) risk factors, coxib prescribing rates as a proportion of NSAID agents were 64.1%, 66.4%, and 68.6%, respectively; among dual aspirin/NSAID users, coxib prescribing rates were 66.2%, 78.3%, and 68.5% of NSAID prescriptions, respectively. CONCLUSION: The majority of NSAID users were prescribed a gastroprotective strategy, primarily attributable to coxib utilization. Coxib utilization rates were consistently high across all levels of GI risk, including patients without identifiable risk factors. These data indicate that rheumatologists broadly adopted the coxib class of NSAIDs in a nonselective manner with respect to underlying GI risk and concomitant aspirin use. As novel therapeutic classes are introduced, early evaluation of prescribing patterns using arthritis registries can determine the appropriateness of prescribing patterns and may improve patient outcomes
— id: 67870, year: 2006, vol: 55, page: 543, stat: Journal Article,

Peripheral blood leukocytes (PBL) gene expression profiles as biomarkers in patients with human knee osteciarthritis (OA)
Krasnokutsky, S; Attur, M; Belitskaya-Levy, I; Patel, J; Al-Mussawir, H; Smiles, S; Lee, S; Kraus, V; Kong, SY; McDaniel, G; Abramson, SB
2006 DEC ;54(12):4103-4103, Arthritis & rheumatism
— id: 70764, year: 2006, vol: 54, page: 4103, stat: Journal Article,

APRIL and BAFF promote increased viability of replicating human B2 cells via mechanism involving cyclooxygenase 2
Mongini, Patricia K A; Inman, John K; Han, Hanna; Fattah, Rasem J; Abramson, Steven B; Attur, Mukundan
2006 Jun 1;176(11):6736-6751, Journal of immunology
Of relevance to both protective and pathogenic responses to Ag is the recent finding that soluble molecules of the innate immune system, i.e., IL-4, B cell-activation factor of the TNF family (BAFF), and C3, exhibit significant synergy in promoting the clonal expansion of human B2 cells following low-level BCR ligation. Although IL-4, BAFF, and C3dg each contribute to early cell cycle entry and progression to S phase, only BAFF promotes later sustained viability of progeny needed for continued cycling. The present study sought to further clarify the mechanisms for BAFF's multiple functions. By comparing BAFF and a proliferation-inducing ligand (APRIL) efficacy at different stages in the response (only BAFF binds BR3; both bind transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation Ag, the early role was attributed to BR3, while the later role was attributed to TACI/B cell maturation Ag. Importantly, BAFF- and APRIL-promoted viability of cycling lymphoblasts was associated with sustained expression of cyclooxygenase 2 (COX-2), the rate-limiting enzyme for PGE2 synthesis, within replicating cells. Supernatants of cultures with BAFF and APRIL contained elevated PGE2. Although COX-2 inhibitors diminished daughter cell viability, exogenous PGE2 (1-1000 nM) increased the viability and recovery of lymphoblasts. Increased yield of viable progeny was associated with elevated Mcl-1, suggesting that a BAFF/APRIL --> TACI --> COX-2 --> PGE2--> Mcl-1 pathway reduces activation-related, mitochondrial apoptosis in replicating human B2 cell clones
— id: 64789, year: 2006, vol: 176, page: 6736, stat: Journal Article,

APRIL and BAFF promote clonal expansion of human B2 cells via a COX-2-dependent mechanism
Mongini, PKA; Inman, J; Abramson, S; Attur, M
2006 APR 1 ;176(4):S190-S190, Journal of immunology
— id: 68844, year: 2006, vol: 176, page: S190, stat: Journal Article,

Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases
Park, Jean Y; Pillinger, Michael H; Abramson, Steven B
2006 Jun;119(3):229-240, Clinical immunology
Prostaglandin E2 (PGE2) is a principal mediator of inflammation in diseases such as rheumatoid arthritis and osteoarthritis. Nonsteroidal anti-inflammatory medications (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors reduce PGE2 production to diminish the inflammation seen in these diseases, but have toxicities that may include both gastrointestinal bleeding and prothrombotic tendencies. In cells, arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES). Accumulating data suggest that the interaction of various enzymes in the PGE2 synthetic pathway is complex and tightly regulated. In this review, we summarize the synthesis and secretion of PGE2. In particular, we focus on the three isoforms of the terminal PGES, and discuss the potential of targeting PGES as a more precise strategy for inhibiting PGE2 production
— id: 64649, year: 2006, vol: 119, page: 229, stat: Journal Article,

Early-phase PGE(2) production in IL-1-stimulated chondrocytes: Coordinated nuclear localization of COX-1, heat shock protein 90 (Hsp90) and cytosolic prostaglandin e synthase (cPGES)
Park, JY; Marjanovic, N; Attur, M; Al-Mussawir, H; Dave, M; Abeles, AM; Krasnokutsky, S; Pillinger, MH; Abramson, SB
2006 SEP ;54(9):S90-S91, Arthritis & rheumatism
— id: 70103, year: 2006, vol: 54, page: S90, stat: Journal Article,

Comparison of disease activity and functional status among psoriatic arthritis subtypes
Reddy, SM; Schwartzman, JS; Abramson, SB; Chang, H; Kremer, J; Greenberg, JD
2006 SEP ;54(9):S712-S713, Arthritis & rheumatism
— id: 70133, year: 2006, vol: 54, page: S712, stat: Journal Article,

Hyaluronan drugs versus physical therapy in knee osteoarthritis
Samuels, J; Abramson, SB
2006 OCT ;2(10):528-529, Nature clinical practice. Rheumatology
— id: 68789, year: 2006, vol: 2, page: 528, stat: Journal Article,

The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: Findings of a prospective, randomized, double-blind, placebo-controlled trial
Tseng, Chung-E; Buyon, Jill P; Kim, Mimi; Belmont, H Michael; Mackay, Meggan; Diamond, Betty; Marder, Galina; Rosenthal, Pamela; Haines, Kathleen; Ilie, Virginia; Abramson, Steven B
2006 Oct 30;54(11):3623-3632, Arthritis & rheumatism
OBJECTIVE: Serial measurements of anti-double-stranded DNA (anti-dsDNA) and complement are routine in the management of systemic lupus erythematosus (SLE), but their utility as biomarkers in preemptive treatment to prevent flares remains a subject of controversy. We hypothesized that concomitant elevation of anti-dsDNA and C3a can predict SLE activity in patients with stable or inactive disease and that short-term treatment with corticosteroids can avert flares. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, 154 patients were evaluated monthly for up to 18 months, with measurements of C3a, C3, C4, CH50, and anti-dsDNA levels. Patients who remained clinically stable but showed serologic evidence of an SLE flare (elevation of both the anti-dsDNA level by 25% and the C3a level by 50% over the previous 1-2 monthly visits) were randomized to receive either prednisone or placebo therapy at a dosage of 30 mg/day for 2 weeks, 20 mg/day for 1 week, and 10 mg/day for 1 week. RESULTS: Forty-one patients (21 randomized to prednisone and 20 randomized to placebo) experienced a serologic flare. Analysis of severe flares occurring </=90 days from randomization revealed that 6 occurred in patients taking placebo and none occurred in patients taking prednisone (P = 0.007). Severe flares resulted in an increase in the prednisone dosage to >40 mg/day and/or the addition of an immunosuppressive agent. Furthermore, improvement in scores on the Systemic Lupus Erythematosus Disease Activity Index, decreased levels of anti-dsDNA antibodies, and increased levels of C4 occurred 1 month after initiation of prednisone treatment. CONCLUSION: These preliminary data support our hypothesis that in a subset of clinically stable SLE patients with a combination of elevated C3a and anti-dsDNA levels, short-term corticosteroid therapy may avert a severe flare
— id: 69280, year: 2006, vol: 54, page: 3623, stat: Journal Article,

Clinical disease activity index (CDAI) is strongly correlated with DAS28 and change in CDAI is a strong predictor of ACR 20 response
Yazici, Y; Greenberg, J; Reed, G; Hinkle, K; Abramson, S; Kremer, J
2006 JUL ;65(4B):608-608, Annals of rheumatic diseases
— id: 74202, year: 2006, vol: 65, page: 608, stat: Journal Article,

Decreasing disease activity thresholds for initiating TNF antagonists from 2003 to 2005 among 1790 rheumatoid arthritis (RA) patients from the CORRONA database
Yazici, Y; Greenberg, J; Reed, G; Kishimoto, M; Hinkle, K; Abramson, S; Kremer, J
2006 SEP ;54(9):S246-S246, Arthritis & rheumatism
— id: 70110, year: 2006, vol: 54, page: S246, stat: Journal Article,

Reduced TNF utilization in early rheumatoid arthritis (RA) versus late RA in a US cohort
Yazici, Y; Greenberg, J; Reed, G; Kishimoto, M; Hinkle, K; Abramson, S; Kremer, J
2006 JUL ;65(4B):513-513, Annals of rheumatic diseases
— id: 74199, year: 2006, vol: 65, page: 513, stat: Journal Article,

NYU Hospital for Joint Diseases - 2006 Seminar in Advanced Rheumatology
Yazici, Yusuf; Abramson, Steven
2006 ;64(1-2):8-8, Bulletin of the NYU Hospital for Joint Diseases
— id: 71292, year: 2006, vol: 64, page: 8, stat: Journal Article,

Farnesyltransferase inhibitors, but not statins, inhibit matrix metalloproteinase-1 (MMP-1) secretion from rheumatoid synovial fibroblasts
Abeles, AM; Marjanovic, N; Al-Mussawir, HE; Abramson, SB; Pillinger, MH
2005 SEP ;52(9):S453-S454, Arthritis & rheumatism
— id: 59284, year: 2005, vol: 52, page: S453, stat: Journal Article,

The many facets of osteoarthritis: Pathogenesis and markers
Abramson, SB
2005 JUL ;64(4):31-31, Annals of rheumatic diseases
— id: 57652, year: 2005, vol: 64, page: 31, stat: Journal Article,

Current state of therapy for pain and inflammation
Abramson, Steven B; Weaver, Arthur L
2005 ;7 Suppl 4:S1-S6, Arthritis research & therapy
Nonsteroidal anti-inflammatory drugs (NSAIDs), including both traditional nonselective NSAIDs and the selective cyclo-oxygenase (COX)-2 inhibitors, are among the most widely used medications in the USA. Traditional NSAIDs, although effective at relieving pain and inflammation, are associated with a significant increase in the risk for gastrointestinal adverse events. Throughout the 1990s these events were estimated to result in approximately 100,000 hospitalizations and 16,500 deaths each year nationally. Recent studies have indicated that the risk for serious NSAID gastropathy has declined substantially during the past decade as a result of a number of factors, including lower doses of NSAIDs, the use of gastroprotective agents such as proton pump inhibitors and misoprostol, and the introduction of the selective COX-2 inhibitors. One therapeutic approach that may reduce the risk for gastrointestinal side effects associated with traditional NSAIDs while retaining their efficacy is the inclusion of co-therapy with a proton pump inhibitor; these agents inhibit acid secretion and have been demonstrated to promote ulcer healing in patients with NSAID-related gastric ulcers. Alternatively, COX-2 selective agents have been used to treat patients at high risk for such events. Both nonselective and selective COX-2 inhibitors have now been shown to be associated with an increased risk for cardiovascular events. These studies, together with the outcomes of the recent US Food and Drug Administration decision to require 'black box' warnings regarding potential cardiovascular risks associated with NSAIDs, suggest that the use of COX-2 inhibitors as the sole strategy for gastroprotection in patients with arthritis and other pain syndromes must be reconsidered, particularly among those at risk for cardiovascular events
— id: 61421, year: 2005, vol: 7 Suppl 4, page: S1, stat: Journal Article,

Simvastatin and geranyl-geranyl transferase inhibitor exhibit chondroprotective effects
Attur, M; Al-Mussawir, H; Abeles, AM; Pillinger, MH; Abramson, SB
2005 SEP ;52(9):S59-S59, Arthritis & rheumatism
— id: 59270, year: 2005, vol: 52, page: S59, stat: Journal Article,

Prostaglandin E2 exerts catabolic effects in OA cartilage: Evidence for signaling via the EP4 receptor
Attur, M; Dave, M; Patel, J; Pillinger, MH; Abramson, SB
2005 SEP ;52(9):S707-S707, Arthritis & rheumatism
— id: 59298, year: 2005, vol: 52, page: S707, stat: Journal Article,

The inflammatory mediator leukotriene B4 (ltb4) exerts catabolic effects on chondrocyte metabolism
Attur, M; Gomez, PF; Patel, J; Al-Mussawir, H; Pillinger, MH; Abramson, SB
2005 SEP ;52(9):S59-S59, Arthritis & rheumatism
— id: 59269, year: 2005, vol: 52, page: S59, stat: Journal Article,

Oxidative injury in osteoarthritis: Is resveratrol of red wine the answer?
Dave, M; Attur, M; Krasnokutsky, S; Patel, J; Abramson, SB
2005 SEP ;52(9):S499-S499, Arthritis & rheumatism
— id: 59289, year: 2005, vol: 52, page: S499, stat: Journal Article,

Resolution of inflammation: prostaglandin E2 dissociates nuclear trafficking of individual NF-kappaB subunits (p65, p50) in stimulated rheumatoid synovial fibroblasts
Gomez, Paul F; Pillinger, Michael H; Attur, Mukundan; Marjanovic, Nada; Dave, Mander; Park, Jean; Bingham, Clifton O 3rd; Al-Mussawir, Hayf; Abramson, Steven B
2005 Nov 15;175(10):6924-6930, Journal of immunology
NF-kappaB transcription factors regulate inflammatory responses to cytokines such as IL-1beta and TNF-alpha. We tested whether PGE2 regulated nuclear localization of individual NF-kappaB subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1beta/TNF-alpha stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-kappaB activation measured by luciferase reporter assay. PGE2 (10 nM, 6 h) enhanced p50, but inhibited p65 translocation and NF-kappaB activation. In contrast, depletion of endogenous PGE2 by ibuprofen (100 microM) and celecoxib (5 microM) enhanced p65, but inhibited p50 nuclear translocation as well as binding to NF-kappaB DNA binding sites. PGE2 also blocked IL-1beta/TNF-alpha-stimulated ERK activation, and the ERK inhibitor, PD98059, mimicked PGE2 in blocking p65, but enhancing p50 nuclear translocation, suggesting that the effects of PGE2 on p65 and p50 are mediated via effects on ERK. PGE2 also enhanced the expression of IkappaBalpha in an ERK-independent manner, suggesting that PGE2 inhibits NF-kappaB activation by both ERK-dependent and -independent mechanisms. Our data indicate that PGE2 may act to attenuate cytokine-induced inflammatory responses in RA synovial fibroblasts via regulation of the localization of specific NF-kappaB family dimers
— id: 61340, year: 2005, vol: 175, page: 6924, stat: Journal Article,

Cardiovascular (CV) outcomes in high CV risk patients treated with ibuprofen, naproxen or lumiracoxib: Subanalysis of the TARGET trial
Greenberg, J; Abramson, S; Jeger, R; Harrington, R; Kirschner, H; Hochman, J; Chesebro, J; Mellein, B; Matchaba, P; Fuster, V; Farkhouh, M
2005 DEC ;52(12):4057-4057, Arthritis & rheumatism
— id: 63308, year: 2005, vol: 52, page: 4057, stat: Journal Article,

Pilot study of tuberculosis screening strategies for rheumatoid arthritis patients
Greenberg, J; Schloss, S; Kurucz, O; Reddy, S; Abellana, V; McCullagh, E; Abramson, S; Bingham, C
2005 SEP ;52(9):S545-S545, Arthritis & rheumatism
— id: 59291, year: 2005, vol: 52, page: S545, stat: Journal Article,

NSAID and COXIB prescribing by rheumatologist for patients with gastrointestinal (GI) and cardiovascular (CV) risk in 2004-2005
Greenberg, JD; Abramson, SB; Lee, S; Rosenstein, E; Reed, G; Hinkle, K; Kavanaugh, A; Kremer, J
2005 SEP ;52(9):S664-S664, Arthritis & rheumatism
— id: 59296, year: 2005, vol: 52, page: S664, stat: Journal Article,

Coxib prescribing by rheumatologists in the immediate post-rofecoxib era
Greenberg, JD; Abramson, SB; Reed, G; Reddy, SM; Hinkle, K; Kremer, J
2005 JUL ;64(4):405-405, Annals of rheumatic diseases
— id: 57656, year: 2005, vol: 64, page: 405, stat: Journal Article,

Low baseline joint count attenuates response to anti-TNF agents: What are the goals of biologic therapy?
Greenberg, JD; Kishimoto, M; Cohen, SB; Olenginski, TP; Harrington, T; Kafka, SP; Reed, G; Hinkle, K; Kremer, J; Abramson, SB
2005 SEP ;52(9):S562-S562, Arthritis & rheumatism
— id: 59292, year: 2005, vol: 52, page: S562, stat: Journal Article,

Effect of cardiovascular comorbidities and concomitant aspirin use on selection of cyclooxygenase inhibitor among rheumatologists
Greenberg, Jeffrey D; Bingham, Clifton O 3rd; Abramson, Steven B; Reed, George; Sebaldt, Rolf J; Kremer, Joel
2005 Feb 15;53(1):12-17, Arthritis & rheumatism
OBJECTIVE: To evaluate the effects of cardiovascular comorbidities and aspirin coprescription on cyclooxygenase (COX)-2 inhibitor (coxib) prescribing patterns among rheumatologists. METHODS: A prospective cohort study was carried out with rheumatoid arthritis and osteoarthritis patients in the Consortium of Rheumatology Researchers of North America registry. Medication and comorbidity data were obtained prospectively from physician and patient questionnaires between March 2002 and September 2003. Multivariate adjusted associations between coxib use and specific cardiovascular variables, including aspirin use, were examined. RESULTS: A total of 3,522 arthritis patients were included. COX inhibitors, including coxibs, nonselective nonsteroidal antiinflammatory drugs (NSAIDs), and meloxicam, were prescribed to a larger proportion of osteoarthritis patients (68.4%) than rheumatoid arthritis patients (47.1%) in our study (P < 0.001). COX inhibitors were prescribed to the majority of aspirin users (51.5%) and a similar proportion of nonusers (49.8%). In multivariate analyses, independent predictors of coxib use versus nonselective NSAID use included diagnoses of osteoarthritis (odds ratio [OR] 2.52, 95% confidence interval [95% CI] 1.81-3.52) and diabetes (OR 1.63, 95% CI 1.06-2.51). Conversely, aspirin use independently predicted selection of a nonselective NSAID rather than a coxib (OR 0.73, 95% CI 0.55-0.98). Neither a history of myocardial infarction nor stroke predicted utilization of a coxib. Similarly, cardiovascular variables did not predict the use of rofecoxib versus celecoxib. CONCLUSION: Our data indicate that COX inhibitor coprescription among aspirin users is frequent. Despite cardiovascular concerns regarding the coxibs, our data suggest that aspirin use, but not cardiovascular comorbidities, predicted the selection of nonselective NSAIDs over coxibs
— id: 50291, year: 2005, vol: 53, page: 12, stat: Journal Article,

Drug survival time on anti-TNF agents: Does prior anti-TNF use influence RA outcomes?
Kishimoto, M; Greenberg, J; Abramson, SB; Harrington, T; Olenginski, TP; Kafka, SP; Reed, G; Hinkle, K; Kremer, J; Cohen, SB
2005 SEP ;52(9):S347-S347, Arthritis & rheumatism
— id: 59277, year: 2005, vol: 52, page: S347, stat: Journal Article,

Rheumatic Diseases
Lee, Sicy H; Abramson, Steven B
Medical aspects of disability : a handbook for the rehabilitation professional New York, NY, US: Springer Publishing Co, 2005,
The rheumatic diseases detailed in this chapter include rheumatoid arthritis, spondyloarthropathies, and degenerative joint disease. The authors discuss etiology and pathogenesis, functional presentation and disability, complications, treatment and prognosis, and psychological and vocational implications.
— id: 4091, year: 2005, vol: , page: 538, stat: Chapter,

The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction
Mor, Adam; Abramson, Steven B; Pillinger, Michael H
2005 May;115(2):118-128, Clinical immunology
Although multiple cell types are present in the rheumatoid joint, the fibroblast-like synovial cell (FLS) is among the most prominent. It is now appreciated that the FLS is not only space-filling, but is directly responsible for cartilage destruction, and also drives both inflammation and autoimmunity. In this article, we consider the normal role of the FLS in healthy joints, and review evidence that implicates the FLS as a central player in the propagation of rheumatoid arthritis
— id: 55952, year: 2005, vol: 115, page: 118, stat: Journal Article,

Coxibs and NSAIDs - clearing the air
Moskowitz, RW; Abramson, SB; Berenbaum, F
2005 JUL ;13(7):545-547, Osteoarthritis & cartilage
— id: 56287, year: 2005, vol: 13, page: 545, stat: Journal Article,

Expression and subcellular localization of COX 1 and 2 and their associated terminal synthases, cPGES and mPGES, in Il-1-stimulated chondrocytes
Pillinger, MH; Attur, M; Marjanovic, N; Dave, M; Abeles, AM; Merola, J; Krasnokutsky, S; Abramson, SB
2005 SEP ;52(9):S475-S475, Arthritis & rheumatism
— id: 59288, year: 2005, vol: 52, page: S475, stat: Journal Article,

Matrix metalloproteinase secretion by gastric epithelial cells is regulated by E prostaglandins and mitogen-activated protein kinases
Pillinger, Michael H; Marjanovic, Nada; Kim, Seok-Yong; Scher, Jose U; Izmirly, Peter; Tolani, Sonia; Dinsell, Victoria; Lee, Yong-Chan; Blaser, Martin J; Abramson, Steven B
2005 Mar 18;280(11):9973-9979, Journal of biological chemistry
Since matrix metalloproteinases (MMP) play roles in inflammatory tissue injury, we asked whether MMP secretion by gastric epithelial cells may contribute to gastric injury in response to signals involved in H. pylori-induced inflammation and/or cyclooxygenase inhibition. TNF-alpha, IL-1beta and epidermal growth factor (EGF) stimulated gastric cell MMP-1 secretion, indicating that MMP-1 secretion occurs in inflammatory as well as non-inflammatory situations. MMP-1 secretion required activation of the mitogen-activated protein kinase (MAPK) Erk, and subsequent protein synthesis, but was downregulated by the alternate MAPK, p38. In contrast, secretion of MMP-13 was stimulated by TNF-alpha/IL-1beta but not EGF, was Erk-independent and mediated by p38. MMP-13 secretion was more rapid (peak 6 h) than MMP-1 (peak = 30 h) and only partly depended on protein synthesis, suggesting initial release of a pre-existing MMP-13 pool. Therefore, MMP-1 and MMP-13 secretion are differentially regulated by MAPKs. MMP-1 secretion was regulated by E prostaglandins (PGEs) in an Erk-dependent manner. PGEs enhanced Erk activation and MMP-1 secretion in response to EGF, but inhibited Erk and MMP-1 when TNF-alpha/IL-1beta were the stimuli, indicating that the effects of PGEs on gastric cell responses are context-dependent. These data show that secretion of MMPs is differentially regulated by MAPKs, and suggest mechanisms through which H pylori infection and/or cyclooxygenase inhibition may induce epithelial cell signaling to contribute to gastric ulcerogenesis
— id: 48227, year: 2005, vol: 280, page: 9973, stat: Journal Article,

Comparison of disease activity measures and radiographic features of psoriatic arthritis and a matched rheumatoid arthritis cohort
Reddy, SM; Greenberg, JD; Abramson, SB; Reed, G; Hinkle, K; Kremer, J
2005 JUL ;64(4):337-338, Annals of rheumatic diseases
— id: 57655, year: 2005, vol: 64, page: 337, stat: Journal Article,

Comparative analysis of disease activity, radiographic features, and bone density in psoriatic and rheumatoid arthritis
Reddy, SM; Reed, G; Anandarajah, A; Greenbeg, JD; Abramson, SB; Kremer, J; Ritchlin, CT
2005 SEP ;52(9):S640-S641, Arthritis & rheumatism
— id: 59294, year: 2005, vol: 52, page: S640, stat: Journal Article,

Inflammation and the revolution in the treatment of rheumatoid arthritis
Abramson, SB
2004 AUG 22 ;228(2):U941-U941, Abstracts of papers (American Chemical Society)
— id: 48745, year: 2004, vol: 228, page: U941, stat: Journal Article,

Inflammation in osteoarthritis
Abramson, Steven B
2004 May;70(1):70-76, Journal of rheumatology. Supplement
— id: 46024, year: 2004, vol: 70, page: 70, stat: Journal Article,

Salutary effects of statins in vitro on cartilage and bone metabolism
Attur, M; Dave, M; Abramson, SB
2004 SEP ;50(9):S287-S288, Arthritis & rheumatism
— id: 49036, year: 2004, vol: 50, page: S287, stat: Journal Article,

Human osteoarthritis chondrocytes produce leukotriene B4 and lipoxin A4: Counter regulatory impact in cartilage
Attur, M; Dave, M; Serhan, C; Abramson, SB
2004 SEP ;50(9):S282-S282, Arthritis & rheumatism
— id: 49035, year: 2004, vol: 50, page: S282, stat: Journal Article,

A family of novel phospholipase A2 enzymes are expressed in synovial tissue and differentially regulated by proinflammatory cytokines in rheumatoid synovial fibroblasts
Bingham, CO; Reddy, SM; Al-Mussawir, H; Attur, M; Abramson, SB
2004 SEP ;50(9):S327-S327, Arthritis & rheumatism
— id: 49040, year: 2004, vol: 50, page: S327, stat: Journal Article,

Nitric oxide sustains nuclear factor kappaB activation in cytokine-stimulated chondrocytes
Clancy, R M; Gomez, P F; Abramson, S B
2004 Aug;12(7):552-558, Osteoarthritis & cartilage
OBJECTIVE: In the current studies we have examined the effects of nitric oxide, and its redox derivatives peroxynitrite and S-nitrosothiol, S-nitrosocysteine, on nuclear factor kappaB (NF-kappaB) activation in cytokine-stimulated bovine chondrocytes. METHODS: The kinetics of NF-kappaB activation (p65 nuclear translocation) were assessed by immunofluorescence and immunoblot assays. RESULTS: We observed that the two nitric oxide redox species, peroxynitrite and S-nitrosocysteine, exert opposing effects on NF-kappaB activation. However, in lipopolysaccharide (LPS)/cytokine-stimulated chondrocytes (LPS, IL-1beta and TNF-alpha (LIT)) in the presence or absence of the NOS inhibitor L-NG-monomethyl arginine citrate (L-NMMA), the results indicate that nitric oxide causes persistent activation of NF-kappaB, most likely via generation of the free radical derivative peroxynitrite. CONCLUSION: The studies indicate that while nitric oxide is not required for immediate NF-kappaB activation in cytokine-stimulated chondrocytes, its effect is to sustain nuclear translocation of p65 and thereby provide a persistent 'on signal' to NF-kappaB dependent gene transcription. Persistent activation of NF-kappaB may represent a mechanism by which nitric oxide sustains catabolic processes and promotes cartilage degeneration in osteoarthritis
— id: 46153, year: 2004, vol: 12, page: 552, stat: Journal Article,

Resveratrol exerts salutary effects on cartilage metabolism: A French paradox for osteoarthritis?
Dave, MN; Attur, MG; Patel, JN; Abramson, SB
2004 MAR 15 ;12(11):S50-S50, Osteoarthritis & cartilage
— id: 50139, year: 2004, vol: 12, page: S50, stat: Journal Article,

Utilization of gastrointestinal prophylaxis for aspirin and NSAID-related gastropathy
Greenberg, JD; Bingham, CO; Reed, G; Hinkle, K; Abramson, SB
2004 SEP ;50(9):S316-S316, Arthritis & rheumatism
— id: 49038, year: 2004, vol: 50, page: S316, stat: Journal Article,

Overview of benefit/risk of biological agents
Imperato, A K; Bingham, C O 3rd; Abramson, S B
2004 Sep-Oct;22(5 Suppl 35):S108-S114, Clinical & experimental rheumatology
Targeted tumor necrosis factor-alpha antagonists, first approved by the FDA in 1998, have had a significant impact on the treatment of patients with rheumatoid arthritis. In general, the benefit/ risk ratio for these agents and the IL-1 receptor antagonist, anakinra, has been quite favorable. However, infrequent adverse events can be serious and require continued pharmacovigilance. Infections, particularly tuberculosis and less commonly fungal infections, are among the most serious adverse events, especially given delays in diagnosis due to subtle or atypical presentations. Questions have also arisen regarding whether anti-TNF-alpha agents increase the risk of lymphoma, a complicated issue confounded by the multiple risk factors for lymphoma in patients with rheumatoid arthritis and low observed incidence rates of lymphoma, requiring prolonged monitoring. Additional rare reported complications include systemic lupus erythematosus-like syndromes, congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy). Ongoing post-marketing surveillance of these and other serious adverse events is necessary to determine the true incidence rates, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-alpha antagonists will be required
— id: 48105, year: 2004, vol: 22, page: S108, stat: Journal Article,

Long-term risks associated with biologic response modifiers used in rheumatic diseases
Imperato, Anna K; Smiles, Stephen; Abramson, Steven B
2004 Jun;16(3):199-205, Current opinion in rheumatology
PURPOSE OF REVIEW: The introduction of tumor necrosis factor-alpha antagonists in 1998 has had a significant impact on the treatment of rheumatoid arthritis. However, as use of these agents has increased worldwide, infrequent adverse events that were not apparent in pivotal controlled clinical trials required for registration have emerged. RECENT FINDINGS: These adverse events include serious infections, particularly tuberculosis, which may be atypical in presentation. Concern regarding increased risk of lymphoma has also emerged, although it remains unclear whether the risk exceeds that observed in other rheumatoid arthritis patients with comparable disease activity. Development of a systemic lupus erythematosus-like syndrome, which typically abates after discontinuation of the drug, is another rare complication that was further reported during the past year. Finally, additional cases of congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy) have been reported that appear to be related to the tumor necrosis factor-alpha antagonists. SUMMARY: Additional postmarketing surveillance of these and other serious adverse events is necessary to determine the true risk of their occurrence, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-alpha antagonists will be required
— id: 46027, year: 2004, vol: 16, page: 199, stat: Journal Article,

Nonvertebral infections of the musculoskeletal system by mycobacerium tuberculosis
Kramer SB; Lee HSS; Abramson SB
Tuberculosis Philadelphia : Lippincott Williams & Wilkins, 2004,
— id: 3979, year: 2004, vol: , page: 577, stat: Chapter,

Gastric epithelial cell matrix metalloproteinase secretion is stimulated by H. pvlori and inflammatory cytokines, and inhibited by E prostaglandins: Regulation by MAP kinases
Pillinger, MH; Marjanovic, N; Izmirly, P; Dinsell, V; Tolani, S; Blaser, MJ; Abramson, SB
2004 SEP ;50(9):S327-S327, Arthritis & rheumatism
— id: 49039, year: 2004, vol: 50, page: S327, stat: Journal Article,

Regulation of metalloproteinases and NF-kappaB activation in rabbit synovial fibroblasts via E prostaglandins and Erk: contrasting effects of nabumetone and 6MNA
Pillinger, Michael H; Dinsell, Victoria; Apsel, Beth; Tolani, Sonia N; Marjanovic, Nada; Chan, Edwin S L; Gomez, Paul; Clancy, Robert; Chang, Lih-Fan; Abramson, Steven B
2004 Jul;142(6):973-982, British journal of pharmacology
1 Nabumetone is a prodrug that is converted in vivo into 6-methoxy-2-naphthylacetic acid (6MNA), a cyclooxygenase inhibitor with anti-inflammatory properties. We tested the effects of nabumetone and 6MNA on the inflammatory responses of synovial fibroblasts (SFs). 2 Brief exposures to 6MNA (50-150 microm) had no effect on IL-1beta/TNF-alpha (each 20 ng ml(-1))-stimulated Erk activation. Longer exposures depleted prostaglandin E1 (PGE1) as much as 70%, and stimulated Erk as much as 300%. Nabumetone (150 microm) inhibited Erk activation by 60-80%. 6MNA (50-150 microm) stimulated (approximately 200%) and nabumetone (150 microm) inhibited (approximately 50%) matrix metalloproteinase (MMP)-1, but not MMP-13 secretion from SFs. 3 6MNA stimulation of MMP-1 secretion was inhibited approximately 30% by PGE1 (1 microm) and approximately 80% by the Erk pathway inhibitor UO126 (10 microm), confirming that PGE depletion and Erk activation mediate MMP-1 secretion by 6MNA. 4 Consistent with its role as an Erk inhibitor, nabumetone (150 microm) abrogated 6MNA enhancement of MMP-1 secretion. 5 UO126 (10 microm) and nabumetone (150 microm) inhibited (approximately 70 and 40%, respectively), but 6MNA (150 microm) enhanced (approximately 40%), NF-kappaB activation. 6 Our data indicate that 6MNA shares with other COX inhibitors several proinflammatory effects on synovial fibroblasts. In contrast, nabumetone demonstrates anti-inflammatory and potentially arthroprotective effects that have not been previously appreciated
— id: 48069, year: 2004, vol: 142, page: 973, stat: Journal Article,

Molecular basis of joint destruction in osteoarthritis
Abramson, S
2003 JUL ;62(3):30-31, Annals of rheumatic diseases
— id: 49055, year: 2003, vol: 62, page: 30, stat: Journal Article,

Paracrine pathways of cartilage destruction in osteoarthritis
Abramson, S; Attur, M; Dave, M; Leung, M; Patel, J; Gomez, P; Amin, A
2003 FEB ;5(1):S1-S1, Arthritis research & therapy
— id: 46848, year: 2003, vol: 5, page: S1, stat: Journal Article,

The resolution of inflammation: Prostaglandin E dissociates nuclear trafficking of individual NF-kB subunits (p65, p50) in stimulated rheumatoid synoviocytes
Gomez, PF; Pillinger, M; Clancy, R; Attur, M; Amin, A; Al-mussawir, H; Apsel, B; Bingham, CO; Abramson, SB
2003 SEP ;48(9):S253-S253, Arthritis & rheumatism
— id: 55434, year: 2003, vol: 48, page: S253, stat: Journal Article,

Predictors of aspirin co-prescription among NSAID and COX-2 inhibitor users with cardiovascular risk factors
Greenberg, JD; Bingham, CO; Abramson, SB; Reed, G; Kremer, J
2003 SEP ;48(9):S218-S218, Arthritis & rheumatism
— id: 55433, year: 2003, vol: 48, page: S218, stat: Journal Article,

Differential effects of cyclooxygenase inhibitors on fibroblast-like synovial cells: Regulation of matrix metalloproteinase production via effects on Erk
Pillinger, MH; Dinsell, V; Tolani, SN; Apsel, B; Chang, LF; Gomez, P; Clancy, RM; Abramson, SB
2003 SEP ;48(9):S546-S547, Arthritis & rheumatism
— id: 55445, year: 2003, vol: 48, page: S546, stat: Journal Article,

Cyclooxygenase-2-derived E prostaglandins down-regulate matrix metalloproteinase-1 expression in fibroblast-like synoviocytes via inhibition of extracellular signal-regulated kinase activation
Pillinger, Michael H; Rosenthal, Pamela B; Tolani, Sonia N; Apsel, Beth; Dinsell, Victoria; Greenberg, Jeffrey; Chan, Edwin S L; Gomez, Paul F; Abramson, Steven B
2003 Feb;171(11):6080-6089, Journal of immunology
We examined the regulation of matrix metalloproteinase (MMP) production by mitogen-activated protein kinases and cyclooxygenases (COXs) in fibroblast-like synoviocytes (FLSCs). IL-1beta and TNF-alpha stimulated FLSC extracellular signal-regulated kinase (ERK) activation as well as MMP-1 and -13 release. Pharmacologic inhibitors of ERK inhibited MMP-1, but not MMP-13 expression. Whereas millimolar salicylates inhibited both ERK and MMP-1, nonsalicylate COX and selective COX-2 inhibitors enhanced stimulated MMP-1 release. Addition of exogenous PGE(1) or PGE(2) inhibited MMP-1, reversed the effects of COX inhibitors, and inhibited ERK activation, suggesting that COX-2 activity tonically inhibits MMP-1 production via ERK inhibition by E PGs. Exposure of FLSCs to nonselective COX and selective COX-2 inhibitors in the absence of stimulation resulted in up-regulation of MMP-1 expression in an ERK-dependent manner. Moreover, COX inhibition sufficient to reduce PGE levels increased ERK activity. Our data indicate that: 1) ERK activation mediates MMP-1 but not MMP-13 release from FLSCs, 2) COX-2-derived E PGs inhibit MMP-1 release from FLSCs via inhibition of ERK, and 3) COX inhibitors, by attenuating PGE inhibition of ERK, enhance the release of MMP-1 by FLSC
— id: 46269, year: 2003, vol: 171, page: 6080, stat: Journal Article,

Moderate dose steroids prevent severe flares in a prospective Multicenter study of serologically active, clinically stable systemic lupus erythematosus (SLE) patients
Tseng, C; Buyon, J; Kim, M; Belmont, HM; Mackay, M; Diamond, B; Marder, G; Rosenthal, P; Haines, K; Abramson, S
2003 SEP ;48(9):S260-S261, Arthritis & rheumatism
— id: 55436, year: 2003, vol: 48, page: S260, stat: Journal Article,

Blocking the effects of IL-1 in rheumatoid arthritis protects bone and cartilage
Abramson, S B; Amin, A
2002 Sep;41(9):972-980, Rheumatology (Oxford)
Destruction of articular joints occurs progressively in patients with rheumatoid arthritis (RA). Although the exact aetiology of RA has not been fully elucidated, a large body of evidence supports a role for interleukin-1 (IL-1) in cartilage and bone erosion. In vitro studies suggest that IL-1 can cause cartilage destruction by stimulating the release of matrix metalloproteinases and other degradative products, and it can increase bone resorption by stimulating osteoclast differentiation and activation. In animal models of RA, blocking the effects of IL-1 with either IL-1 receptor antagonist (IL-1Ra; endogenous), anti-IL-1 monoclonal antibodies, or soluble IL-1 type II receptors significantly reduced cartilage destruction and bone erosion. Gene therapy with IL-1Ra was also effective in reducing joint destruction in experimental RA and osteoarthritis (OA) models. In clinical studies, anakinra, a human recombinant IL-1 receptor antagonist (IL-1ra; exogenous), significantly slowed radiographic progression of RA relative to placebo and significantly reduced clinical symptoms when used as monotherapy or in addition to existing methotrexate therapy. These results demonstrate that blocking IL-1 protects bone and cartilage from progressive destruction in RA
— id: 39598, year: 2002, vol: 41, page: 972, stat: Journal Article,

Comparing biologic therapies in rheumatoid arthritis : making sense of the data
Abramson, Steven B
Toronto ON : Journal of Radiology, 2002,
— id: 2154, year: 2002, vol: , page: , stat: ,

Et tu, acetaminophen?
Abramson, Steven B
2002 Nov;46(11):2831-2835, Arthritis & rheumatism
— id: 141616, year: 2002, vol: 46, page: 2831, stat: Journal Article,

"A system biology" approach to bioinformatics and functional genomics in complex human diseases: arthritis
Attur, M G; Dave, M N; Tsunoyama, K; Akamatsu, M; Kobori, M; Miki, J; Abramson, S B; Katoh, M; Amin, A R
2002 Oct;4(4):129-146, Current issues in molecular biology
Human and other annotated genome sequences have facilitated generation of vast amounts of correlative data, from human/animal genetics, normal and disease-affected tissues from complex diseases such as arthritis using gene/protein chips and SNP analysis. These data sets include genes/proteins whose functions are partially known at the cellular level or may be completely unknown (e.g. ESTs). Thus, genomic research has transformed molecular biology from 'data poor' to 'data rich' science, allowing further division into subpopulations of subcellular fractions, which are often given an '-omic' suffix. These disciplines have to converge at a systemic level to examine the structure and dynamics of cellular and organismal function. The challenge of characterizing ESTs linked to complex diseases is like interpreting sharp images on a blurred background and therefore requires a multidimensional screen for functional genomics ('functionomics') in tissues, mice and zebra fish model, which intertwines various approaches and readouts to study development and homeostasis of a system. In summary, the post-genomic era of functionomics will facilitate to narrow the bridge between correlative data and causative data by quaint hypothesis-driven research using a system approach integrating 'intercoms' of interacting and interdependent disciplines forming a unified whole as described in this review for Arthritis
— id: 34864, year: 2002, vol: 4, page: 129, stat: Journal Article,

Differential expression of novel secretory phospholipase A2 enzymes in osteoarthritic and normal human chondrocytes
Bingham, CO; Reddy, S; Attur, M; Amin, A; Abramson, SB
2002 SEP ;46(9):S220-S221, Arthritis & rheumatism
— id: 55552, year: 2002, vol: 46, page: S220, stat: Journal Article,

Intracellular peroxynitrite formation promotes NFKB translocation and apoptosis in cytokine activated chondrocytes
Clancy, R; Gomez, P; Abramson, SB
2002 SEP ;46(9):S594-S594, Arthritis & rheumatism
— id: 55554, year: 2002, vol: 46, page: S594, stat: Journal Article,

Circulating endothelial cells (CEC) in systemic lupus erythematosus: Activation markers and relationship to disease activity
Lee, E; Sesin, C; Abramson, S; Buyon, J; Clancy, R
2002 SEP ;46(9):S214-S214, Arthritis & rheumatism
— id: 55551, year: 2002, vol: 46, page: S214, stat: Journal Article,

II-1beta and TNF-alpha stimulate matrix metalloproteinase-1 expression in fibroblast-like synoviocytes via MAP kinase Erk activation: Regulation by cyclooxygenase-2-derived E series prostaglandins
Pillinger, MH; Rosenthal, P; Dinsell, V; Tolani, S; Abramson, SB
2002 SEP ;46(9):S569-S569, Arthritis & rheumatism
— id: 37125, year: 2002, vol: 46, page: S569, stat: Journal Article,

Controversies in COX-2 selective inhibition
Simon, Lee S; Smolen, Josef S; Abramson, Steven B; Appel, Gerald; Bombardier, Claire; Brater, D Craig; Breedveld, Ferdinand C; Brune, K; Burmester, Gerd R; Crofford, Leslie J; Dougados, Maxime; DuBois, Raymond N; Fitzgerald, Garret A; Frishman, W; Garcia Rodriguez, Luis A; Hochberg, Marc C; Kalden, Joachim R; Laine, Loren; Langman, Michael J S; Prescott, Stephen M; van de Putte, Leo B A; Whelton, Andrew; White, William B; Willaims, Gordon H
2002 Jul;29(7):1501-1510, Journal of rheumatology
— id: 141617, year: 2002, vol: 29, page: 1501, stat: Journal Article,

C3, C4, CH50, anti-dsDNA antibodies and C3a complement split products are specific but not sensitive for predicting flares of systemic lupus (SLE)
Tseng, CE; Abramson, SB; Kim, M; Blemont, HM; Haines, K; Petri, M; Buyon, JP
2002 SEP ;46(9):S214-S214, Arthritis & rheumatism
— id: 37119, year: 2002, vol: 46, page: S214, stat: Journal Article,

Controversies in COX-2 inhibitor therapy. Introduction
Abramson SB
2001 Nov-Dec;19(6 Suppl 25):S1-S2, Clinical & experimental rheumatology
— id: 48716, year: 2001, vol: 19, page: S1, stat: Journal Article,

The role of nitric oxide in tissue destruction
Abramson SB; Amin AR; Clancy RM; Attur M
2001 Dec;15(5):831-845, Bailliere's best practice & research. Clinical rheumatology
Nitric oxide (NO) is synthesized via the oxidation of arginine by a family of nitric oxide synthases (NOS), which are either constitutive (ie. endothelial (ec)NOS and neuronal (nc)NOS) or inducible (iNOS). The production of nitric oxide plays a vital role in the regulation of physiological processes, host defence, inflammation and immunity. Pro-inflammatory effects include vasodilation, oedema, cytotoxicity and the mediation of cytokine-dependent processes that can lead to tissue destruction. Nitric oxide-dependent tissue injury has been implicated in a variety of rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis and osteoarthritis. Conversely, the production of NO by endothelial cell NOS may serve a protective, or anti-inflammatory, function by preventing the adhesion and release of oxidants by activated neutrophils in the microvasculature. In this chapter we describe the multifaceted role of nitric oxide in inflammation and address the potential therapeutic implications of NOS inhibition
— id: 34868, year: 2001, vol: 15, page: 831, stat: Journal Article,

Nitric oxide and inflammatory mediators in the perpetuation of osteoarthritis
Abramson SB; Attur M; Amin AR; Clancy R
2001 Dec;3(6):535-541, Current rheumatology reports
Articular chondrocyte production of nitric oxide (NO) and other inflammatory mediators, such as eicosanoids and cytokines, are increased in human osteoarthritis. The excessive production of nitric oxide inhibits matrix synthesis and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, nitric oxide promotes cellular injury and renders the chondrocyte susceptible to cytokine-induced apoptosis. PGE(2) exerts anabolic and catabolic effects on chondrocytes, depending on the microenvironment and physiologic condition. The increased expression of inducible NOS (iNOS) and cyclo-oxygenase-2 (COX-2) in OA chondrocytes is largely due to the increased expression of pro-inflammatory cytokines, particularly IL-1, which act in an autocrine/paracrine fashion to perpetuate a catabolic state that leads to progressive destruction of articular cartilage. The initiating factors for the production of inflammatory mediators include altered biomechanical forces; their continued production may be augmented by an increase in extracellular matrix proteins acting through ligation of surface integrins
— id: 26505, year: 2001, vol: 3, page: 535, stat: Journal Article,

Controversies in COX-2 inhibitor therapy: closing remarks
Abramson SB; Furst DE; Hochberg MC; Patrono C
2001 Nov-Dec;19(6 Suppl 25):S77-S80, Clinical & experimental rheumatology
— id: 48717, year: 2001, vol: 19, page: S77, stat: Journal Article,

Vascular manifestations of systemic autoimmune diseases
Asherson, Ronald A; Cervera, Richard; Abramson, Steven B; Piette, Jean-Charles; Triplett, Douglas A
Boca Raton FL : CRC Press, 2001,
— id: 2153, year: 2001, vol: , page: , stat: ,

Osteopontin: an intrinsic inhibitor of inflammation in cartilage
Attur MG; Dave MN; Stuchin S; Kowalski AJ; Steiner G; Abramson SB; Denhardt DT; Amin AR
2001 Mar;44(3):578-584, Arthritis & rheumatism
OBJECTIVE: To identify extracellular and intraarticular matrix components that are differentially expressed in normal and osteoarthritis (OA)-affected cartilage and to investigate their functions with respect to regulation of mediators of inflammation. METHODS: Differential-display reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of a pool of messenger RNA (mRNA) from 10 human OA cartilage samples and 5 normal cartilage samples was performed using arbitrary primers. Confirmatory analysis of the up-regulated transcripts of fibronectin (FN) and osteopontin (OPN) was performed by RT-PCR of individual RNA samples from a separate set of donors. The effect of recombinant OPN (or anti-OPN antiserum) on chondrocyte function was examined by analyzing the spontaneous or interleukin-1 (IL-1)-induced release of nitric oxide (NO) and prostaglandin E2 (PGE2) from human OA-affected cartilage under ex vivo conditions. RESULTS: Up-regulation (300-700%) of FN and OPN mRNA was observed in human OA-affected cartilage as compared with normal cartilage. Functional analysis of the role of OPN in OA cartilage showed that 1) Addition of 1 microg/ml (20 nM) of recombinant OPN to human OA-affected cartilage under ex vivo conditions inhibited spontaneous and IL-1beta-induced NO and PGE2 production, and 2) neutralization of intraarticular OPN with anti-OPN antiserum augmented NO production. CONCLUSION: The data indicate that one of the functions of intraarticular OPN, which is overexpressed in OA cartilage, is to act as an innate inhibitor of IL-1, NO, and PGE2 production. These findings suggest that the production of pleiotropic mediators of inflammation that influence cartilage homeostasis, such as NO and PGE2, is regulated by the interaction of chondrocytes with differentially expressed proteins within the extracellular matrix
— id: 26765, year: 2001, vol: 44, page: 578, stat: Journal Article,

Circulating activated endothelial cells in systemic lupus erythematosus: further evidence for diffuse vasculopathy
Clancy R; Marder G; Martin V; Belmont HM; Abramson SB; Buyon J
2001 May;44(5):1203-1208, Arthritis & rheumatism
OBJECTIVE: In flares of systemic lupus erythematosus (SLE), endothelial cells (EC; activated by immune stimuli) are potential participants in the inflammatory processes that contribute to tissue damage. Accordingly, elevated levels of circulating endothelial cells (CEC) may be a marker for vascular injury. This study was undertaken to examine the possibility that stimulated EC are found in the circulation in patients with active SLE. METHODS: The study cohort included 38 patients with SLE and 16 healthy controls. Immunostaining was performed on mononuclear isolates, using mouse P1H12 (endothelial-specific antibody) and rabbit antinitrotyrosine (a 'footprint' of a reactive form of nitric oxide [peroxynitritel). RESULTS: Levels of CEC were significantly higher in patients with active SLE compared with those in healthy controls (mean +/- SEM 32+/-7/ml versus 5+/-2/ml; P = 0.0028) and were correlated positively with plasma C3a in these patients (r = 0.81, P = 0.0008). Furthermore, CEC from these patients expressed an activated phenotype, as indicated by staining for nitrotyrosine. CONCLUSION: Elevated levels of CEC observed in patients with active SLE may represent a marker of endothelial injury. The activated phenotype of these cells suggests that they may be capable of further potentiating vascular injury by the production of inflammatory and prothrombotic mediators and engaging in heterotypic aggregation with neutrophils or platelets
— id: 20665, year: 2001, vol: 44, page: 1203, stat: Journal Article,

Activation of stress-activated protein kinase in osteoarthritic cartilage: evidence for nitric oxide dependence
Clancy R; Rediske J; Koehne C; Stoyanovsky D; Amin A; Attur M; Iyama K; Abramson SB
2001 May;9(4):294-299, Osteoarthritis & cartilage
Objective We have demonstrated in bovine chondrocytes that nitric oxide (NO) mediates IL1 dependent apoptosis under conditions of oxidant stress. This process is accompanied by activation of c-Jun NH2-terminal kinase (JNK; also called stress-activated protein kinase). In these studies we examined activation of JNK in explant cultures of human osteoarthritic cartilage obtained at joint replacement surgery and we characterized the role of peroxynitrite to act as an upstream trigger.Design A novel technique to isolate chondrocyte proteins (<10% of total cartilage protein) from cartilage specimens was developed. It was used to analyse JNK activation by a western blot technique. To examine the hypothesis that chondrocyte JNK activation is a result of increased peroxynitrite, in vitro experiments were performed in which cultured chondrocytes were incubated with this oxidant.Results Activated JNK was detected in the cytoplasm of osteoarthritis (OA) affected chondrocytes but not in that of controls. In vitro, chondrocytes produce NO and superoxide anion. IL-1 (48 h), which induces nitric oxide synthase, resulted in an activation of JNK; this effect was reversed by N-monomethylarginine (NMA). TNFalpha treated chondrocytes at 48 h produce superoxide anion (EPR method). Exposure of cells to peroxynitrite led to an accumulation of intracellular oxidants, in association with JNK activation and cell death by apoptosis.Conclusion We suggest that JNK activation is among the IL-1 elicited responses that injure articular chondrocytes and this activation of JNK is dependent on intracellular oxidant formation (including NO peroxynitrite). In addition, the extraction technique here described is a novel method that permits the quantitation and study of proteins such as JNK involved in the signaling pathways of chondrocytes within osteoarthritic cartilage.
— id: 20617, year: 2001, vol: 9, page: 294, stat: Journal Article,

Osteoarthritis, an inflammatory disease - Potential implication for the selection of new therapeutic targets
Pelletier, JP; Martel-Pelletier, J; Abramson, SB
2001 JUN ;44(6):1237-1247, Arthritis & rheumatism
— id: 54842, year: 2001, vol: 44, page: 1237, stat: Journal Article,

A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee
Pincus, T; Koch, G G; Sokka, T; Lefkowith, J; Wolfe, F; Jordan, J M; Luta, G; Callahan, L F; Wang, X; Schwartz, T; Abramson, S B; Caldwell, J R; Harrell, R A; Kremer, J M; Lautzenheiser, R L; Markenson, J A; Schnitzer, T J; Weaver, A; Cummins, P; Wilson, A; Morant, S; Fort, J
2001 Jul;44(7):1587-1598, Arthritis & rheumatism
OBJECTIVE: To perform a randomized, double-blind, crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee. METHODS: Patients in 12 ambulatory care settings were eligible if they were age >40 years and if they had Kellgren/Lawrence radiographic grade 2-4 osteoarthritis of the knee or hip and a score of > or =30 mm on a 100-mm visual analog pain scale. Patients were randomized to one of two groups, 75 mg diclofenac + 200 microg misoprostol twice daily or 1,000 mg acetaminophen 4 times daily (each for 6 weeks), and were then crossed over to the other treatment for 6 weeks. A placebo was included in each treatment regimen to enable double blinding. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index and the visual analog pain scale of the Multidimensional Health Assessment Questionnaire. Safety was assessed using a standard form to review adverse events. RESULTS: We enrolled 227 patients, of whom 218 provided data for the first treatment period and 181 provided data for both treatment periods. Significantly higher levels of improvement in the primary outcomes were seen for diclofenac + misoprostol than for acetaminophen (P < 0.001). Adverse events were more common when patients took diclofenac + misoprostol (P = 0.046). Diclofenac + misoprostol was rated as 'better' or 'much better' by 57% of the 174 patients who provided such ratings for both treatment periods, while acetaminophen was rated as 'better' or 'much better' by 20% of these patients, and 22% reported no difference (P < 0.001). Differences favoring diclofenac + misoprostol over acetaminophen were greater in patients with more severe osteoarthritis according to baseline pain scores, radiographs, or number of involved joints. CONCLUSION: Patients with osteoarthritis of the hip or knee had significantly greater improvements in pain scores over 6 weeks with diclofenac + misoprostol than with acetaminophen, although patients with mild osteoarthritis had similar improvements with both drugs. Acetaminophen was associated with fewer adverse events
— id: 90247, year: 2001, vol: 44, page: 1587, stat: Journal Article,

COX-2, NO, and cartilage damage and repair
Amin AR; Dave M; Attur M; Abramson SB
2000 Dec;2(6):447-453, Current rheumatology reports
The production of nitric oxide (NO) and prostaglandin E2 (PGE(2)) is increased in human osteoarthritis-affected cartilage. These and other inflammatory mediators are spontaneously released by OA cartilage explants ex vivo. The excessive production of nitric oxide inhibits matrix synthesis, and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, nitric oxide promotes cellular injury, and renders the chondrocyte susceptible to cytokine-induced apoptosis. PGE(2) exerts both anabolic and catabolic effects on chondrocytes, depending on the microenvironment and physiological condition. Thus, NO and PGE(2), produced by activated chondrocytes in diseased cartilage, may modulate disease rogression in osteoarthritis, and should therefore be considered potential targets for therapeutic intervention
— id: 48712, year: 2000, vol: 2, page: 447, stat: Journal Article,

Reversal of autocrine and paracrine effects of IL-1 in human arthritis by type II IL-1 decoy receptor:Potential for pharmacological intervention
Attur MG; Dave M; Cipolletta C; Kang P; Goldring MB; Patel IR; Abramson SB; Amin AR
2000 Dec;275(51):40307-40315, Journal of biological chemistry
Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, play a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family related genes in human joint tissue. Gene array analysis of human (normal and OA-affected) cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses of soluble (s) IL-1RII, at picomolar concentrations, significantly inhibited IL-1? induced nitric oxide (NO) and/or prostaglandin (PG) E2 production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC50 for inhibition of NO production by sIL-1RII was two log orders lower than that for sIL-1RI. IL-1RII+ transfected human chondrocytes were resistant to IL-1 induced IL-1? mRNA accumulation, and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) by chondrocytes may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed towards correcting this unfavorable tissue dependent imbalance
— id: 11486, year: 2000, vol: 275, page: 40307, stat: Journal Article,

Functional genomic analysis in arthritis-affected cartilage: yin-yang regulation of inflammatory mediators by alpha 5 beta 1 and alpha V beta 3 integrins
Attur MG; Dave MN; Clancy RM; Patel IR; Abramson SB; Amin AR
2000 Mar 1;164(5):2684-2691, Journal of immunology
Osteoarthritis-affected cartilage exhibits enhanced expression of fibronectin (FN) and osteopontin (OPN) mRNA in differential display and bioinformatics screen. Functional genomic analysis shows that the engagement of the integrin receptors alpha 5 beta 1 and alpha v beta 3 of FN and OPN, respectively, have profound effects on chondrocyte functions. Ligation of alpha 5 beta 1 using activating mAb JBS5 (which acts as agonist similar to FN N-terminal fragment) up-regulates the inflammatory mediators such as NO and PGE2 as well as the cytokines, IL-6 and IL-8. Furthermore, up-regulation of these proinflammatory mediators by alpha 5 beta1 integrin ligation is mediated via induction and autocrine production of IL-1 beta, because type II soluble IL-1 decoy receptor inhibits their production. In contrast, alpha v beta 3 complex-specific function-blocking mAb (LM609), which acts as an agonist similar to OPN, attenuates the production of IL-1 beta, NO, and PGE2 (triggered by alpha 5 beta 1, IL-1 beta, IL-18, or IL-1 beta, TNF-alpha, plus LPS) in a dominant negative fashion by osteoarthritis-affected cartilage and activated bovine chondrocytes. These data demonstrate a cross-talk in signaling mechanisms among integrins and show that integrin-mediated 'outside in' and 'inside out' signaling very likely influences cartilage homeostasis, and its deregulation may play a role in the pathogenesis of osteoarthritis
— id: 9724, year: 2000, vol: 164, page: 2684, stat: Journal Article,

Differential anti-inflammatory effects of immunosuppressive drugs: cyclosporin, rapamycin and FK-506 on inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and PGE2 production
Attur MG; Patel R; Thakker G; Vyas P; Levartovsky D; Patel P; Naqvi S; Raza R; Patel K; Abramson D; Bruno G; Abramson SB; Amin AR
2000 Jan;49(1):20-26, Inflammation research
OBJECTIVE AND DESIGN: Cyclosporin, FK-506 and rapamycin have similar but distinct modes of interaction with cyclophilins, calcineurins and transcription factors. These immunosuppressive drugs have also been shown to inhibit cytotoxic and inflammatory responses in macrophage. Therefore, we evaluated the mechanism of action of these drugs on iNOS and COX-2 expression by macrophages, the products of which (NO and PGE2) have cytotoxic and proinflammatory activities. MATERIALS AND METHODS: The murine macrophage cell line RAW 264.7 was grown as monolayer cultures. The effects of pharmacologically relevant concentrations of cyclosporin, rapamycin and FK-506 were evaluated in the presence and absence of lipopolysaccharide (LPS) which is a known inducer of iNOS and COX-2. Subsequently the expression of iNOS and COX-2 were analyzed by Western and Northern analysis. The production of NO and PGE2 were assayed by Greiss and RIA respectively. RESULTS: Cyclosporin (1-5 microg/ml) and rapamycin (1.0-10 nM) but not FK-506 (5-10 nM) inhibited both iNOS and COX-2 expression at mRNA level which led to significant inhibition of NO and PGE2 production. CONCLUSION: These studies characterize differential mechanistic capacity of the immunophilin-binding immunosuppressive drugs (comparable to hydrocortisone) to inhibit both iNOS and COX-2 expression. Inhibition of iNOS and COX-2 mRNA accumulation by cyclosporin and rapamycin seem to be distinct. These studies also highlight potential anti-inflammatory properties of these drugs in addition to their known immunosuppressive activity
— id: 48710, year: 2000, vol: 49, page: 20, stat: Journal Article,

Model protocol to study pharmacogenomics in inflammatory diseases: Human rheumatoid arthritis
Attur, M; Bingham, CO; Dave, M; Abramson, SB; Amin, AR
2000 JAN ;49(1):29-33, Drug development research
Pharmacogenomics is a revolution in molecular medicine, especially in view of the development of microarray technologies and proteomics to monitor gene and protein expression. The ability to monitor up to 60,000 potential parameters in a clinical setting gives a whole new meaning to 1) toxic effects, 2) side effects, 3) primary and secondary targets, and il) drug resistance and nonresponders during a clinical trial. Pharmacogenomics may set a new standard to monitor the effects of drugs such as NSAIDS or disease-modifying drugs in diseases such as arthritis. The present article outlines a pharmacogenomics clinical protocol that is in progress, a study that will address some of the above questions. (C) 2000 Wiley-Liss, Inc
— id: 54733, year: 2000, vol: 49, page: 29, stat: Journal Article,

Functional genomic analysis in arthritis-affected cartilage: Yin-yang regulation of inflammatory mediators by a5bl and avb3
Attur, MG; Dave, MN; Clancy, RM; Patel, IR; Abramson, SB; Amin, AR
2000 APR 20 ;14(6):A1152-A1152, FASEB journal
— id: 54645, year: 2000, vol: 14, page: A1152, stat: Journal Article,

Gene discovery and functional genomics in human osteoarthritis: Upregulation of osteopontin in human-osteoarthritis affected cartilage and regulation of of nitric oxide and prostaglandin E2
Attur, MG; Dave, MN; Stuchin, SA; Kowalski, AS; Lopez, CA; Zhang, J; Abramson, SB; Denhardt, DT; Amin, AR
2000 APR 20 ;14(6):A1152-A1152, FASEB journal
— id: 54644, year: 2000, vol: 14, page: A1152, stat: Journal Article,

A novel mechanism of action of chemically modified tetracyclines (CMTS): inhibition of COX-2 mediated PGE2 production
Attur, MG; Patel, RN; Dave, MN; Patel, IV; Abramson, SB; Amin, AR
2000 APR 20 ;14(6):A1078-A1078, FASEB journal
— id: 54640, year: 2000, vol: 14, page: A1078, stat: Journal Article,

Tetracycline upregulates COX-2 expression and PGE2 production independent of its effect on nitric oxide
Attur, MG; Patel, RN; Patel, PD; Abramson, SB; Amin, AR
2000 APR 20 ;14(6):A1129-A1129, FASEB journal
— id: 54642, year: 2000, vol: 14, page: A1129, stat: Journal Article,

Nitric oxide synthase/COX cross-talk: nitric oxide activates COX-1 but inhibits COX-2-derived prostaglandin production
Clancy R; Varenika B; Huang W; Ballou L; Attur M; Amin AR; Abramson SB
2000 Aug 1;165(3):1582-1587, Journal of immunology
It is recognized that there is molecular cross-talk between the inflammatory mediators NO and PGs that may regulate tissue homeostasis and contribute to pathophysiological processes. However, the literature is divided with respect to whether NO activates or inhibits PG production. In this study, we sought to determine whether conflicting observations could be accounted for by divergent effects of NO on the two cyclooxygenase (COX) isoforms. Exposure of resting macrophages to NO (30 microM) enhanced PGE2 release by 4. 5-fold. This enhancement was inhibited by indomethacin but not by the COX-2 selective inhibitor NS398. To separate the activation of phospholipase A2 and COX, we performed experiments using fibroblasts derived from COX-1-deficient or COX-2-deficient mice. These cells exhibit increased basal PG production, which is due to a constitutively stimulated cytosolic phospholipase A2 and enhanced basal expression of the remaining COX isozyme. The exposure of COX- 2-deficient cells to exogenous NO (10 microM) resulted in a 2.4-fold increase of PGE2 release above controls. Further studies indicated that NO stimulated PGE2 release in COX-2-deficient cells, without altering COX-1 mRNA or protein expression. In contrast, NO inhibited COX-2-derived PGE2 production in both LPS-stimulated macrophages and COX-1 knockout cells. This inhibition was associated with both decreased expression and nitration of COX-2. Thus, these studies demonstrate divergent effects of NO on the COX isoforms. The regulation of PGE production by NO is therefore complex and will depend on the local environment in which these pleiotropic mediators are produced
— id: 48711, year: 2000, vol: 165, page: 1582, stat: Journal Article,

Acetylcholine prevents intercellular adhesion molecule 1 (CD54)-induced focal adhesion complex assembly in endothelial cells via a nitric oxide-cGMP-dependent pathway
Clancy RM; Abramson SB
2000 Oct;43(10):2260-2264, Arthritis & rheumatism
OBJECTIVE: Nitric oxide (NO) is induced by exposure of endothelial cells (EC) to acetylcholine, where it acts in a paracrine manner to relax smooth muscle and as a defensive molecule to inhibit the adhesion of leukocytes to EC. The mechanism(s) of the antiadhesive properties of constitutive NO are poorly understood. In these studies, we found that NO induced by acetylcholine exerts autocrine effects, which interfere with normal adhesion mechanisms. METHODS: The function of the adhesion molecule intercellular adhesion molecule 1 (CD54) of EC was measured using latex beads coated with antibody to CD54 as a model for CD54 ligation by the leukocyte beta2 integrin. Recruitment of filamentous actin (F-actin) and of the signaling molecule vasodilator-stimulated phosphoprotein (VASP) was measured by immunofluorescence microscopy. RESULTS: Exposure of EC to anti-CD54 beads induced the subplasmalemmal assembly of F-actin and VASP. Acetylcholine blocked the anti-CD54 bead-induced translocation of F-actin and VASP; this effect was reversed by inhibition of NO production. The NO action did not interfere with binding, but completely inhibited the assembly of the focal activation complex, which we believe is necessary for firm heterotypic adhesion between leukocyte and EC. Further studies indicated that the NO effect was due to its capacity to raise cGMP. Platelet endothelial cell adhesion molecule 1 (CD31, also implicated in leukocyte adhesion) did not mimic CD54 responses. CONCLUSION: These results indicate that the ligation of endothelial cell CD54 induces the assembly of subplasmalemmal F-actin and the recruitment of VASP. NO derived from constitutive nitric oxide synthase acts to disrupt these CD54-elicited endothelial cell responses. This action may protect vascular endothelium from leukocyte-mediated injury
— id: 39535, year: 2000, vol: 43, page: 2260, stat: Journal Article,

Basic biology and clinical application of specific cyclooxygenase-2 inhibitors
Crofford LJ; Lipsky PE; Brooks P; Abramson SB; Simon LS; van de Putte LB
2000 Jan;43(1):4-13, Arthritis & rheumatism
In summary, COX-2 is a highly regulated gene product that catalyzes the local production of PGs in pathologic and physiologic situations (Figure 1). It is clear that COX-2 is the isoform responsible for production of the PGs that mediate inflammation, pain, and fever. However, the role for COX-2 in normal physiology is still being defined. Specific COX-2 inhibitors represent a significant conceptual advance in therapy for patients with arthritis. Although there is no expectation of superior efficacy, clinical trials suggest that efficacy will be comparable with that of nonselective NSAIDs. Clinical trials demonstrate the potential for clinically meaningful reductions in the incidence of the most serious GI complications found with nonselective NSAIDs, i.e., ulcer, perforation, and GI bleeding. Over the next several years, treatment of large numbers of patients with specific COX-2 inhibitors will help to define the biology of COX-2. The magnitude of this advance in the therapy of rheumatic diseases is yet to be accurately determined, but the development of specific COX-2 inhibitors may afford significant new treatment options for many patients
— id: 9725, year: 2000, vol: 43, page: 4, stat: Journal Article,

Analysis of the effect of COX-2 specific inhibitors and recommendations for their use in clinical practice
Lipsky PE; Abramson SB; Breedveld FC; Brook P; Burmester R; Buttgereit F; Cannon GW; Catella-Lawson F; Crofford LJ; Doherty M; Dougados M; DuBois RN; Froelich J; Garcia Rodriguez LA; Gibofsky A; Hernandez-Diaz S; Hochberg MC; Krause A; Liang MH; Machold K; Peloso PM; Raisz LG; Schayes B; Scheiman JM; Simon LS; Smolen J
2000 Jun;27(6):1338-1340, Journal of rheumatology
— id: 9722, year: 2000, vol: 27, page: 1338, stat: Journal Article,

Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease
Lipsky PE; Brooks P; Crofford LJ; DuBois R; Graham D; Simon LS; van de Putte LB; Abramson SB
2000 Apr 10;160(7):913-920, Archives of internal medicine
Originally suggested to function mainly in inflammatory situations, recent data have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive biologic processes, renal and neurologic function, and the antithrombotic activities of endothelial cells. As cyclooxygenase-2-specific inhibitors have recently become available as analgesic and anti-inflammatory drugs, a comprehensive view of this rapidly evolving field is necessary to anticipate both the potential therapeutic benefits and toxic effects associated with these agents
— id: 9723, year: 2000, vol: 160, page: 913, stat: Journal Article,

Regulation of cytosolic COX-2 and prostaglandin E2 production by nitric oxide in activated murine macrophages
Patel, RN; Attur, MG; Dave, MN; Abramson, SB; Amin, AR
2000 APR 20 ;14(6):A1129-A1129, FASEB journal
— id: 54643, year: 2000, vol: 14, page: A1129, stat: Journal Article,

The role of COX-2 produced by cartilage in arthritis
Abramson SB
1999 Jul;7(4):380-381, Osteoarthritis & cartilage
The development of selective COX-2 inhibitors has renewed interest in the treatment of osteoarthritis with prostaglandin synthesis inhibitors. The therapeutic effects of COX inhibitors in OA may be due to their analgesic properties. However, it is now apparent that stable prostaglandins are produced by chondrocytes in OA cartilage where they may act to alter matrix synthesis and degradation. In vitro, PGEs activate metalloproteinases, but also enhance proteoglycan and type II collagen synthesis. Their net effect on matrix homeostasis in vivo remains to be determined
— id: 56459, year: 1999, vol: 7, page: 380, stat: Journal Article,

Patients, physicians, and clinical trials: the other side of the coins
Abramson SB; Flexner C; Snyderman R; Dieterich DT; Korn D; Temple R; Sherwood L; Goldblatt D
1999 Sep;47(8):343-357, Journal of investigative medicine
— id: 9726, year: 1999, vol: 47, page: 343, stat: Journal Article,

Nitric oxide synthase and cyclooxygenases: distribution, regulation, and intervention in arthritis
Amin AR; Attur M; Abramson SB
1999 May;11(3):202-209, Current opinion in rheumatology
Nitric oxide (NO) and prostaglandin E2 (PGE2) are two pleiotropic inflammatory mediators overproduced in arthritis-affected joints. The inducible isoform of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) are found both in the synovial tissue and in the cartilage. Their expression is regulated by catabolic cytokines, such as interleukin-1beta and tumor necrosis factor-alpha. These inflammatory mediators play a profound role in the pathogenic processes that arise in the pannus of rheumatoid arthritis and also interfere with cartilage homeostasis in osteoarthritis. Several drugs, including nonsteroidal anti-inflammatory drugs, immunosuppressive agents, and tetracyclines, attenuate the activity of NO and PGE2. These pleiotropic mediators are targets for pharmacologic intervention and gene therapy
— id: 48704, year: 1999, vol: 11, page: 202, stat: Journal Article,

The pleiotropic functions of aspirin: mechanisms of action
Amin AR; Attur MG; Pillinger M; Abramson SB
1999 Oct 15;56(3-4):305-312, Cellular & molecular life sciences: CMLS
Recent studies have suggested that aspirin and aspirin-like compounds have a variety of actions in addition to their well-studied ability to inhibit cyclooxygenases. These actions include inhibition of the uncoupling of oxidative phosphorylation, decreases in adenosine triphosphate stores. increases in extracellular adenosine, downregulation of the expression and activity of inducible nitric oxide synthetase, inhibition and/or stimulation of various mitogen-activated protein kinase activities and inhibition of nuclear factor binding kappaB site (NF-kappaB) activation. Moreover, aspirin-like compounds have recently been shown to have previously unappreciated clinical and biological effects, some apparently independent of cyclooxygenase. In this review we discuss the various mechanisms of action of aspirin-like compounds and their relevance to clinical disease and therapy
— id: 23915, year: 1999, vol: 56, page: 305, stat: Journal Article,

Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide
Attur MG; Patel RN; Patel PD; Abramson SB; Amin AR
1999 Mar 15;162(6):3160-3167, Journal of immunology
Tetracyclines (doxycycline and minocycline) augmented (one- to twofold) the PGE2 production in human osteoarthritis-affected cartilage (in the presence or absence of cytokines and endotoxin) in ex vivo conditions. Similarly, bovine chondrocytes stimulated with LPS showed (one- to fivefold) an increase in PGE2 accumulation in the presence of doxycycline. This effect was observed at drug concentrations that did not affect nitric oxide (NO) production. In murine macrophages (RAW 264.7) stimulated with LPS, tetracyclines inhibited NO release and increased PGE2 production. Tetracycline(s) and L-N-monomethylarginine (L-NMMA) (NO synthase inhibitor) showed an additive effect on inhibition of NO and PGE2 accumulation, thereby uncoupling the effects of tetracyclines on NO and PGE2 production. The enhancement of PGE2 production in RAW 264.7 cells by tetracyclines was accompanied by the accumulation of both cyclooxygenase (COX)-2 mRNA and cytosolic COX-2 protein. In contrast to tetracyclines, L-NMMA at low concentrations (< or = 100 microM) inhibited the spontaneous release of No in osteoarthritis-affected explants and LPS-stimulated macrophages but had no significant effect on the PGE2 production. At higher concentrations, L-NMMA (500 microM) inhibited NO release but augmented PGE2 production. This study indicates a novel mechanism of action of tetracyclines to augment the expression of COX-2 and PGE2 production, an effect that is independent of endogenous concentration of NO
— id: 48702, year: 1999, vol: 162, page: 3160, stat: Journal Article,

Joint efforts: tackling arthritis using gene therapy. First International Meeting on the Gene Therapy of Arthritis and Related Disorders. Bethesda, MD, USA, 2-3 December 1998
Evans CH; Rediske JJ; Abramson SB; Robbins PD
1999 Apr;5(4):148-151, Molecular medicine today
— id: 9727, year: 1999, vol: 5, page: 148, stat: Journal Article,

Selective cyclooxygenase-2 inhibitors
Golden BD; Abramson SB
1999 May;25(2):359-378, Rheumatic diseases clinics of North America
The identification of COX-2 less than a decade ago has been followed by an unprecedented period of discovery and drug development. An awareness of the existence of two COX isoforms has led to potential novel insights into disease pathogenesis (arthritis, Alzheimer's disease, cancer) and the regulation of normal physiology (brain, kidney). The preliminary in vivo experience with COX-2-selective inhibitors has provided evidence for proof of concept for the COX-1 and COX-2 hypothesis, namely that the selective inhibition of COX-2-derived prostaglandins is sufficient to inhibit inflammation and is nonulcerogenic. It may be that we have moved closer to the 'better aspirin' envisioned by Sir John Vane for the treatment of degenerative and inflammatory arthritides; however, caution is still warranted. Some toxicities of current NSAIDs may result from COX-2 inhibition, as in the kidney and brain; such side effects may be shared by the selective compounds. In addition, unexpected toxicities may arise simply because new chemical compounds will be widely prescribed. Finally, since the efficacy of traditional NSAIDs derives largely from their capacity to inhibit COX-2, it may be that the COX-2 selective drugs will not prove to be therapeutically superior to available agents. Given the well-recognized toxicity of NSAIDs, however, the availability of COX-2-selective agents promises to provide significant advantage to patients with chronic diseases, such as RA and OA
— id: 48706, year: 1999, vol: 25, page: 359, stat: Journal Article,

Regulation of cytosolic COX-2 and prostaglandin E2 production by nitric oxide in activated murine macrophages
Patel R; Attur MG; Dave M; Abramson SB; Amin AR
1999 Apr 1;162(7):4191-4197, Journal of immunology
Murine macrophages (RAW 264.7) when stimulated with LPS show 90% distribution of cyclooxygenase-2 (COX-2) in the nuclear fraction and approximately 10% in the cytosolic fraction. Further analysis of this cytosolic fraction at 100,000 x g indicates that the COX-2 is distributed both in the 100,000 x g soluble fraction and membrane fraction. Stimulation of RAW 264.7 cells with LPS in the presence of inducible nitric oxide synthase inhibitor L-NMMA at concentrations that inhibit nitrite accumulation by </=80% is inadequate to augment PGE2 production. However, inhibition of nitrite accumulation by >/=85% with higher concentrations of L-NMMA shows 1) up-regulation of PGE2 production, 2) accumulation of COX-2 protein in the 100,000 x g soluble and membrane fractions of the cytosolic fraction, and 3) with no significant effects on the accumulation of COX-2 mRNA. These experiments suggest that low concentrations of nitric oxide (10-15% of the total) attenuate PGE2 production in response to LPS in RAW 264.7 cells. This inhibition is, in part, due to decreased expression of cytosolic COX-2 protein
— id: 48703, year: 1999, vol: 162, page: 4191, stat: Journal Article,

Regulation of nitric oxide and prostaglandin E2 production by CSAIDS (SB203580) in murine macrophages and bovine chondrocytes stimulated with LPS
Patel R; Attur MG; Dave MN; Kumar S; Lee JC; Abramson SB; Amin AR
1999 Jun;48(6):337-343, Inflammation research
OBJECTIVE AND DESIGN: To compare two anti-inflammatory drugs: CSAIDS (SB203580) and hydrocortisone on iNOS and COX-2 expression. MATERIAL OR SUBJECTS: Murine macrophages and bovine chondrocytes stimulated with LPS and human OA-affected cartilage were used in this study. TREATMENT: The macrophages and chondrocytes were preincubated (30 min) with 0.1-1.0 microM CSAIDS or 10 microM of hydrocortisone before stimulating them with 1-100 microg/ml LPS. METHODS: The end products of iNOS and COX-2: nitric oxide (NO) and PGE2 were estimated by Greiss method and RIA, respectively. RESULTS: CSAIDS (1 microM) inhibited the production of NO and PGE2 (p< or =0.01) in bovine chondrocytes, but not in murine macrophages (RAW 264.7) (p< or =0.1). In fact, CSAIDS (in murine macrophages) marginally augmented nitrite accumulation (approximately 20%) at 14-24 h of LPS stimulation. Western blot analysis of COX-2 in bovine chondrocytes show decrease in COX-2 expression by hydrocortisone but not CSAIDS, although hydrocortisone and CSAIDS inhibit PGE2 accumulation. Hydrocortisone inhibited both PGE2 and NO production significantly (p< or =0.01) in murine macrophages. Furthermore, hydrocortisone significantly inhibited (p< or =0.01) PGE2 but marginally (p< or =0.05) NO in bovine chondrocytes. CONCLUSION: These experiments demonstrate differential action of CSAIDS and hydrocortisone on NO and PGE2 production in bovine chondrocytes and RAW 264.7 cells
— id: 48707, year: 1999, vol: 48, page: 337, stat: Journal Article,

A novel mechanism of action of chemically modified tetracyclines: inhibition of COX-2-mediated prostaglandin E2 production
Patel RN; Attur MG; Dave MN; Patel IV; Stuchin SA; Abramson SB; Amin AR
1999 Sep 15;163(6):3459-3467, Journal of immunology
Tetracyclines (doxycycline and minocycline) inhibit inducible NO synthase expression and augment cyclooxygenase (COX)-2 expression and PGE2 production. In contrast, chemically modified tetracyclines (CMTs), such as CMT-3 and -8 (but not CMT-1, -2, and -5), that lack antimicrobial activity, inhibit both NO and PGE2 production in LPS-stimulated murine macrophages, bovine chondrocytes, and human osteoarthritis-affected cartilage, which spontaneously produces NO and PGE2 in ex vivo conditions. Furthermore, CMT-3 augments COX-2 protein expression but inhibits net PGE2 accumulation. This coincides with the ability of CMT-3 and -8 to inhibit COX-2 enzyme activity in vitro. The action of CMTs is distinct from that observed with tetracyclines because 1) CMT-3-mediated inhibition of PGE2 production coincides with modification of COX-2 protein, which is distinct from the nonglycosylated COX-2 protein generated in the presence of tunicamycin, as observed by Western blot analysis and 2) CMT-3 and -8 have no significant effect on COX-2 mRNA accumulation. In contrast, CMT-3 and -8 do not inhibit COX-1 expression in A549 human epithelial cells at the level of protein and mRNA accumulation or modification of COX-1 protein. CMT-3 and -8 inhibit the sp. act. of COX-2 (but not COX-1) in cell-free extracts. These results demonstrate differential action of CMT-3 (Metastat) on COX-1 and -2 expression, which is distinct from other tetracyclines
— id: 48708, year: 1999, vol: 163, page: 3459, stat: Journal Article,

Second International Workshop of the Osteoarthritis Research Society International (OARSI) - Florence, Italy, - 15-17 October 1998 - Foreword
Pelletier, JP; Abramson, SB
1999 JUL ;7(4):359-360, Osteoarthritis & cartilage
— id: 54011, year: 1999, vol: 7, page: 359, stat: Journal Article,

SLE: mechanisms of vascular injury
Abramson SB; Belmont HM
1998 Apr;33(4):107-10, 113, Hospital practice (office edition)
The chronic elevation of complement split products seen in many patients with systemic lupus erythematosus should be regarded as equivalent to silent hypertension, or hyperglycemia in a patient with incipient diabetes mellitus. Although the consequences may not be immediately evident, such patients should be monitored and perhaps even treated
— id: 9730, year: 1998, vol: 33, page: 107, stat: Journal Article,

The role of nitric oxide in articular cartilage breakdown in osteoarthritis
Amin AR; Abramson SB
1998 May;10(3):263-268, Current opinion in rheumatology
It is increasingly appreciated that mediators typically associated with inflammatory arthritis, such as catabolic cytokines and nitric oxide, are produced by synovium and cartilage in osteoarthritis. The role that such mediators play in the progression of cartilage degradation in osteoarthritis is under intensive investigation. Nitric oxide is a highly reactive, cytotoxic free radical that has been implicated in tissue injury in a variety of diseases. Cartilage obtained from patients with osteoarthritis produces significant amounts of nitric oxide ex vivo, even in the absence of added stimuli such as interleukin-1 or lipopolysaccharide. In vitro, nitric oxide exerts detrimental effects on chondrocyte functions, including the inhibition of collagen and proteoglycan synthesis, enhanced apoptosis, and an inhibition of B1 integrin-dependent adhesion to the extra-cellular matrix. This paper reviews recent observations regarding the role of nitric oxide in osteoarthritis and presents evidence suggesting that the inhibition of nitric oxide production could be a desirable future therapeutic strategy
— id: 9729, year: 1998, vol: 10, page: 263, stat: Journal Article,

Localization and regulation of COX-2 by nitric oxide in activated murine macrophages
Amin, A; Attur, M; Dave, M; Abramson, S
1998 SEP ;41(9):S143-S143, Arthritis & rheumatism
— id: 53739, year: 1998, vol: 41, page: S143, stat: Journal Article,

Autocrine production of IL-1-beta by human osteoarthritis-affected cartilage and differential regulation of endogenous nitric oxide IL-6, prostaglandin E-2 and IL-8
Amin, AR; Attur, MG; Patel, IR; Patel, RN; Abramson, SB
1998 MAR ;46(3):226A-226A, Journal of investigative medicine
— id: 53498, year: 1998, vol: 46, page: 226A, stat: Journal Article,

Inflammatory mediators (nitric oxide PGE(2)) spontaneously produced by osteoarthritis-affected cartilage regulate stromelysin (MMP-3) production
Amin, AR; Barail, V; Attur, M; Patel, R; Abramson, SB
1998 MAR ;46(3):226A-226A, Journal of investigative medicine
— id: 53497, year: 1998, vol: 46, page: 226A, stat: Journal Article,

TNF-alpha convertase (TACE) from human arthritis-affected cartilage isolation of cDNA by differential display, expression of the active enzyme and regulation of TNF-alpha
Amin, AR; Patel, IR; Attur, MG; Patel, R; Stuchin, SA; Abagyan, R; Abramson, SB
1998 MAR ;46(3):226A-226A, Journal of investigative medicine
— id: 53499, year: 1998, vol: 46, page: 226A, stat: Journal Article,

Tetracyclines upregulate COX-2 expression and PGE(2) production independently from the inhibition of nitric oxide
Amin, AR; Patel, RN; Attur, MG; Patel, PD; Abramson, SB
1998 MAR ;46(3):227A-227A, Journal of investigative medicine
— id: 53500, year: 1998, vol: 46, page: 227A, stat: Journal Article,

Tetracyclines upregulate COX-2 expression and PGE(2) production independently from the inhibition of nitric oxide
Arnin, AR; Patel, RN; Attur, MG; Patel, PD; Abramson, SB
1998 SEP ;41(9):S342-S342, Arthritis & rheumatism
— id: 53749, year: 1998, vol: 41, page: S342, stat: Journal Article,

Autocrine production of IL-1 beta by human osteoarthritis-affected cartilage and differential regulation of endogenous nitric oxide, IL-6, prostaglandin E2, and IL-8
Attur MG; Patel IR; Patel RN; Abramson SB; Amin AR
1998 Jan-Feb;110(1):65-72, Proceedings of the Association of American Physicians
Interleukin-1 beta (IL-1 beta) plays a central role in the pathophysiology of cartilage damage and degradation in arthritis. In noninflammatory arthropathies such as osteoarthritis (OA), the synovial-derived IL-1 beta has been implicated in the disease process. In this study, we report that human OA-affected cartilage demonstrates upregulated IL-1 beta mRNA not seen in normal cartilage. The OA-affected cartilage in ex vivo conditions spontaneously releases detectable amounts of autocrine IL-1 beta, nitric oxide (NO), and prostaglandin E2 (PGE2), known to be involved in cartilage damage and inflammation, that cannot be detected in normal cartilage. The autocrine IL-1 beta released by the OA-affected cartilage (for at least 72 hr in ex vivo conditions) is present in sufficient quantities to modulate NO and PGE2 production because addition of recombinant soluble IL-1 beta receptor (but not soluble tumor necrosis factor-alpha receptor) and cytokine-suppressive antiinflammatory drugs (CSAIDs) significantly attenuates the spontaneous release of NO and PGE2. Furthermore, OA-affected cartilage releases significant amounts of IL-6 and IL-8 in ex vivo conditions. Addition of CSAIDs to OA-affected cartilage differentially regulates IL-6 and IL-8 production by inhibiting the spontaneous release of IL-6 but not IL-8 in ex vivo conditions. These experiments demonstrate that the human OA-affected cartilage itself releases sufficient amounts of functionally active autocrine IL-1 beta that can modulate endogenous NO, PGE2, and IL-6, but not IL-8, all of which are known to be stimulated by IL-1 beta in vitro. These IL-1 beta induced pleotropic inflammatory mediators in OA-affected cartilage may be sufficient to facilitate or augment cartilage degradation and inhibit cartilage repair, and therefore lead the cartilage into an autodestructive pathway in osteoarthritis
— id: 7997, year: 1998, vol: 110, page: 65, stat: Journal Article,

Regulation of nitric oxide production by salicylates and tenidap in human OA-affected cartilage, rat chondrosarcomas and bovine chondrocytes
Attur MG; Patel R; DiCesare PE; Steiner GC; Abramson SB; Amin AR
1998 Jul;6(4):269-277, Osteoarthritis & cartilage
OBJECTIVE: To examine the effects of non-steroidal anti-inflammatory drugs (NSAIDS) on nitric oxide (NO) and prostaglandin E2 (PGE2) production in chondrocytes from three different species. METHODS: We have estimated NO production by Griess method, and PGE2 by RIA from the supernatants of articular cartilage obtained from osteoarthritis joints (OA-affected cartilage), rat chondrosarcomas (in ex vivo conditions) and bovine chondrocytes (stimulated with cytokines + endotoxin in vitro conditions) in the presence or absence of aspirin, indomethacin, sodium salicylate, tenidap and glucocorticoids. RESULTS: NO, which was spontaneously released in ex vivo conditions by OA-affected cartilage and rat chondrosarcomas (maintained in vivo), was susceptible to inhibition by pharmacologically relevant concentrations of aspirin, sodium salicylate and tenidap, but not to concentrations of indomethacin or glucocorticoids that significantly inhibited PGE2 production under the same conditions. Similarly, the production of NO by bovine chondrocytes grown in monolayer cultures that had been stimulated with cytokines + endotoxins (in vitro) to release both NO and PGE2 (at 48-72 h post stimulation), were inhibited by aspirin, sodium salicylate and tenidap, but not by indomethacin or glucocorticoids at concentrations sufficient to PGE2 production. Inhibition of NO in the cytokines + endotoxin stimulated bovine chondrocytes (like the human OA-affected cartilage) augmented PGE2 production. CONCLUSION: These experiments demonstrate that NO production by chondrocytes across species show a similar profile of susceptibility to inhibition by selected anti-inflammatory drugs. The insensitivity of NO production to glucocorticoids is an important characteristics of these cells that merits further investigation
— id: 57098, year: 1998, vol: 6, page: 269, stat: Journal Article,

The role of nitric oxide in inflammation and immunity
Clancy RM; Amin AR; Abramson SB
1998 Jul;41(7):1141-1151, Arthritis & rheumatism
— id: 9728, year: 1998, vol: 41, page: 1141, stat: Journal Article,

Activation of stress activated protein kinase in osteoarthritic cartilage: Evidence for nitric oxide dependence
Clancy, RM; Rediske, J; Nijher, N; Abramson, SB
1998 SEP ;41(9):S40-S40, Arthritis & rheumatism
— id: 53731, year: 1998, vol: 41, page: S40, stat: Journal Article,

IL-1 beta disrupts cross-talk between beta 3 and beta 1 integrins in osteoarthritic chondrocytes via the production of nitric oxide
Clancy, RM; Rediske, J; Nijher, N; Abramson, SB
1998 SEP ;41(9):S342-S342, Arthritis & rheumatism
— id: 53750, year: 1998, vol: 41, page: S342, stat: Journal Article,

Activation of endothelial cell cNOS prevents ICAM-1 induced focal adhesion complex assembly: A novel role for acetylcholine
Clancy, RM; Varenika, B; Nijher, N; Huang, W; Abramson, SB
1998 MAR ;46(3):196A-196A, Journal of investigative medicine
— id: 53493, year: 1998, vol: 46, page: 196A, stat: Journal Article,

The quantitation of nitric oxide dependent activation of stress activated protein kinase in osteoarthritic cartilage using a novel method of protein extraction
Clancy, RM; Veranika, B; Amin, A; Rediske, J; Abramson, SB
1998 MAR ;46(3):227A-227A, Journal of investigative medicine
— id: 53501, year: 1998, vol: 46, page: 227A, stat: Journal Article,

Up-regulation of inducible nitric oxide synthase and production of nitric oxide by the Swarm rat and human chondrosarcoma
Di Cesare PE; Carlson CS; Attur M; Kale AA; Abramson SB; Della Valle C; Steiner G; Amin AR
1998 Nov;16(6):667-674, Journal of orthopaedic research
Production of nitric oxide by solid tumors may have important ramifications regarding tumor growth and potential metastasis. This study demonstrated that the chondrosarcoma of the Swarm rat has upregulated mRNA for inducible nitric oxide synthase and produces nitric oxide. These results were confirmed by (a) the presence of a 4.4-kb band of mRNA detected by Northern blot using a probe for inducible nitric oxide synthase, (b) a 133-kDa band of protein that was detected with either a polyclonal or monoclonal antibody to the inducible nitric oxide synthase of the murine macrophage, and (c) the detection of nitrites from the culture medium of freshly cultured, isolated chondrosarcoma cells. This study showed that the expression of inducible nitric oxide synthase and the production of nitric oxide by the tumor can be increased by stimulation with endotoxin lipopolysaccharide and can be inhibited by inducible nitric oxide synthase inhibitors (L-N(g)-monomethyl arginine and aminoguanidine). Immunostaining confirmed the presence of inducible nitric oxide synthase within the tumor cells and appeared to localize the enzyme to the cytoplasm of the cells. A human chondrosarcoma was also shown to have an upregulated inducible nitric oxide synthase by both the detection of mRNA for inducible nitric oxide synthase and the presence of nitrites from the culture medium of the tumor in organ culture. Because the chondrosarcoma of the Swarm rat is a well differentiated solid tumor that rarely metastasizes, nitric oxide may be produced by the tumor to promote local growth by effects on vascular supply
— id: 7323, year: 1998, vol: 16, page: 667, stat: Journal Article,

Cyclooxygenase in biology and disease [see comments]
Dubois RN; Abramson SB; Crofford L; Gupta RA; Simon LS; Van De Putte LB; Lipsky PE
1998 Sep;12(12):1063-1073, FASEB journal
Cyclooxygenase (COX), the key enzyme required for the conversion of arachidonic acid to prostaglandins was first identified over 20 years ago. Drugs, like aspirin, that inhibit cyclooxygenase activity have been available to the public for about 100 years. In the past decade, however, more progress has been made in understanding the role of cyclooxygenase enzymes in biology and disease than at any other time in history. Two cyclooxygenase isoforms have been identified and are referred to as COX-1 and COX-2. Under many circumstances the COX-1 enzyme is produced constitutively (i.e., gastric mucosa) whereas COX-2 is inducible (i.e., sites of inflammation). Here, we summarize the current understanding of the role of cyclooxygenase-1 and -2 in different physiological situations and disease processes ranging from inflammation to cancer. We have attempted to include all of the most relevant material in the field, but due to the rapid progress in this area of research we apologize that certain recent findings may have been left out
— id: 7553, year: 1998, vol: 12, page: 1063, stat: Journal Article,

The classification of cyclooxygenase inhibitors
Lipsky LP; Abramson SB; Crofford L; Dubois RN; Simon LS; van de Putte LB
1998 Dec;25(12):2298-2303, Journal of rheumatology
In summary, precise classification of COX inhibitors has important clinical implications for efficacy and toxicity. However, classification of these agents clinically is difficult because there are insufficient data to predict correlations between biochemical and pharmacologic properties and the clinical effect of a given agent. In any case, specific COX-2 inhibitors are expected to show antiinflammatory and analgesic activities equivalent to those of NSAID, as well as significant reductions in the incidence of the life threatening side effects (i.e., GI bleeding) associated with COX-1 inhibition. The advantages of preferential COX-2 inhibitors may be more subtle and therefore more difficult to verify in clinical trials
— id: 7944, year: 1998, vol: 25, page: 2298, stat: Journal Article,

TNF-alpha convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-alpha
Patel IR; Attur MG; Patel RN; Stuchin SA; Abagyan RA; Abramson SB; Amin AR
1998 May 1;160(9):4570-4579, Journal of immunology
A snake venom-like protease isolated by a differential display screen between normal and osteoarthritis (OA)-affected cartilage (designated as cSVP) has a cDNA sequence identical to TNF-alpha convertase enzyme (TACE). TACE shows the presence of an unknown prodomain, a cysteine switch, a catalytic domain, a zinc binding region, a disintegrin region, an EGF-like domain, a transmembrane domain, and a unique cytoplasmic region. A TACE construct harboring the signal + prodomain + catalytic region (TACE-SPCdeltaDETCy), expressed in baculovirus could cleave preferentially (approximately 12-fold) the TNF-specific peptide over the matrix metalloproteases peptide in vitro. This recombinant protein also cleaved the natural substrate GST-ProTNF-alpha to TNF-alpha (17 kDa) in vitro. The mRNA for TACE, which is broadly distributed and differentially expressed in a variety of human tissues, is up-regulated in arthritis-affected cartilage, but not normal cartilage. OA-affected cartilage also expressed TNF-alpha mRNA that was not detected in normal cartilage. The OA-affected cartilage (in explant assays) spontaneously released TNF-alpha and IL-8 in ex vivo conditions. Addition of TNF-alphaR fused to IgG Fc fragment (TNF-alphaR:Fc) in the presence or absence of soluble IL-1R (with which it acted additively) significantly attenuated the spontaneous/autocrine release of articular IL-8 in this assay. These experiments demonstrate a functional paracrine/autocrine role of TNF-alpha in OA-affected cartilage that may depend, in part, on up-regulated levels of chondrocyte-derived TACE
— id: 7737, year: 1998, vol: 160, page: 4570, stat: Journal Article,

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide
Amin AR; Attur M; Patel RN; Thakker GD; Marshall PJ; Rediske J; Stuchin SA; Patel IR; Abramson SB
1997 Mar 15;99(6):1231-1237, Journal of clinical investigation
Cartilage specimens from osteoarthritis (OA)-affected patients spontaneously released PGE2 at 48 h in ex vivo culture at levels at least 50-fold higher than in normal cartilage and 18-fold higher than in normal cartilage + cytokines + endotoxin. The superinduction of PGE2 production coincides with the upregulation of cyclooxygenase-2 (COX-2) in OA-affected cartilage. Production of both nitric oxide (NO) and PGE2 by OA cartilage explants is regulated at the level of transcription and translation. Dexamethasone inhibited only the spontaneously released PGE2 production, and not NO, in OA-affected cartilage. The NO synthase inhibitor HN(G)-monomethyl-L-arginine monoacetate inhibited OA cartilage NO production by > 90%, but augmented significantly (twofold) the spontaneous production of PGE2 in the same explants. Similarly, addition of exogenous NO donors to OA cartilage significantly inhibited PGE2 production. Cytokine + endotoxin stimulation of OA explants increased PGE2 production above the spontaneous release. Addition of L-NMMA further augmented cytokine-induced PGE2 production by at least fourfold. Inhibition of PGE2 by COX-2 inhibitors (dexamethasone or indomethacin) or addition of exogenous PGE2 did not significantly affect the spontaneous NO production. These data indicate that human OA-affected cartilage in ex vivo conditions shows (a) superinduction of PGE2 due to upregulation of COX-2, and (b) spontaneous release of NO that acts as an autacoid to attenuate the production of the COX-2 products such as PGE2. These studies, together with others, also suggest that PGE2 may be differentially regulated in normal and OA-affected chondrocytes
— id: 9734, year: 1997, vol: 99, page: 1231, stat: Journal Article,

Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines
Amin AR; Patel RN; Thakker GD; Lowenstein CJ; Attur MG; Abramson SB
1997 Jun 30;410(2-3):259-264, FEBS letters
Chemically modified tetracyclines [CMT-3 (IC50 approximately 6-13 microM = approximately 2.5-5 microg/ml) and CMT-8 (IC50 approximately 26 microM = 10 microg/ml), but not CMT-1, -2 or -5], which lack anti-microbial activity, inhibited nitrite production in LPS-stimulated macrophages. Unlike competitive inhibitors of L-arginine which inhibited the specific activity of inducible nitric oxide synthase (iNOS) in cell-free extracts, CMTs exerted no such direct effect on the enzyme. CMTs could, however, be shown to inhibit both iNOS mRNA accumulation and protein expression in LPS-stimulated cells. Tetracyclines (doxycycline and CMT-3) unlike hydrocortisone had no significant effect on murine macrophages transfected with iNOS promoter (tagged to a luciferase reporter gene) in the presence of LPS. However, doxycycline and CMT-3 augmented iNOS mRNA degradation, in LPS-stimulated murine macrophages. These studies show a novel mechanism of action of tetracyclines which harbours properties to increase iNOS mRNA degradation and decrease iNOS protein expression and nitric oxide production in macrophages. This property of tetracyclines may have beneficial effects in the treatment of various diseases where excess nitric oxide has been implicated in the pathophysiology of these diseases
— id: 56923, year: 1997, vol: 410, page: 259, stat: Journal Article,

Autocrine production of IL-1 beta by human osteoarthritis-affected cartilage and differential regulation of endogenous nitric oxide IL-6, prostaglandin E-2 and IL-8
Amin, AK; Attur, MG; Patel, IR; Patel, RN; Thakker, GD; Abramson, SB
1997 SEP ;40(9):902-902, Arthritis & rheumatism
— id: 53194, year: 1997, vol: 40, page: 902, stat: Journal Article,

Inflammatory mediators (nitric oxide, PGE(2)) spontaneously produced by osteoarthritis-affected cartilage regulate stromelysin (MMP-3) production
Amin, AR; Baraji, V; Attur, M; Patel, R; Abramson, SB
1997 SEP ;40(9):904-904, Arthritis & rheumatism
— id: 53195, year: 1997, vol: 40, page: 904, stat: Journal Article,

A novel snake venom-like protease (SVP) from human arthritis-affected cartilage has properties of TNF-alpha convertase regulation in arthritis-affected cartilage
Amin, AR; Patel, IR; Attur, M; Patel, R; Thakker, G; Solomon, K; Abagyan, R; Abramson, SB
1997 SEP ;40(9):285-285, Arthritis & rheumatism
— id: 53181, year: 1997, vol: 40, page: 285, stat: Journal Article,

Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines
Amin, AR; Patel, RN; Thakker, GD; Attur, MG; Lowenstein, CJ; Patel, IR; Abramson, SB
1997 SEP ;40(9):398-398, Arthritis & rheumatism
— id: 53184, year: 1997, vol: 40, page: 398, stat: Journal Article,

Interleukin-17 up-regulation of nitric oxide production in human osteoarthritis cartilage
Attur MG; Patel RN; Abramson SB; Amin AR
1997 Jun;40(6):1050-1053, Arthritis & rheumatism
OBJECTIVE: To examine the effect of human interleukin-17 (IL-17) on nitric oxide (NO) production in human osteoarthritis (OA) cartilage under ex vivo conditions. METHODS: OA cartilage from patients undergoing knee replacement surgery was used in explant assays to assess the effect of IL-17. NO production was measured by estimating the stable NO metabolite, nitrite, in conditioned medium. RESULTS: IL-17 augmented the spontaneous production of nitric oxide. This augmentation was sensitive to cycloheximide and pyrrolidine dithiocarbamate, but not to dexamethasone or soluble IL-1 receptor. CONCLUSION: IL-17 augments nitric oxide production in OA cartilage via nuclear factor kappaB activation, but independently of IL-1beta signaling
— id: 56924, year: 1997, vol: 40, page: 1050, stat: Journal Article,

Transplantation of adenovirally transduced allogeneic chondrocytes into articular cartilage defects in vivo
Baragi VM; Renkiewicz RR; Qiu L; Brammer D; Riley JM; Sigler RE; Frenkel SR; Amin A; Abramson SB; Roessler BJ
1997 Jul;5(4):275-282, Osteoarthritis & cartilage
Gene transfer to chondrocytes followed by intra-articular transplantation may allow for functional modulation of chondrocyte biology and enhanced repair of damaged articular cartilage. We chose to examine the loss of chondrocytes transduced with a recombinant adenovirus containing the gene for Escherichia coli beta-galactosidase (Ad.RSVntlacZ), followed by transplantation into deep and shallow articular cartilage defects using New Zealand White rabbits as an animal model. A type I collagen matrix was used as a carrier for the growth of the transduced chondrocytes and to retain the cells within the surgically created articular defects. Histochemical analysis of matrices recovered from the animals 1, 3 and 10 days after implantation showed the continued loss of lacZ positive chondrocytes. The number of cells recovered from the matrices was also compared with the initial innoculum of transduced cells present within the matrices at the time of implantation. The greatest loss of transduced cells was observed in the first 24 h after implantation. The numbers of transduced cells present within the matrices were relatively constant between 1 and 3 days postimplantation, but had progressively declined by 10 days postimplantation. These results suggest that transduction of chondrocytes followed by intra-articular transplantation in this rabbit model may enable us to examine the biological effects of focal transgenic overexpression of proteins involved in cartilage homeostasis and repair
— id: 9731, year: 1997, vol: 5, page: 275, stat: Journal Article,

Increased nitric oxide production accompanied by the up-regulation of inducible nitric oxide synthase in vascular endothelium from patients with systemic lupus erythematosus
Belmont HM; Levartovsky D; Goel A; Amin A; Giorno R; Rediske J; Skovron ML; Abramson SB
1997 Oct;40(10):1810-1816, Arthritis & rheumatism
OBJECTIVE: To investigate whether systemic lupus erythematosus (SLE) is accompanied by increased serum nitrite levels, whether active compared with inactive disease is associated with greater nitric oxide (NO) production, and whether endothelial cells or keratinocytes serve as cellular sources of NO by virtue of their increased expression of either constitutive nitric oxide synthase (cNOS) or inducible NOS (iNOS). METHODS: Fifty-one serum samples (46 from patients with SLE) were analyzed for NO production by measuring nitrite levels in a calorimetric assay. Skin biopsy samples from 21 SLE patients and 11 healthy volunteers were evaluated immunohistochemically, using monoclonal antibodies, for endothelial cell and keratinocyte cNOS and iNOS expression. RESULTS: Serum nitrite levels were significantly elevated in the 46 patients with SLE (mean +/- SEM 37 +/- 6 microM/liter) compared with controls (15 +/- 7 microM/liter; P < 0.01), and were elevated in patients with active SLE compared with those with inactive disease (46 +/- 7 microM/liter versus 30 +/- 7 microM/liter; P < 0.01). Serum nitrite levels correlated with disease activity (r = 0.47, P = 0.04) and with levels of antibodies to double-stranded DNA (r = 0.35, P = 0.02). Endothelial cell expression of iNOS in SLE patients (mean +/- SEM score 1.5 +/- 0.2) was significantly greater compared with controls (0.6 +/- 0.2; P < 0.01), and higher in patients with active disease compared with those with inactive SLE (1.7 +/- 0.2 versus 1.2 +/- 0.2; P < 0.01). Keratinocyte expression of iNOS was also significantly elevated in SLE patients (0.9 +/- 0.1) compared with controls (0.4 +/- 0.1; P < 0.001). With regard to expression of cNOS, there were no differences between patients with active SLE, those with inactive SLE, and normal controls in either the vascular endothelium or the keratinocytes. CONCLUSION: NO production is increased in patients with SLE, and 2 potential sources of excessive NO are activated endothelial cells and keratinocytes via up-regulated iNOS
— id: 9732, year: 1997, vol: 40, page: 1810, stat: Journal Article,

Differential phosphorylation of the beta2 integrin CD11b/CD18 in the plasma and specific granule membranes of neutrophils
Buyon JP; Philips MR; Merrill JT; Slade SG; Leszczynska-Piziak J; Abramson SB
1997 Mar;61(3):313-321, Journal of leukocyte biology
Neutrophil aggregation is mediated by the beta2 integrin CD11b/CD18, which has limited expression on the surface membrane of resting cells but is recruited from intracellular organelles after cell activation. We have previously found that CD11b/CD18 newly translocated to the plasma membrane does not contribute to adhesion but must be modified to be functional. Because neutrophil aggregation induced by phorbol myristate acetate (PMA) is accompanied by de novo phosphorylation of the CD18 cytoplasmic tail, we sought to determine whether CD11b/CD18 phosphorylation is separately regulated in the different cellular compartments. Accordingly, [32P]-labeled CD11b/CD18 was immunoprecipitated from purified neutrophil-specific granule or plasma membrane lysates. In plasma membrane fractions, as in whole cell lysates, CD18 became phosphorylated in cells exposed to PMA but not in untreated cells or cells treated with N-formyl-methionyl-leucyl-phenylalanine (fMLP). The alpha chain, CD11b, was phosphorylated under all conditions. In contrast, only marginal phosphorylation of specific granule-associated CD18 or CD11b was observed. Calyculin A, an inhibitor of serine/threonine phosphatases (pp1 > pp2a), induced strong phosphorylation of CD18 in the plasma membrane but not in the specific granules. Addition of intact specific granule membranes to the plasma membranes from PMA-treated neutrophils markedly decreased phosphorylation in both CD11b and CD18 subunits. These data suggest that the phosphorylation of CD11b/CD18, which accompanies neutrophil activation, is limited to plasma membrane-associated molecules. Phosphorylation, either constitutive or induced, is absent in the specific granule membranes. The difference may be due to a specific granule-associated phosphatase, probably distinct from ppl. Therefore adhesion-competent plasma membrane CD11b/CD18 and adhesion-incompetent specific granule CD11b/CD18 differ in their state of phosphorylation
— id: 9735, year: 1997, vol: 61, page: 313, stat: Journal Article,

Nitric oxide attenuates cellular hexose monophosphate shunt response to oxidants in articular chondrocytes and acts to promote oxidant injury
Clancy RM; Abramson SB; Kohne C; Rediske J
1997 Aug;172(2):183-191, Journal of cellular physiology
Nitric oxide (NO) has been implicated in both cartilage degradation and cell survival. Importantly, NO has been shown, in a cell-type-dependent manner, to directly cause cell death or indirectly promote cell death by compromising the ability of cells to detoxify intra- or extracellular oxidants. In this study we examined the role of NO in the survival of bovine chondrocytes exposed to catabolic cytokines (interleukin-1 (IL-1); tumor necrosis factor [TNF]) with or without the addition of an exogenous oxidant stress (e.g., H2O2, HOOCl, etc.). The exposure of chondrocytes to a mixture of IL-1 and TNF (IL-1/TNF) results in the release of NO but did not alter cell viability. However, there was evidence of NO-dependent oxidative responses in the IL-1/TNF group, as we observed an increased level of intracellular oxidants as well as the appearance of a 55 kD nitrated protein which reflects the formation of peroxynitrite. We next analyzed viability with H2O2. The LD50 for IL-1/TNF-treated cells was 0.1 mM (vs. 1 mM for control). The enhanced sensitivity was completely reversed when cells were incubated with the NO synthase inhibitor 1-n5-1-iminoethylornithine (NIO). To test whether cell death was caused by compromising the ability of cells to detoxify extracellular oxidants, we examined the hexose monophosphate shunt (HMPS) response in cells given H2O2. Treatment of control cells with H2O2 resulted in a fourfold increase in HMPS activity. In contrast, IL-1/TNF cells exhibited no increase in HMPS activity. The attenuation of stimulated HMPS activity was reversed by the coaddition of NIO. Thus, these data indicate that 1) endogenous NO mediates cytokine-dependent susceptibility to oxidant injury and 2) this effect is in part due to impaired activation of the HMPS. In inflamed joints replete with cytokines and oxidants, NO may contribute to chondrocyte death and progressive joint destruction
— id: 7132, year: 1997, vol: 172, page: 183, stat: Journal Article,

Outside-in signaling in the chondrocyte. Nitric oxide disrupts fibronectin-induced assembly of a subplasmalemmal actin/rho A/focal adhesion kinase signaling complex
Clancy RM; Rediske J; Tang X; Nijher N; Frenkel S; Philips M; Abramson SB
1997 Oct 1;100(7):1789-1796, Journal of clinical investigation
Elevated levels of fibronectin (Fn) in articular cartilage have been linked to the progression of both rheumatoid and osteoarthritis. In this study, we examined intracellular events which follow ligation of Fn to its receptor, the integrin alpha5beta1. In addition, we examined the regulatory influence of nitric oxide on these events, since this free radical has been implicated in cartilage degradation. Exposure of chondrocytes to Fn-coated beads resulted in the circumferential clustering of the alpha5beta1 integrin receptor, which was accompanied by the subplasmalemmal assembly of a focal activation complex comprised of F-actin, the tyrosine kinase, focal adhesion kinase (FAK), the ras related G protein rho A, as well as tyrosine-phosphorylated proteins. Treatment with exogenous nitric oxide (NO) or catabolic cytokines which induce nitric oxide synthase blocked the assembly of F-actin, FAK, rho A and tyrosine-phosphorylated proteins while not affecting the total number of beads bound per cell nor the clustering of alpha5beta1 integrin. Use of a cGMP antagonist (Rp-8-Br cGMPS) or cGMP agonist (Sp-cGMPS) either abolished or mimicked the NO effect, respectively. Adherence of chondrocytes to fibronectin enhanced proteoglycan synthesis by twofold (vs. albumin). In addition, basic fibroblast growth factor (FGF) and insulin growth factor (IGF-1) induced proteoglycan synthesis in chondrocytes adherent to Fn but not albumin suggesting a costimulatory signal transduced by alpha5betal and the FGF receptor. Both constitutive and FGF stimulated proteoglycan synthesis were completely inhibited by nitric oxide. These data indicate that the ligation of alpha5beta1 in the chondrocyte induced the intracellular assembly of an activation complex comprised of the cytoplasmic tail of alpha5beta1 integrin, actin, and the signaling molecules rho A and FAK. We show that NO inhibits the assembly of the intracellular activation complex and the synthesis of proteoglycans, but has no effect on the extracellular aggregation of alpha5beta1 integrin. These observations provide a basis by which nitric oxide can interfere with chondrocyte functions by affecting chondrocyte-matrix interactions
— id: 9733, year: 1997, vol: 100, page: 1789, stat: Journal Article,

Activation of endothelial cell cNOS prevents ICAM-1 induced focal adhesion complex assembly: A novel role for acetylcholine
Clancy, R; Abramson, SB
1997 SEP ;40(9):594-594, Arthritis & rheumatism
— id: 53189, year: 1997, vol: 40, page: 594, stat: Journal Article,

Fibronectin and growth factors induce MAP kinase activation and promote proteoglycan synthesis in chondrocytes: Inhibition by nitric oxide via a cGMP dependent pathway
Clancy, R; Rediske, J; Pillinger, M; Abramson, SB
1997 SEP ;40(9):264-264, Arthritis & rheumatism
— id: 53180, year: 1997, vol: 40, page: 264, stat: Journal Article,

Exogenous nitric oxide or nitric oxide produced endogenously in response to FMLP inhibits neutrophil chemotaxis and augments degranulation via cyclic GMP kinase
Clancy, RM; Abramson, SB
1997 SEP ;40(9):595-595, Arthritis & rheumatism
— id: 53190, year: 1997, vol: 40, page: 595, stat: Journal Article,

A novel mechanism of action of tetracyclines: effects on nitric oxide synthases
Amin AR; Attur MG; Thakker GD; Patel PD; Vyas PR; Patel RN; Patel IR; Abramson SB
1996 Nov 26;93(24):14014-14019, Proceedings of the National Academy of Sciences of the United States of America
Tetracyclines have recently been shown to have 'chondroprotective' effects in inflammatory arthritides in animal models. Since nitric oxide (NO) is spontaneously released from human cartilage affected by osteoarthritis (OA) or rheumatoid arthritis in quantities sufficient to cause cartilage damage, we evaluated the effect of tetracyclines on the expression and function of human OA-affected nitric oxide synthase (OA-NOS) and rodent inducible NOS (iNOS). Among the tetracycline group of compounds, doxycycline > minocycline blocked and reversed both spontaneous and interleukin 1 beta-induced OA-NOS activity in ex vivo conditions. Similarly, minocycline > or = doxycycline inhibited both lipopolysaccharide- and interferon-gamma-stimulated iNOS in RAW 264.7 cells in vitro, as assessed by nitrite accumulation. Although both these enzyme isoforms could be inhibited by doxycycline and minocycline, their susceptibility to each of these drugs was distinct. Unlike acetylating agents or competitive inhibitors of L-arginine that directly inhibit the specific activity of NOS, doxycycline or minocycline has no significant effect on the specific activity of iNOS in cell-free extracts. The mechanism of action of these drugs on murine iNOS expression was found to be, at least in part, at the level of RNA expression and translation of the enzyme, which would account for the decreased iNOS protein and activity of the enzyme. Tetracyclines had no significant effect on the levels of mRNA for beta-actin and glyceraldehyde-3-phosphate dehydrogenase nor on levels of protein of beta-actin and cyclooxygenase 2 expression. These studies indicate that a novel mechanism of action of tetracyclines is to inhibit the expression of NOS. Since the overproduction of NO has been implicated in the pathogenesis of arthritis, as well as other inflammatory diseases, these observations suggest that tetracyclines should be evaluated as potential therapeutic modulators of NO for various pathological conditions
— id: 9736, year: 1996, vol: 93, page: 14014, stat: Journal Article,

Osteoarthritis-affected cartilage spontaneously produces COX-2-derived prostaglandin E(2): Regulation by nitric oxide synthase
Amin, AR; Attur, M; Patel, RN; Thakker, GD; Marshall, PJ; Rediske, J; Stuchin, SA; Abramson, SB
1996 SEP ;39(9):1466-1466, Arthritis & rheumatism
— id: 52788, year: 1996, vol: 39, page: 1466, stat: Journal Article,

Nonsteroidal antiinflammatory drugs inhibit the activity of COX-2 and nitric oxide synthase expressed in osteoarthritis-affected cartilage
Amin, AR; Attur, M; Vyas, P; DiCesare, PE; Patel, P; Patel, RN; Steiner, G; Abramson, SB
1996 SEP ;39(9):326-326, Arthritis & rheumatism
— id: 52778, year: 1996, vol: 39, page: 326, stat: Journal Article,

Regulation of osteoarthritis-affected nitric oxide synthase (OA-NOS) by anti-inflammatory drugs
Amin, AR; Attur, M; Vyas, P; DiCesare, PE; Patel, P; Steiner, G; Abramson, SB
1996 MAR ;44(3):A221-A221, Journal of investigative medicine
— id: 52941, year: 1996, vol: 44, page: A221, stat: Journal Article,

Human neutrophils express mRNA for inducible nitric oxide synthase and exhibit intracellular nitric oxide-dependent autacoid functions upon activation, but lack detectable translated product and nitric oxide synthase enzyme activity
Amin, AR; Attur, M; Vyas, P; LeszczynskaPiziak, J; Levartovsky, D; Rediske, J; Clancy, RM; Vora, KA; Abramson, SB
1996 MAR ;44(3):A267-A267, Journal of investigative medicine
— id: 52957, year: 1996, vol: 44, page: A267, stat: Journal Article,

A novel mechanism of action of tetracyclines: Inhibitory effects on nitric oxide synthase activity in osteoarthritis
Amin, AR; Attur, MG; Thakker, DG; Patel, PD; Vyas, PR; Patel, RN; Patel, IR; Abramson, SB
1996 SEP ;39(9):1103-1103, Arthritis & rheumatism
— id: 52783, year: 1996, vol: 39, page: 1103, stat: Journal Article,

Prostaglandin E(2) (PGE(2)) is an inflammatory component in osteoarthritis-affected cartilage: The yin-yang regulation of nitric oxide synthase and cyclooxygenase-2
Amin, AR; Marshall, PJ; Attur, M; Vyas, P; DiCesare, PE; Stuchin, SA; Rediske, J; Abramson, SB
1996 MAR ;44(3):A292-A292, Journal of investigative medicine
— id: 52962, year: 1996, vol: 44, page: A292, stat: Journal Article,

Nitric oxide produced by cartilage-specific nitric oxide synthase is a common mediator of cartilage degradation in both rheumatoid arthritis and osteoarthritis
Amin, AR; Patel, P; Vyas, P; DiCesare, PE; Attur, M; Abramson, SB
1996 MAR ;44(3):A236-A236, Journal of investigative medicine
— id: 52948, year: 1996, vol: 44, page: A236, stat: Journal Article,

Differential effect of the immunosuppressive drugs cyclosporin, rapamycin and FK506 on inducible nitric oxide synthase and cyclooxygenase-2 expression and function
Attur, M; Vyas, P; Levartovsky, D; Thakker, G; Patel, P; Assef, F; Naqvi, S; Raza, R; Abramson, SB; Amin, AR
1996 MAR ;44(3):A240-A240, Journal of investigative medicine
— id: 52954, year: 1996, vol: 44, page: A240, stat: Journal Article,

Pathology and pathogenesis of vascular injury in systemic lupus erythematosus. Interactions of inflammatory cells and activated endothelium
Belmont HM; Abramson SB; Lie JT
1996 Jan;39(1):9-22, Arthritis & rheumatism
— id: 9738, year: 1996, vol: 39, page: 9, stat: Journal Article,

''Outside/in'' signalling in the chondrocyte: Effect of nitric oxide on fibronectin induced actin assembly and focal adhesion kinase-dependent tyrosine phosphorylation
Clancy, RM; Rediske, J; Tang, X; Frenkel, S; Abramson, SB
1996 MAR ;44(3):A241-A241, Journal of investigative medicine
— id: 52955, year: 1996, vol: 44, page: A241, stat: Journal Article,

alpha 5 beta 1 integrin signaling in the chondrocyte: Nitric oxide disrupts fibronectin induced assembly of a subplasmalemmal actin Rho A FAK activation complex
Clancy, RM; Rediske, J; Tang, XY; Frenkel, SR; Abramson, SB
1996 SEP ;39(9):843-843, Arthritis & rheumatism
— id: 52781, year: 1996, vol: 39, page: 843, stat: Journal Article,

Nitric oxide promotes the ADP-ribosylation of actin via the inhibition of cytosolic ADP-ribase(s)
Clancy, RM; Tang, X; Abramson, SB
1996 MAR ;44(3):A267-A267, Journal of investigative medicine
— id: 52958, year: 1996, vol: 44, page: A267, stat: Journal Article,

Nitric oxide promotes the ADP ribosylation of actin via the inhibition of cytosolic ADP ribase 1
Clancy, RM; Tang, XY; Abramson, SB
1996 SEP ;39(9):62-62, Arthritis & rheumatism
— id: 52776, year: 1996, vol: 39, page: 62, stat: Journal Article,

Effects of nitric oxide on chondrocyte migration, adhesion, and cytoskeletal assembly
Frenkel SR; Clancy RM; Ricci JL; Di Cesare PE; Rediske JJ; Abramson SB
1996 Nov;39(11):1905-1912, Arthritis & rheumatism
OBJECTIVE: The migration of cells of chondrocyte lineage is believed to play a role in cartilage growth and repair. The present study examined 1) whether chondrocytes are capable of migration in vitro; and 2) the effects of nitric oxide (NO) on chondrocyte migration, adhesion, and cytoskeletal assembly. METHODS: Chondrocyte migration was evaluated by 2 assays: 1) 'centrifugal' migration within a 3-dimensional collagen matrix (dot culture); and 2) directed migration under agarose in response to bone morphogenetic protein. To assess the effects of NO, chondrocytes were treated with either exogenous NO (S-nitrosoglutathione [SNO-GSH]) or a mixture of cytokines known to induce endogenous NO production. The effects of NO on chondrocyte adhesion to fibronectin-coated surfaces, as well as on actin polymerization (determined by indirect immunofluorescence), were also examined. RESULTS: The capacity of chondrocytes to migrate was demonstrated both by the dot culture and by agarose methods. Both SNO-GSH and endogenous NO induced by cytokines inhibited this migration. Exposure to NO also inhibited attachment of chondrocytes to fibronectin and disrupted assembly of actin filaments. These effects of SNO-GSH and cytokine-induced NO production were reversed in the presence of hemoglobin and the NO synthase inhibitor NG-monomethyl arginine, respectively. CONCLUSION: NO interferes with chondrocyte migration and attachment to fibronectin, an extracellular matrix protein, probably via effects on the actin cytoskeleton. These effects of NO may result in impairment of cartilage repair, by interfering with the extracellular matrix regulation of chondrocyte function
— id: 9737, year: 1996, vol: 39, page: 1905, stat: Journal Article,

Inducible nitric oxide synthase is upregulated in vascular endothelial and keratinocytes of nonlesional skin in patients with active SLE
Goel, A; Belmont, HM; Giorno, R; Amin, AR; Abramson, SB
1996 SEP ;39(9):1581-1581, Arthritis & rheumatism
— id: 52791, year: 1996, vol: 39, page: 1581, stat: Journal Article,

Infections of the musculoskeletal system by M. tuberculosis
Lee, Sicy H; Abramson, Steven B
Tuberculosis Boston : Little Brown, 1996,
— id: 4846, year: 1996, vol: , page: ?, stat: Chapter,

A double-blind, placebo-controlled study of anti-CD5 immunoconjugate in patients with rheumatoid arthritis
Olsen, NJ; Brooks, RH; Cush, JJ; Lipsky, PE; StClair, EW; Matteson, EL; Gold, KN; Cannon, GW; Jackson, CG; McCune, WJ; Fox, DA; Teal, G; Gruber, J; Espinoza, L; Caldwell, J; Weisman, M; Lee, S; Abramson, S; Calabrese, L; Medsger, T; Nelson, B; Lorenz, T; Strand, V
1996 JUL ;39(7):1102-1108, Arthritis & rheumatism
Objective. To evaluate the efficacy of an anti-CD5 ricin-linked immunoconjugate (CD5-IC) in patients with rheumatoid arthritis (RA). Methods. A total of 104 evaluable patients were enrolled in a multicenter, double-blind, multiple-dose, placebo-controlled study of CDS-IC. Results. Treatment with CDS-IC in doses up to 8 mg/m(2)/day for 4 days in 1 month failed to produce marked or prolonged T cell depletion and was no more effective than placebo in ameliorating disease manifestations. An unexpectedly high placebo response was observed in 48% of the patients, Adverse events were correlated with the dose of CD5-IC, but the treatment was generally well-tolerated. Conclusion. At the doses used in this study, CDS-IC was ineffective for treating RA
— id: 52857, year: 1996, vol: 39, page: 1102, stat: Journal Article,

Cloning and expression of a functional, dimeric, multi-cofactor-requiring inducible nitric oxide synthase in a novel bacteria-to-bacmid transposition-baculovirus system
Patel, IR; Vyas, P; Attur, M; Abramson, SB; Amin, AR
1996 MAR ;44(3):A205-A205, Journal of investigative medicine
— id: 52937, year: 1996, vol: 44, page: A205, stat: Journal Article,

Expression of nitric oxide synthase in human peripheral blood mononuclear cells and neutrophils
Amin AR; Attur M; Vyas P; Leszczynska-Piziak J; Levartovsky D; Rediske J; Clancy RM; Vora KA; Abramson SB
1995 96;47(4):190-205, Journal of inflammation
It has been clearly demonstrated in rodents that nitric oxide (NO) plays an important role in host defense and immunity. However, evidence that human leukocytes express inducible nitric oxide synthase (iNOS) or its products has been inconclusive and a source of controversy. We report that iNOS could not be detected in human monocytes, HL-60 cells, neutrophils, and T cells by Western blotting analysis (< or = 10 pg) or by radiolabeled L-arginine-to-L-citrulline conversion (< or = 20 pmol L-citrulline) under conditions sufficient to induce iNOS in the rodent system and in human hepatocytes, which include activation with cytokines, endotoxins, and/or chemoattractants. However, sensitive methods such as RT-PCR and Northern blot analysis show 'constitutively expressed' iNOS mRNA from human monocytes, neutrophils, Jurkat cells, and HL-60 cells. This iNOS mRNA is 4.4 kb and is similar to that seen in human hepatocytes and rodent macrophages. In spite of the constitutive expression of mRNA in neutrophils and the lack of detectable NOS activity (based on Western blotting and L-arginine-to-L-citrulline conversion assay), stimulation of human neutrophils unit FMLP in vitro induced the ADP-ribosylation of an intracellular NO target, glyceraldehyde-3-PO4 dehydrogenase (GAPDH), in a NO-dependent manner. These studies indicate that low levels of NOS protein are expressed in neutrophils (and perhaps T cells and monocytes) and produce NO following stimulation. The data indicate that, in addition to its phagocytic and tumoricidal activity. NO may also function as an autacoid signaling molecule within the cells
— id: 56922, year: 1995, vol: 47, page: 190, stat: Journal Article,

The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase
Amin AR; Di Cesare PE; Vyas P; Attur M; Tzeng E; Billiar TR; Stuchin SA; Abramson SB
1995 Dec 1;182(6):2097-2102, Journal of experimental medicine
Classically, osteoarthritis (OA) has been considered a noninflammatory disease. However, the detection of selected inflammatory mediators in osteoarthritic fluid, in the absence of significant inflammatory cell infiltrate, is increasingly appreciated. We sought to identify the inflammatory component in human OA-affected cartilage that may be involved in cartilage damage/destruction. Using Western blot analysis and an antibody to the conserved region of nitric oxide synthase (NOS), we have observed up-regulation of NOS, one of the 'key players' of inflammation, in chondrocytes of OA-affected patients. Remarkably, none of the cartilage samples examined from normal joints demonstrated detectable amounts of this NOS. Western blot analysis using the same alpha-NOS antibody indicated that this NOS from OA-affected cartilage (OA-NOS) was larger in size than (and distinct from) transfected human hepatocyte or murine inducible NOS (iNOS) (150 versus 133 kD) and similar in size to neuronal constitutive NOS (ncNOS). Antibodies specific for iNOS showed binding to murine and human iNOS but not to OA-NOS, endothelial constitutive NOS, or ncNOS. Antibodies specific for ncNOS bound to ncNOS and also to OA-NOS, but not to murine or human iNOS or endothelial constitutive NOS. Incubation of OA cartilage in serum-free medium resulted in spontaneous release, for up to 72 h, of substantial amounts of nitrite (up to approximately 80 microM/100 mg wet tissue), which could be inhibited by at least 80% with various inhibitors of iNOS, including inhibitors of protein synthesis and transcription factor NF-kappa B, but which (unlike murine macrophage iNOS) was not sensitive to hydrocortisone or TGF-beta. Exposure of OA-affected cartilage to interleukin 1 beta, tumor necrosis factor-alpha, and lipopolysaccharide resulted in approximately 20-50% augmentation of nitrite accumulation, which was also sensitive to cycloheximide and pyrrolidine dithiocarbamate. Hence, our data indicate that OA-NOS (based on immunoreactivity and molecular weight) is similar to ncNOS and that it releases nitric oxide, which may contribute to the inflammation and pathogenesis of cartilage destruction in OA
— id: 9739, year: 1995, vol: 182, page: 2097, stat: Journal Article,

The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase
Amin AR; Vyas P; Attur M; Leszczynska-Piziak J; Patel IR; Weissmann G; Abramson SB
1995 Aug 15;92(17):7926-7930, Proceedings of the National Academy of Sciences of the United States of America
Nitric oxide synthesized by inducible nitric oxide synthase (iNOS) has been implicated as a mediator of inflammation in rheumatic and autoimmune diseases. We report that exposure of lipopolysaccharide-stimulated murine macrophages to therapeutic concentrations of aspirin (IC50 = 3 mM) and hydrocortisone (IC50 = 5 microM) inhibited the expression of iNOS and production of nitrite. In contrast, sodium salicylate (1-3 mM), indomethacin (5-20 microM), and acetaminophen (60-120 microM) had no significant effect on the production of nitrite at pharmacological concentrations. At suprapharmacological concentrations, sodium salicylate (IC50 = 20 mM) significantly inhibited nitrite production. Immunoblot analysis of iNOS expression in the presence of aspirin showed inhibition of iNOS expression (IC50 = 3 mM). Sodium salicylate variably inhibited iNOS expression (0-35%), whereas indomethacin had no effect. Furthermore, there was no significant effect of these nonsteroidal anti-inflammatory drugs on iNOS mRNA expression at pharmacological concentrations. The effect of aspirin was not due to inhibition of cyclooxygenase 2 because both aspirin and indomethacin inhibited prostaglandin E2 synthesis by > 75%. Aspirin and N-acetylimidazole (an effective acetylating agent), but not sodium salicylate or indomethacin, also directly interfered with the catalytic activity of iNOS in cell-free extracts. These studies indicate that the inhibition of iNOS expression and function represents another mechanism of action for aspirin, if not for all aspirin-like drugs. The effects are exerted at the level of translational/posttranslational modification and directly on the catalytic activity of iNOS
— id: 9740, year: 1995, vol: 92, page: 7926, stat: Journal Article,

HUMAN OSTEOARTHRITIS-AFFECTED CHONDROCYTES SPONTANEOUSLY RELEASE NITRIC-OXIDE BY AN INDUCIBLE NEURONAL NITRIC-OXIDE SYNTHASE (OA-NOS) - A NEW TARGET FOR PHARMACOLOGICAL INTERVENTION
AMIN, AR; DICESARE, PE; VYAS, P; ATTUR, M; TZENG, E; BILLIAR, TR; STUCHIN, SA; ABRAMSON, SB
1995 SEP ;38(9):63-63, Arthritis & rheumatism
— id: 86685, year: 1995, vol: 38, page: 63, stat: Journal Article,

PROSTAGLANDIN E(2) (PGE(2)) IS AND INFLAMMATORY COMPONENT IN OSTEOARTHRITIS-AFFECTED CARTILAGE - THE YIN-YANG REGULATION OF NITRIC-OXIDE SYNTHASE AND CYCLOOXYGENASE-2
AMIN, AR; MARSHALL, PJ; ATTUR, M; VYAS, P; REDISKE, J; ABRAMSON, SB
1995 SEP ;38(9):64-64, Arthritis & rheumatism
— id: 86686, year: 1995, vol: 38, page: 64, stat: Journal Article,

A NOVEL MECHANISM OF ACTION FOR NONSTEROIDAL ANTIINFLAMMATORY DRUGS - EFFECTS ON INDUCIBLE NITRIC-OXIDE SYNTHASE
AMIN, AR; VYAS, P; ATTUR, M; LESZCZYNSKAPIZIAK, J; PATEL, IR; WEISSMANN, G; ABRAMSON, SB
1995 SEP ;38(9):1144-1144, Arthritis & rheumatism
— id: 86699, year: 1995, vol: 38, page: 1144, stat: Journal Article,

DIFFERENTIAL REGULATION OF INDUCIBLE NITRIC-OXIDE SYNTHASE BY IMMUNOPHILINS IN MURINE MACROPHAGES
ATTUR, M; VYAS, P; LEVARTOVSKY, D; THAKKER, G; PATEL, P; ASSEF, F; NAQVI, S; RAZA, R; ABRAMSON, SB; AMIN, AR
1995 SEP ;38(9):725-725, Arthritis & rheumatism
— id: 86696, year: 1995, vol: 38, page: 725, stat: Journal Article,

Misoprostol and Prednisone Treatment of Lupus Nephritis
Belmont HM; Kitsis E; Skovron ML; Buyon J; McCullagh E; Abramson S
1995 Dec;2(12):928-932, American journal of therapeutics
Fourteen patients were enrolled in a placebo-controlled double-blind randomized trial of 8 weeks of treatment for active lupus nephritis. Seven patients received prednisone at a dose of 1 mg kg(minus sign1) day(minus sign1) plus misoprostol at a dose of 200 &mgr;g P.O. Q.I.D.; 7 patients received prednisone plus placebo. The patients included 12 females, 2 males; 3 African-Americans, 3 Asians, 5 Hispanics, and 3 Caucasians. There were no serious side effects associated with prednisone or misoprostol treatment during the 8-week study period. Laboratory measures obtained at baseline, 4, 8, and 12 weeks included complete blood count (CBC), ESR, C reactive protein (CRP), serum creatinine, creatinine clearance, 24-h urine protein excretion, C3, C4, and anti-double stranded DNA (anti-dsDNA). Statistical analysis was conducted assessing change in measures over time in the entire study group by paired t-tests. The effect of treatment on change over time was examined by analysis of covariance. Log transformation of the variables was performed prior to statistical analysis. For the entire study group, the mean levels of ESR, CRP, 24-h protein excretion, C3, C4, and anti-dsDNA were improved at 4, 8, and 12 weeks. The mean ESR at baseline was 70 plus minus 8 compared to 42 plus minus 8 at 12 weeks (p < 0.01). The mean CRP at baseline was 0.6 plus minus 0.2 compared to 0.2 plus minus 0.1 at 12 weeks (p < 0.01). The 24-h protein excretion was 4367 plus minus 769 mg at baseline compared to 2512 plus minus 709 mg at 12 weeks (p = 0.02). The mean C3 at baseline was 40 plus minus 4 mg dl(minus sign1) compared to 60 plus minus 4 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean C4 at baseline was 14 plus minus 1 mg dl(minus sign1) compared to 23 plus minus 2 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean anti-dsDNA at baseline was 4268 plus minus 1780 compared to 316 plus minus 111 at 12 weeks (p < 0.001). The baseline serum creatinine (1.12 plus minus.15 mg dl(minus sign1)) and creatinine clearance (82 plus minus 15 ml min(minus sign1)) were not significantly changed at 12 weeks (1.10 plus minus 0.2 mg dl(minus sign1) and 80 plus minus 17 ml min(minus sign1), respectively). Comparing the misoprostol treatment group to the placebo group, there were no statistically significant differences for ESR, CRP, creatinine, creatinine clearance, 24-h protein excretion, C3, C4, or anti-dsDNA at any time points. However, comparing the misoprostol treatment group at 4 weeks to the placebo group, a more rapid decrease in anti-dsDNA (reduction of 3297 plus minus 2374) was observed in the misoprostol treatment group versus 304 plus minus 409 in the placebo group), as well as lower mean anti-dsDNA levels (464 plus minus 140) in the misoprostol treatment group versus 4118 plus minus 3834 in the placebo group). Also, the C3 and C4 levels at 12 weeks in the misoprostol treatment group (67 plus minus 5 and 27 plus minus 3 mg dl(minus sign1), respectively) were greater than levels in the placebo group (52 plus minus 4 and 19 plus minus 3 mg dl(minus sign1), respectively). The data demonstrate that oral prednisone is effective in reducing proteinuria and improving the biological markers of disease activity (i.e., ESR, CRP, C3, C4, and anti-dsDNA) following short-term treatment of active lupus nephritis. Additionally, the more rapid change in anti-dsDNA levels and superior normalization of complement levels in the treatment group, although not statistically significant, are consistent with a biologic effect of misoprostol on lymphocyte function and the production of a pathogenic autoantibodies
— id: 39703, year: 1995, vol: 2, page: 928, stat: Journal Article,

New York University/Hospital for Joint Diseases experience with intravenous cyclophosphamide treatment: efficacy in steroid unresponsive lupus nephritis
Belmont HM; Storch M; Buyon J; Abramson S
1995 Apr;4(2):104-108, Lupus
The medical records of patients receiving cyclophosphamide for lupus nephritis between 1987 and 1993 at the New York University/Hospital for Joint Diseases Lupus Study Group Institutions were retrospectively reviewed. We identified 45 patients (38 female, seven male) who received a mean of 9 +/- 1 (range 2-23) pulses of intravenous cyclophosphamide for diffuse proliferative glomerulonephritis (n = 28), focal proliferative glomerulonephritis (n = 7), membranous nephropathy (n = 5), mesangial nephropathy with sclerosis (n = 1) or nephritis without biopsy (n = 4). Forty-two of the 45 patients received cyclophosphamide after failing steroid therapy. During a follow-up period of 52 +/- 3 months, nine patients progressed to end-stage renal disease (ESRD) with three additional patients experiencing a doubling of the creatinine and two patients persistent nephrotic range proteinuria. There were no deaths directly attributable to cyclophosphamide and no patients developed hemorrhagic cystitis or malignancy. Ten of 37 women had ceased menstruating prior to cyclophosphamide therapy. Treatment-associated amenorrhea occurred in only three patients all over 27 years of age. Intermittent intravenous cyclophosphamide therapy of lupus nephritis is well tolerated and usually effective in maintaining renal function in patients unresponsive to steroids although, in our experience, 20% of patients developed ESRD and a total of 14 of 45 (30%) patients had unsatisfactory outcomes
— id: 57339, year: 1995, vol: 4, page: 104, stat: Journal Article,

PROSPECTIVE-STUDY OF PREDNISONE TREATMENT IN ACTIVE LUPUS NEPHRITIS - EXPERIENCE WITH STEROID AS A FIRST LINE AGENT
BELMONT, HM; BUYON, J; SKOVRON, ML; MCCULLAGH, E; KITSIS, E; ABRAMSON, SB
1995 SEP ;38(9):909-909, Arthritis & rheumatism
— id: 86697, year: 1995, vol: 38, page: 909, stat: Journal Article,

PROSPECTIVE-STUDY OF HYDROXYCHLOROQUINE EFFECT ON SERUM-LIPIDS IN PATIENTS WITH SLE AND RHEUMATOID-ARTHRITIS
BELMONT, HM; KITSIS, E; MCCULLAGH, E; SKOVRON, ML; ABRAMSON, SB
1995 SEP ;38(9):408-408, Arthritis & rheumatism
— id: 86693, year: 1995, vol: 38, page: 408, stat: Journal Article,

UP-REGULATED EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN SLE - EVIDENCE FOR ACTIVATED ENDOTHELIUM
BELMONT, HM; LEVARTOVSKY, D; AMIN, AR; SKOVRON, ML; BUYON, J; GIORNO, R; REDISKE, J; ABRAMSON, SB
1995 SEP ;38(9):1422-1422, Arthritis & rheumatism
— id: 86701, year: 1995, vol: 38, page: 1422, stat: Journal Article,

Nitric oxide stimulates ADP ribosylation of actin in association with the inhibition of actin polymerization in human neutrophils
Clancy R; Leszczynska J; Amin A; Levartovsky D; Abramson SB
1995 Aug;58(2):196-202, Journal of leukocyte biology
In these studies we provide conclusive evidence that (beta/gamma) actin present in human neutrophils is a substrate for nitric oxide (NO)-dependent ADP ribosylation and that this modification is associated with the inhibition of actin polymerization. A 43-kDa substrate for NO-dependent ADP ribosylation was identified as actin by four methods: (1) comigration with the botulinum C2 toxin substrate by two-dimensional gel electrophoresis (pI 5.2), (2) identity between the peptide map generated by V8 protease digestion of the NO and botulinum C2 substrates, (3) immunoprecipitation with antiactin antibodies, and (4) the ability of NO to ADP ribosylate purified neutrophil G-actin in the presence of plasma membrane cofactors. Because the ADP ribosylation of actin by the botulinum C2 toxin is known to inhibit F-actin polymerization, we examined the effect of NO on actin assembly. Flow cytometry revealed that NO inhibited formyl-methionine-leucine-phenylalanine (fMLP)-dependent (30 s at 37 degrees C) F-actin formation (108 +/- 8 vs. 89 +/- 6 relative fluorescence units, P < .02). These results were confirmed by quantification of F-actin formation by gel scanning (10% sodium dodecyl sulfate gel, Coomassie, and densitometry): pretreatment of polymorphonuclear leukocytes with NO resulted in a reduction of fMLP-induced, cytoskeletal-associated F-actin, which was accompanied by an increase of Triton-soluble G-actin. NO also inhibited F-actin formation, as observed by means of rhodamine phalloidin staining of neutrophils adherent to a fibronectin-coated surface. This effect was accompanied by a dose-dependent inhibition of neutrophil adherence in NO-treated cells. The data indicate that NO inhibits cytoskeletal assembly and adherence in human neutrophils in association with the ADP ribosylation of actin
— id: 56748, year: 1995, vol: 58, page: 196, stat: Journal Article,

Nitric oxide: a novel mediator of inflammation
Clancy RM; Abramson SB
1995 Nov;210(2):93-101, Proceedings of the Society for Experimental Biology & Medicine
— id: 8336, year: 1995, vol: 210, page: 93, stat: Journal Article,

NITRIC-OXIDE INHIBITS CHONDROCYTE ADHESION TO FIBRONECTIN VIA EFFECTS ON INTRACELLULAR ACTIN POLYMERIZATION
CLANCY, RM; FRENKEL, SR; DICESARE, P; ABRAMSON, S
1995 SEP ;38(9):429-429, Arthritis & rheumatism
— id: 86694, year: 1995, vol: 38, page: 429, stat: Journal Article,

NITRIC-OXIDE MEDIATES CYTOKINE DEPENDENT OXIDANT INJURY IN CHONDROCYTES - EVIDENCE FOR ACTIVATION OF POLY(ADP-RIBOSE) SYNTHETASE
CLANCY, RM; REDISKE, J; KOEHNE, C; ABRAMSON, SB
1995 SEP ;38(9):239-239, Arthritis & rheumatism
— id: 86690, year: 1995, vol: 38, page: 239, stat: Journal Article,

Translocation of p21rac2 from cytosol to plasma membrane is neither necessary nor sufficient for neutrophil NADPH oxidase activity
Philips MR; Feoktistov A; Pillinger MH; Abramson SB
1995 May 12;270(19):11514-11521, Journal of biological chemistry
Activation of the membrane-associated NADPH oxidase of neutrophils requires several cytosolic factors including p47phox, p67phox and p21rac2. We compared NADPH oxidase activity with the membrane translocation of p47phox, p67phox, and p21rac2. In a cell-free system, GTP gamma S stimulated translocation of p47phox and p67phox to the plasma membrane only in the presence of arachidonate, and this translocation correlated with NADPH oxidase activity of the reisolated plasma membranes (R = 0.94 and 0.97, respectively). In contrast, GTP gamma S-stimulated p21rac2 translocation with or without arachidonate, and the extent of translocation did not correlate with oxidase activity (R = 0.17). Neutrophil cytoplasts were used to relate membrane translocation of p47phox, p67phox and p21rac2 to membrane oxidase activity in response to the inflammatory agonists. Whereas N-formyl-methionyl-leucyl-phenylalanine stimulated equimolar, transient membrane translocation of p47phox and p67phox which kinetically paralleled NADPH oxidase activity, relatively little p21rac2 translocated (moles of p47phox/p21rac2 = 16.6). Moreover, although phorbol 12-myristate 13-acetate stimulated both the stable translocation of p47phox and p67phox and sustained NADPH oxidase activity, it did not stimulate p21rac2 translocation. From these data we conclude that membrane translocation of p21rac2 does not regulate NADPH oxidase activity stoichiometrically
— id: 6712, year: 1995, vol: 270, page: 11514, stat: Journal Article,

The neutrophil in rheumatoid arthritis
Pillinger MH; Abramson SB
1995 Aug;21(3):691-714, Rheumatic diseases clinics of North America
The destructive capacity of the neutrophil has long been appreciated, and the presence of extraordinary numbers of neutrophils in the synovial fluid of patients with RA supports a role for these cells in the pathogenesis of joint destruction. In this article, we reviewed the current state of knowledge of neutrophil function in the inflammatory response, and emphasized the subjects of neutrophil/endothelial adhesion and the role of chemoattractants and cytokines in neutrophil mobilization. We also discussed the mechanisms of action of neutrophil destruction of cartilage and the interplay of signals between the neutrophil and the chondrocyte. The capacity of many of the drugs used to treat RA to interfere with one or several of these processes underscores the importance of the neutrophil in RA and suggests that future therapeutic strategies could target neutrophil activation within the synovial space
— id: 8014, year: 1995, vol: 21, page: 691, stat: Journal Article,

False positive seroreactivity to Borrelia burgdorferi in systemic lupus erythematosus: the value of immunoblot analysis
Weiss NL; Sadock VA; Sigal LH; Phillips M; Merryman PF; Abramson SB
1995 Apr;4(2):131-137, Lupus
The object of this study was to determine the incidence of seropositivity to B. burgdorferi by the commonly available enzyme-linked immunosorbent assay (ELISA) in patients with SLE and other rheumatic diseases and to evaluate immunoblot analysis as a tool to differentiate true from false positive ELISA. Sera were obtained from patients with SLE (n = 35), rheumatoid arthritis (n = 26), seronegative arthritis (n = 28) and Lyme disease (n = 18). Reactivity to B. burgdorferi antigens was analysed by two available diagnostic techniques: ELISA and immunoblot. Correlations were made between seroreactivity to B. burgdorferi and standard serological tests of autoimmunity: antibodies to nuclear antigens, dsDNA, cardiolipin, SSA and SSB. Seroreactivity to B. burgdorferi antigens by the ELISA system was detected in 40% of patients with SLE, 8% of patients with rheumatoid arthritis and 4% with seronegative arthritis. Among patients seropositive by ELISA, immunoblots were negative in all cases. However, eight of 14 patients with rheumatoid arthritis (57%) showed cross-reactivity to multiple borreli antigens. No significant correlations were found between Lyme seropositivity by ELISA and other autoantibodies except IgM rheumatoid factor (r = 0.61, P < 0.01) in patients with rheumatoid arthritis. In conclusion: a positive ELISA for Lyme disease was found in up to 40% of patients with established SLE and also in other rheumatic diseases. However, specific serum antibodies to Borrelia were not confirmed by the more specific immunoblot technique.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 9741, year: 1995, vol: 4, page: 131, stat: Journal Article,

Inhibition of neutrophil function by aspirin-like drugs (NSAIDS): requirement for assembly of heterotrimeric G proteins in bilayer phospholipid
Abramson SB; Leszczynska-Piziak J; Clancy RM; Philips M; Weissmann G
1994 Feb 9;47(3):563-572, Biochemical pharmacology
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit neutrophil functions via mechanisms that are independent of their effects on prostaglandin biosynthesis. We examined the effects of sodium salicylate and piroxicam on GTP/GDP exchange by a regulatory G protein (G alpha i). Plasma membrane and cytosol of human neutrophils were prepared by nitrogen cavitation and discontinuous sucrose density centrifugation. Salicylate (3 mM) and piroxicam (50 microM) reduced [35S]GTP gamma S binding to purified plasma membranes [65 +/- 3.7 and 75 +/- 5.3% (P < 0.003) of control, respectively]. Membrane-associated G alpha/beta gamma was solubilized by treatment of plasma membranes with sodium cholate. NSAIDs did not inhibit binding of GTP to solubilized G alpha/beta gamma derived from detergent-treated plasma membranes. Lipid reconstitution was achieved by detergent dialysis followed by the addition of bilayer liposomes (phosphatidylcholine). Salicylate and piroxicam inhibited GTP gamma S binding to G alpha/beta gamma derived from solubilized plasma membranes reconstituted in phosphatidylcholine vesicles (bilayer structures) but had no effect when phosphatidylethanolamine (hexagonal phase II structure) was used for reconstitution. Salicylate and piroxicam had no effect on GTP binding to cytosolic fractions in which soluble G alpha i exists as a free subunit, suggesting that the effect required either assembly of G alpha i/beta gamma heterotrimer or the presence of a lipid bilayer. Although the addition of purified bovine beta gamma subunits to dialyzed cytosol increased both the total GIP binding capacity and the pertussis toxin-dependent ADP-ribosylation of G alpha i, consistent with assembly of a G protein heterotrimer, NSAIDs had no effect on GTP binding. In contrast, NSAIDs inhibited GTP binding to heterotrimeric G alpha cytosol/beta gamma bovine when the complex was inserted into bilayer liposomes. The data indicate that salicylate and piroxicam disrupt neutrophil function via their capacity to interfere with GTP/GDP exchange at an alpha subunit of a regulatory G protein, an effect which requires assembly of the active heterotrimer G alpha i/beta gamma in a phospholipid bilayer
— id: 6306, year: 1994, vol: 47, page: 563, stat: Journal Article,

NITRIC-OXIDE INHIBITS CYTOSKELETAL ASSEMBLY IN ACTIVATED NEUTROPHILS VIA THE ADP-RIBOSYLATION OF ACTIN
ABRAMSON, SB; LESZCZYNSKAPIZIAK, J; CLANCY, RM
1994 APR ;42(2):A134-A134, Clinical research
— id: 52485, year: 1994, vol: 42, page: A134, stat: Journal Article,

Up-regulation of endothelial cell adhesion molecules characterizes disease activity in systemic lupus erythematosus. The Shwartzman phenomenon revisited
Belmont HM; Buyon J; Giorno R; Abramson S
1994 Mar;37(3):376-383, Arthritis & rheumatism
OBJECTIVE. To test the hypothesis that during exacerbations of systemic lupus erythematosus (SLE), endothelial cells are activated to increase their expression of adhesion molecules. METHODS. Endothelial cell expression of E-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) was quantitated immunohistochemically in 20 biopsy specimens from nonlesional, non-sun-exposed skin from 16 SLE patients. Disease activity was evaluated with the SLE Disease Activity Index (SLEDAI) and with measurements of complement components C3a desArg, C3, and C4. RESULTS. The mean expression of all 3 adhesion molecules was significantly elevated in patients with SLE versus healthy controls, as well as in patients with active versus inactive SLE. The mean C3a desArg level was significantly higher in patients with active SLE compared with those with inactive SLE. The SLEDAI scores correlated directly with C3a desArg levels and inversely with C3 and with C4 levels. Evaluation of serial biopsy specimens demonstrated loss of endothelial cell adhesion molecules and reduction of C3a levels with clinical improvement. CONCLUSION. Our findings demonstrate up-regulation of the surface expression of 3 distinct adhesion molecules, E-selectin, VCAM-1, and ICAM-1, in patients with SLE. The abnormal expression of these endothelial cell adhesion molecules is most marked in patients with active disease characterized by significant elevations of the complement split product C3a desArg. We suggest that in certain SLE patients, excessive complement activation in association with primed endothelial cells induces leukocyte-endothelial cell adhesion and leuko-occlusive vasculopathy
— id: 56498, year: 1994, vol: 37, page: 376, stat: Journal Article,

Nitric oxide reacts with intracellular glutathione and activates the hexose monophosphate shunt in human neutrophils: evidence for S-nitrosoglutathione as a bioactive intermediary
Clancy RM; Levartovsky D; Leszczynska-Piziak J; Yegudin J; Abramson SB
1994 Apr 26;91(9):3680-3684, Proceedings of the National Academy of Sciences of the United States of America
We performed experiments to determine whether nitric oxide promoted the formation of intracellular S-nitrosothiol adducts in human neutrophils. At concentrations sufficient to inhibit chemoattractant-induced superoxide anion production, nitric oxide caused a depletion of measurable intracellular glutathione as determined by both the monobromobimane HPLC method and the glutathione reductase recycling assay. The depletion of glutathione could be shown to be due to the formation of intracellular S-nitrosoglutathione as indicated by the ability of sodium borohydride treatment of cytosol to result in the complete recovery of measurable glutathione. The formation of intracellular S-nitrosylated compounds was confirmed by the capacity of cytosol derived from nitric oxide-treated cells to ADP-ribosylate glyceraldehyde-3-phosphate dehydrogenase. Depletion of intracellular glutathione was accompanied by a rapid and concomitant activation of the hexose monophosphate shunt (HMPS) following exposure to nitric oxide. Kinetic studies demonstrated that nitric oxide-dependent activation of the HMPS was reversible and paralleled nitric oxide-induced glutathione depletion. Synthetic preparations of S-nitrosoglutathione shared with nitric oxide the capacity to inhibit superoxide anion production and activate the HMPS. These data suggest that nitric oxide may regulate cellular functions via the formation of intracellular S-nitrosothiol adducts and the activation of the HMPS
— id: 56508, year: 1994, vol: 91, page: 3680, stat: Journal Article,

ENDOTHELIAL-DERIVED RELAXATION FACTOR (NITRIC-OXIDE) AUGMENTS HUMAN NEUTROPHIL CHEMOTAXIS WHILE INHIBITING SUPEROXIDE ANION GENERATION
CLANCY, RM; ABRAMSON, SB
1994 APR ;42(2):A255-A255, Clinical research
— id: 52496, year: 1994, vol: 42, page: A255, stat: Journal Article,

NITRIC-OXIDE REACTS WITH INTRACELLULAR GLUTATHIONE AND ACTIVATES THE HEXOSE-MONOPHOSPHATE SHUNT IN HUMAN NEUTROPHILS - EVIDENCE FOR S-NITROSOGLUTATHIONE AS A BIOACTIVE INTERMEDIARY
CLANCY, RM; LEVARTOVSKY, D; LESZCZYNSKAPIZIAK, J; ABRAMSON, SB
1994 APR ;42(2):A113-A113, Clinical research
— id: 52481, year: 1994, vol: 42, page: A113, stat: Journal Article,

NITRIC-OXIDE PRODUCED BY HUMAN NEUTROPHILS ACTS AS A 2ND MESSENGER TO INHIBIT SUPEROXIDE ANION PRODUCTION AND ADP-RIBOSYLATE CYTOSOLIC PROTEINS
LEVARTOVSKY, D; CLANCY, RM; LESZCZYNSKAPIZIAK, J; ABRAMSON, SB
1994 APR ;42(2):A112-A112, Clinical research
— id: 52480, year: 1994, vol: 42, page: A112, stat: Journal Article,

Intravascular neutrophil activation in systemic lupus erythematosus (SLE): dissociation between increased expression of CD11b/CD18 and diminished expression of L-selectin on neutrophils from patients with active SLE
Molad Y; Buyon J; Anderson DC; Abramson SB; Cronstein BN
1994 Jun;71(3):281-286, Clinical immunology & immunopathology
Previous studies have shown that neutrophils in the circulation of patients with active systemic lupus erythematosus (SLE) are activated as judged by their increased surface expression of the beta 2-integrin CD11b/CD18. Since activation of neutrophils leads to altered expression of another adhesion molecule, L-selectin (LS), we examined neutrophils from patients with SLE for changes in the expression of CD11b/CD18 and LS by cytofluorographic analysis of immunofluorescent-labeled cells. Overall there was no difference between surface expression of CD11b/CD18 on neutrophils from SLE patients or controls [mean fluorescence 225 +/- 26 vs 225 +/- 13 relative fluorescence units (RFU), respectively]. However, as previously reported, neutrophils from patients with more active disease (activity score > or = 3, UCH Middlesex activity score) expressed greater CD11b/CD18 than neutrophils from controls (319 +/- 40 RFU, P < 0.03, n = 9) or from patients with less active disease (193 +/- 10 RFU, P < 0.006). Indeed, CD11b/CD18 expression correlated directly with disease activity (r = 0.54, P < 0.02). Stimulation of neutrophils ex vivo with the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (100 nM) induced up-regulation of CD11b/CD18 in cells from both SLE patients and controls (205 +/- 12% vs 239 +/- 15% of basal, respectively), but neutrophils from the most active patients (score > or = 3) increased CD11b/CD18 expression less than controls (175 +/- 12% of basal, P < 0.003, n = 9). The magnitude of the stimulated increment in expression of CD11b/CD18 on neutrophils correlated inversely with SLE activity (r = -0.64, P < 0.003, n = 20). Surprisingly, we observed no change in LS expression on neutrophils from SLE patients compared to controls (143 +/- 14 vs 141 +/- 16 RFU, respectively) even in patients with the highest activity indices (154 +/- 21 RFU). In contrast to CD11b/CD18, there was no correlation between LS expression and disease activity (r = 0.12, P = NS). Stimulation of neutrophils reduced the expression of LS similarly in both controls and SLE patients (67 +/- 3% vs 58 +/- 4% reduction, respectively) and did not correlate with disease activity (r = 0.07, P = NS, n = 20). These results show, for the first time, that changes in CD11b/CD18 expression do not correlate with LS expression on neutrophils from patients with active SLE.(ABSTRACT TRUNCATED AT 400 WORDS)
— id: 56565, year: 1994, vol: 71, page: 281, stat: Journal Article,

The role of nitric oxide in the pathogenesis of preeclampsia
Seligman SP; Buyon JP; Clancy RM; Young BK; Abramson SB
1994 Oct;171(4):944-948, American journal of obstetrics & gynecology
OBJECTIVE: Nitric oxide, a potent vasodilator released by endothelial cells, inhibits platelet aggregation and adhesion to vascular endothelial surfaces. Because endothelial cell damage is considered pivotal in the pathogenesis of preeclampsia, this study was initiated to determine whether nitric oxide production is decreased in patients with preeclampsia. STUDY DESIGN: Twenty-six patients with preeclampsia (as defined by a blood pressure > or = 140 mm Hg systolic or 90 mm Hg diastolic plus proteinuria, > or = 300 mg per 24 hours or > or = 2+ by dipstick, both occurring on two occasions > or = 4 hours apart) and 26 normotensive women with singleton gestations in the third trimester were studied. Because nitric oxide is spontaneously oxidized to both nitrite and nitrate, two analytic assays were used serially. Serum nitrite levels were initially determined with the Greiss reagent and subsequently analyzed with Escherichia coli nitrate reductase. RESULTS: With the Greiss reagent alone the mean +/- SEM of serum nitrite level in 26 patients with preeclampsia was significantly decreased compared with 26 normotensive patients (3.46 +/- 1.43 mumol/L vs 4.65 +/- 0.85 mumol/L, p = 0.02). With the addition of the nitrate reductase enzyme of Escherichia coli the mean +/- SEM of serum nitrite level in 26 preeclamptic patients was again significantly decreased compared with 26 normotensive patients (20.04 +/- 1.25 mumol/L vs 27.38 +/- 2.23 mumol/L, p = 0.02). One patient with the syndrome of hemolysis, elevated liver enzymes, and low platelets demonstrated a concurrent decrease in serum nitrite over a 2-week period, emphasizing the relationship of nitric oxide to the pathophysiologic features of the syndrome. CONCLUSIONS: Circulating levels of nitrite are decreased in patients with preeclampsia. These data support the concept that diminished nitric oxide synthesis contributes to the pathophysiologic changes seen in preeclampsia
— id: 6747, year: 1994, vol: 171, page: 944, stat: Journal Article,

Medical education database
Abramson, Steven; Levin, Richard I
[New York, NY : The School, 1993],
— id: 426, year: 1993, vol: , page: , stat: ,

Report of the Institutional self-study : subcommittee reports : prepared for the site visit of the Liaison Committee on Medical Education, March 1-4, 1993
Abramson, Steven; Levin, Richard I
[New York, NY : The School, 1993],
— id: 428, year: 1993, vol: , page: , stat: ,

Report of the Institutional self-study : summary : prepared for the site visit of the Liaison Committee on Medical Education, March 1-4, 1993
Abramson, Steven; Levin, Richard I
[New York, NY : The School, 1993],
— id: 427, year: 1993, vol: , page: , stat: ,

UP-REGULATION OF ENDOTHELIAL-CELL ADHESION MOLECULES IN SYSTEMIC LUPUS-ERYTHEMATOSUS - THE SHWARTZMAN PHENOMENON REVISITED
BELMONT, HM; BUYON, J; GIORNO, R; ABRAMSON, SB
1993 APR ;41(2):A317-A317, Clinical research
— id: 54279, year: 1993, vol: 41, page: A317, stat: Journal Article,

NYU HJD LUPUS STUDY-GROUP CYCLOPHOSPHAMIDE (CY) EXPERIENCE - RETROSPECTIVE STUDY OF 51 PATIENTS
BELMONT, HM; STORCH, M; BUYON, J; ABRAMSON, S
1993 SEP ;36(9):S229-S229, Arthritis & rheumatism
— id: 52192, year: 1993, vol: 36, page: S229, stat: Journal Article,

PAST AND PRESENT USAGE OF ORAL-CONTRACE
BUYON, JP; ABRAMSON, S; BELMONT, HM
1993 SEP ;36(9):S229-S229, Arthritis & rheumatism
— id: 52193, year: 1993, vol: 36, page: S229, stat: Journal Article,

INTEGRIN CD11B/CD18 IS DIFFERENTIALLY PHOSPHORYLATED IN PLASMA VERSUS SPECIFIC GRANULE MEMBRANES OF NEUTROPHILS
BUYON, JP; PHILIPS, MR; SLADE, SG; LESZCZYNSKAPIZIAK, J; ABRAMSON, SB
1993 APR ;41(2):A377-A377, Clinical research
— id: 54285, year: 1993, vol: 41, page: A377, stat: Journal Article,

Nitric oxide stimulates the ADP-ribosylation of actin in human neutrophils
Clancy RM; Leszczynska-Piziak J; Abramson SB
1993 Mar 31;191(3):847-852, Biochemical & biophysical research communications
ADP-ribosylation is an important post-translational protein modification; however, endogenous substrates are poorly characterized. In these studies we examined the effects of nitric oxide on the ADP-ribosylation of neutrophil proteins. Purified cytosol and plasma membrane were incubated with 32P-NAD (5 microM, 1 microCi, 30 min) in the presence or absence of nitric oxide. Nitric oxide induced the ADP-ribosylation of the 37 kD substrate present only in cytosol. Nitric oxide treatment of plasma membrane plus cytosol revealed the ADP-ribosylation of an additional 43 kD protein. This 43 kD substrate was identified as actin by both phalloidin precipitation and immunoblot (2-D) gel using specific anti-actin antibodies. The data indicate that nitric oxide stimulates the ADP-ribosylation of two discrete substrates in fractionated PMN, one of which can be identified as actin. NO-induced ADP-ribosylation may contribute to the modulatory effect of nitric oxide on neutrophil functions, including F-actin assembly
— id: 6335, year: 1993, vol: 191, page: 847, stat: Journal Article,

NITRIC-OXIDE AND S-NITROSOGLUTATHIONE AUGMENT HUMAN NEUTROPHIL CHEMOTAXIS WHILE INHIBITING SUPEROXIDE ANION GENERATION - ROLE OF INTRACELLULAR S-NITROSOTHIOL FORMATION
CLANCY, R; YEGUDIN, J; LEVARTOVSKY, D; ABRAMSON, SB
1993 SEP ;36(9):S243-S243, Arthritis & rheumatism
— id: 52195, year: 1993, vol: 36, page: S243, stat: Journal Article,

NITRIC-OXIDE STIMULATES THE ADP-RIBOSYLATION OF ACTIN IN HUMAN NEUTROPHILS
CLANCY, RM; LESZCZYNSKAPIZIAK, J; ABRAMSON, SB
1993 APR ;41(2):A247-A247, Clinical research
— id: 54269, year: 1993, vol: 41, page: A247, stat: Journal Article,

EDRFS (NITRIC-OXIDE, S-NITROSOTHIOLS) AUGMENT HUMAN NEUTROPHIL CHEMOTAXIS WHILE INHIBITING SUPEROXIDE ANION GENERATION - ROLE OF INTRACELLULAR S-NITROSOTHIOL FORMATION
CLANCY, RM; LESZCZYNSKAPIZIAK, J; YEGUDIN, J; LEVARTOVSKY, D; ABRAMSON, SB
1993 APR ;41(2):A224-A224, Clinical research
— id: 54267, year: 1993, vol: 41, page: A224, stat: Journal Article,

INTRACELLULAR NITRIC-OXIDE PRODUCED BY HUMAN NEUTROPHILS ACTS AS AN AUTACOID TO REGULATE SUPEROXIDE ANION PRODUCTION
LEVARTOVSKV, D; CLANCY, R; ABRAMSON, SB
1993 SEP ;36(9):S70-S70, Arthritis & rheumatism
— id: 52187, year: 1993, vol: 36, page: S70, stat: Journal Article,

Modulation of human T cell responses by nitric oxide and its derivative, S-nitrosoglutathione
Merryman PF; Clancy RM; He XY; Abramson SB
1993 Oct;36(10):1414-1422, Arthritis & rheumatism
OBJECTIVE. To examine the effects of nitric oxide (NO) and its more stable derivative, S-nitrosoglutathione (SNO-GSH), on the response of activated T lymphocytes. METHODS. The effects of NO and SNO-GSH on DNA synthesis, interleukin-2 (IL-2) production, IL-2 receptor expression, and cGMP accumulation were determined in phytohemagglutinin-activated peripheral blood mononuclear cells (PBMC) and spleen T cells. RESULTS. Nitric oxide (half-life [T1/2] < 15 seconds) did not inhibit T cell proliferation. However, the derivative SNO-GSH (25 microM) (T1/2 > 2 hours) inhibited DNA synthesis by a mean +/- SD of 65 +/- 19.6% (P < 0.001) in PBMC and 75 +/- 15% (P < 0.001) in spleen cells. Macrophage depletion of PBMC did not abrogate the inhibition. SNO-GSH had no effect on IL-2 production or IL-2 receptor expression. NO (25 microM) increased the cGMP content of PBMC (0.65 +/- 0.15 pmoles/10(6) cells; P < 0.04), as did SNO-GSH (25 microM) in both PBMC (3.8 +/- 1; P < 0.001) and spleen T cells (5.2 +/- 1.2; P < 0.001). Methylene blue and hemoglobin, which are NO inhibitors, inhibited SNO-GSH-induced cGMP accumulation (P < 0.001). CONCLUSION. SNO-GSH inhibits T cell DNA synthesis independently of IL-2 production and in association with cGMP accumulation via a NO-dependent mechanism. We suggest that NO and its S-nitrosothiol derivatives may act as endogenous inhibitors of T cell-mediated inflammation
— id: 9742, year: 1993, vol: 36, page: 1414, stat: Journal Article,

NITRIC-OXIDE DERIVATIVE, S-NITROSOGLUTATHIONE, BLOCKS IL-2 DEPENDENT DNA-SYNTHESIS VIA INHIBITION OF RIBONUCLEOTIDE REDUCTASE-ACTIVITY IN HUMAN T-CELLS
MERRYMAN, PF; CLANCY, RM; HAINES, KA; HE, Y; ABRAMSON, SB
1993 SEP ;36(9):S113-S113, Arthritis & rheumatism
— id: 52191, year: 1993, vol: 36, page: S113, stat: Journal Article,

TENIDAP POTENTIATES THE RESPONSE OF HUMAN T-LYMPHOCYTES TO NITRIC-OXIDE DERIVATIVE S-NITROSOGLUTATHIONE
MERRYMAN, PF; CLANCY, RM; HE, Y; ABRAMSON, SB
1993 APR ;41(2):A373-A373, Clinical research
— id: 54284, year: 1993, vol: 41, page: A373, stat: Journal Article,

TRANSLOCATION OF A RAS-RELATED PROTEIN, P22(RAC2), REGULATES NEUTROPHIL O2 GENERATION
PHILLIPS, MR; FEOKTISTOV, AS; MUSCAT, SD; ABRAMSON, SB; WEISSMANN, G
1993 SEP ;36(9):S69-S69, Arthritis & rheumatism
— id: 52186, year: 1993, vol: 36, page: S69, stat: Journal Article,

EDRFS (NITRIC-OXIDE, S-NITROSOTHIOLS) AUGMENT HUMAN NEUTROPHIL CHEMOTAXIS WHILE INHIBITING SUPEROXIDE ANION GENERATION - ROLE OF INTRACELLULAR S-NITROSOTHIOL FORMATION
YEGUDIN, J; LEVARTOVSKY, D; CLANCY, RM; ABRAMSON, SB
1993 MAY ;36(5):R32-R32, Arthritis & rheumatism
— id: 54131, year: 1993, vol: 36, page: R32, stat: Journal Article,

Treatment of gout and crystal arthropathies and uses and mechanisms of action of nonsteroidal anti-inflammatory drugs
Abramson SB
1992 Jun;4(3):295-300, Current opinion in rheumatology
Nonsteroidal anti-inflammatory agents have anti-inflammatory, analgesic, and antipyretic actions. Nonsteroidal anti-inflammatory drugs are the preferred class of agents for the treatment of gout and other crystal-induced arthropathies. The use of colchicine for other than the prophylaxis of acute attacks is discouraged owing to side effects, which include death. The inhibition of the enzyme prostaglandin H synthase by most nonsteroidal anti-inflammatory drugs explains many of their effects and toxicities. However, it is likely that additional biologic actions are important. These include the inhibition of the transcription of the gene for prostaglandin H synthase, a direct central effect on peripheral inflammation, and the modulation of the functions of a variety of cells (eg, neutrophils, lymphocytes, and chondrocytes). This review focuses on the current controversy in the treatment of gout and discusses the recent literature on the actions of nonsteroidal anti-inflammatory drugs
— id: 9749, year: 1992, vol: 4, page: 295, stat: Journal Article,

Activation of the complement pathway: comparison of normal pregnancy, preeclampsia, and systemic lupus erythematosus during pregnancy
Abramson SB; Buyon JP
1992 Oct-Dec;28(3-4):183-187, American Journal of Reproductive Immunology (1989)
To evaluate a flare of systemic lupus erythematosus (SLE) during pregnancy and to differentiate it from diseases of pregnancy, serological parameters are often utilized. However, there are conflicting reports regarding the merit of conventional measurements of complement and activation products. While in normal pregnancy the levels of serum C3, C4, and CH50 gradually rise, a decline in these levels occurs during the course of pregnancy in selected SLE patients. There is controversy regarding whether such falls represent decreases in the overall synthesis of complement or activation, the former theory being supported by a report of normal levels of the C1s-C1 inhibitor complex. During normal pregnancies, increases of complement split products, such as plasma C3a, may occur, and these correlate positively with elevations of C3. In pregnancies complicated by lupus, increases of C3a are often accompanied by a decline in total C3 and CH50. In a minority of non-SLE patients, preeclampsia has been associated with elevations of a variety of complement split products. Ba, C3a, C4d, SC5b-9, indicating activation of both the classical and alternative pathways. The CH50 levels tend to remain normal in these patients. In contrast, elevations of complement split products frequently accompany disease flares in patients with SLE. A high ratio of CH50/Ba may differentiate patients with preeclampsia from those with active SLE. A decline in conventional measures of C3, C4, or CH50 which is accompanied by elevations of complement split products appears to differentiate a lupus flare from non-SLE diseases of pregnancy
— id: 9744, year: 1992, vol: 28, page: 183, stat: Journal Article,

NITRIC OXIDE-INDUCED ADP-RIBOSYLATION OF A 37KDA CYTOSOLIC PROTEIN IN HUMAN NEUTROPHILS PROMOTES ACTIN DEGRADATION
ABRAMSON, SB; LESZCZYNSKAPIZIAK, J; CLANCY, RM
1992 APR ;40(2):A248-A248, Clinical research
— id: 51987, year: 1992, vol: 40, page: A248, stat: Journal Article,

ASSEMBLY OF HETEROTRIMERIC G-PROTEINS IN A LIPID BILAYER IS REQUIRED FOR THE INHIBITION OF NEUTROPHIL FUNCTION BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS
ABRAMSON, SB; LESZCZYNSKAPIZIAK, J; CLANCY, RM; PHILIPS, M; WEISSMANN, G
1992 APR ;40(2):A191-A191, Clinical research
— id: 51975, year: 1992, vol: 40, page: A191, stat: Journal Article,

THE SHWARTZMAN PHENOMENON IN SYSTEMIC LUPUS-ERYTHEMATOSUS - A NOVEL MECHANISM OF VASCULAR INJURY
BELMONT, HM; BUYON, J; GIORNO, R; ABRAMSON, S
1992 SEP ;35(9):S211-S211, Arthritis & rheumatism
— id: 51851, year: 1992, vol: 35, page: S211, stat: Journal Article,

Assessment of disease activity and impending flare in patients with systemic lupus erythematosus. Comparison of the use of complement split products and conventional measurements of complement
Buyon JP; Tamerius J; Belmont HM; Abramson SB
1992 Sep;35(9):1028-1037, Arthritis & rheumatism
OBJECTIVE. To determine whether increased levels of the complement split products generated in the activation of the alternative or classical pathway accompany more severe disease activity in patients with systemic lupus erythematosus (SLE) and whether these measurements are useful in predicting flares of disease. METHODS. Levels of Ba, Bb, SC5b-9, and C4d were measured in 380 plasma samples obtained from 86 SLE patients who were prospectively followed up for 15 months. RESULTS. In the 20 patients who had inactive disease at the initiation of the study, the mean values of all of the complement split products at entry were within the normal range. In the 47 patients with stable or moderate disease activity, levels of Ba were significantly increased, while the mean values for Bb, SC5b-9, and C4d did not differ significantly from those in patients with inactive disease. The mean entry value of each analyte was highest in the group of 19 patients who had the most severe disease activity at initial evaluation. Traditional measurements of complement, i.e., C3, C4, and CH50, followed similar trends, but did not discriminate between the 3 groups of patients as well as did measurements of the split products. Analysis of the disease course in the patients with inactive or stable/moderate disease revealed that an elevated level of C4d had the most sensitivity with regard to subsequent flare, while an elevated Bb level had the highest specificity and the greatest predictive value. CONCLUSION. These data suggest that elevated levels of complement split products, particularly products of alternative and terminal pathway activation, more accurately reflect disease activity than do conventional measurements of complement in SLE and may be useful in the prediction of impending disease flares
— id: 9745, year: 1992, vol: 35, page: 1028, stat: Journal Article,

Activation of the alternative complement pathway accompanies disease flares in systemic lupus erythematosus during pregnancy
Buyon JP; Tamerius J; Ordorica S; Young B; Abramson SB
1992 Jan;35(1):55-61, Arthritis & rheumatism
OBJECTIVE. To assess the activity of systemic lupus erythematosus (SLE) during pregnancy and to distinguish it from preeclampsia. METHODS. We prospectively measured the complement activation products Ba, Bb, SC5b-9, and C4d, as well as the conventional complement determinants C3, C4, and CH50, during pregnancy in 14 patients with SLE and 10 women with preeclampsia. RESULTS. Four of the 14 SLE patients were considered to have disease flares, 3 occurring in the second trimester and 1 postpartum. In these patients, significant abnormalities of Ba, Bb, SC5b-9, and CH50 were noted. In contrast, measures of C4d did not distinguish between pregnant patients who had flares and those whose SLE remained stable. Although decreased values of C3 were rarely seen in the patients with stable disease, normal values of C3 during lupus pregnancy were not reliably associated with stable disease. Three of 10 non-SLE patients with preeclampsia had elevated levels of Ba; however, in each case, the CH50 level was close to or within the normal range. This was in sharp contrast to the findings observed in the 4 patients with active SLE, in whom high levels of plasma Ba were always associated with low CH50 values. Moreover, the ratio of CH50 to Ba was significantly lower in the patients with lupus flares than in the non-SLE patients with preeclampsia. CONCLUSION. While a decline in the CH50 level alone could otherwise be attributed to decreased synthesis of complement components, these data demonstrate that ongoing activation of the alternative complement pathway can accompany disease flares in pregnant women with SLE
— id: 9752, year: 1992, vol: 35, page: 55, stat: Journal Article,

DIFFERENTIAL PHOSPHORYLATION OF CD11B/CD18 IN NEUTROPHIL SPECIFIC GRANULE AND PLASMA-MEMBRANES
BUYON, JP; SLADE, SG; LESZCYNSKAPIZIAK, J; PHILIPS, M; ABRAMSON, SB
1992 SEP ;35(9):S96-S96, Arthritis & rheumatism
— id: 51845, year: 1992, vol: 35, page: S96, stat: Journal Article,

Novel synthesis of S-nitrosoglutathione and degradation by human neutrophils
Clancy RM; Abramson SB
1992 Aug 1;204(2):365-371, Analytical biochemistry
S-nitrosoglutathione (SNO-GSH), a stable derivative of nitric oxide, is an endothelium-derived relaxation factor, which provokes vasodilation, inhibits platelet aggregation, and inhibits neutrophil (PMN) superoxide anion (O2+) generation. We have established a novel method for synthesis of S-nitrosoglutathione using a column containing S-nitrosothiol covalently attached to agarose. S-nitrosoglutathione was a product as assessed after separation using C-18 reverse-phase HPLC and absorption spectroscopy. We examined the stability of SNO-GSH in the presence or absence of PMN. The half-life (mercuric acid diazotization) of SNO-GSH in Hepes was greater than 60 min. The addition of resting PMN did not affect the T1/2 of SNO-GSH. PMN exposed to N-fMet-Leu-Phe (FMLP, 10(-7) M) reduced measurable SNO-GSH (15 microM) at 5 min (48 +/- 5.0% control, P less than 0.05). Incubation (5 min, 37 degrees C) of PMN with 10 microM tenidap (an anti-inflammatory drug which inhibits PMN activation) before addition of FMLP blocked the PMN-dependent degradation of SNO-GSH (42 +/- 3 vs 78 +/- 1.3% control, P = 0.01). We confirmed the recovery of SNO-GSH through measurements by bioassay (platelet aggregation) and HPLC analysis. The degradation of S-nitrosothiols by activated neutrophils may reverse the inhibitory effect of S-nitrosothiols on PMN functions and contribute to tissue injury at sites of inflammation
— id: 9747, year: 1992, vol: 204, page: 365, stat: Journal Article,

Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase
Clancy RM; Leszczynska-Piziak J; Abramson SB
1992 Sep;90(3):1116-1121, Journal of clinical investigation
Nitric oxide provokes vasodilation and inhibits platelet aggregation. We examined the effect of nitric oxide on superoxide anion production by three sources: activated intact neutrophils, xanthine oxidase/hypoxanthine, and the NADPH oxidase. Nitric oxide significantly inhibited the generation of superoxide anion by neutrophils exposed to either FMLP (10(-7)M) or PMA (150 ng/ml) (IC50 = 30 microM). To determine whether the effect of nitric oxide on the respiratory burst was due to simple scavenging of O2+, kinetic studies that compared effects on neutrophils and the cell-free xanthine oxidase system were performed. Nitric oxide inhibited O2+ produced by xanthine oxidase only when added simultaneously with substrate, consistent with the short half-life of NO in oxygenated solution. In contrast, the addition of nitric oxide to neutrophils 20 min before FMLP resulted in the inhibition of O2+ production, which suggests formation of a stable intermediate. The effect of nitric oxide on the cell-free NADPH oxidase superoxide-generating system was also examined: The addition of NO before arachidonate activation (t = -6 min) significantly inhibited superoxide anion production. Nitric oxide did not inhibit O2+ when added at NADPH initiation (t = 0). Treatment of the membrane but not cytosolic component of the oxidase was sufficient to inhibit O2+ generation. The data suggest that nitric oxide inhibits neutrophil O2+ production via direct effects on membrane components of the NADPH oxidase. This action must occur before the assembly of the activated complex
— id: 9746, year: 1992, vol: 90, page: 1116, stat: Journal Article,

NITRIC-OXIDE INHIBITS HUMAN NEUTROPHIL SUPEROXIDE ANION PRODUCTION VIA DIRECT ACTION ON A MEMBRANE COMPONENT OF THE NADPH-OXIDASE
CLANCY, R; LESZCZYNSKAPIZIAK, J; ABRAMSON, S
1992 SEP ;35(9):S96-S96, Arthritis & rheumatism
— id: 51846, year: 1992, vol: 35, page: S96, stat: Journal Article,

ACTIVATED HUMAN NEUTROPHILS DEGRADE S-NITROSOCYSTEINE, AN ENDOTHELIAL DERIVED RELAXATION FACTOR
CLANCY, RM; ABRAMSON, SB
1992 APR ;40(2):A323-A323, Clinical research
— id: 52001, year: 1992, vol: 40, page: A323, stat: Journal Article,

NITRIC-OXIDE INHIBITS HUMAN NEUTROPHIL SUPEROXIDE ANION PRODUCTION VIA DIRECT ACTION ON THE NADPH-OXIDASE
CLANCY, RM; LESZCZYNSKAPIZIAK, J; MUSCAT, S; ABRAMSON, SB
1992 APR ;40(2):A248-A248, Clinical research
— id: 51988, year: 1992, vol: 40, page: A248, stat: Journal Article,

Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors
Cronstein BN; Levin RI; Philips M; Hirschhorn R; Abramson SB; Weissmann G
1992 Apr 1;148(7):2201-2206, Journal of immunology
We have recently demonstrated that human neutrophils (PMN) possess two different classes of adenosine receptors (A1 and A2) that, when occupied, promote chemotaxis and inhibit the generation of reactive oxygen species (e.g., O2- and H2O2), respectively. We have previously demonstrated that adenosine protects endothelial cells (EC) from injury by stimulated neutrophils (PMN) both by diminishing generation of H2O2 and inhibiting adherence of PMN to EC. We therefore determined whether occupancy of A1 or A2 adenosine receptors regulated adherence of PMN to EC. At concentrations similar to those required to inhibit release of O2- by ligation of A2 receptors, both adenosine (IC50 = 56 nM) and 5'N-ethylcarboxamidoadenosine (NECA, IC50 = 8 nM), the most potent A2 agonist, inhibited adherence to EC by stimulated PMN (FMLP, 0.1 microM). In direct contrast, the specific A1 agonists N6-phenylisopropyladenosine and N6-cyclopentyladenosine (CPA) promoted PMN adherence to EC at concentrations of 1-100 nM. To further investigate the mechanisms by which adenosine receptor agonists affected the adherence of stimulated PMN we examined the effect of NECA (A2) and CPA (A1) on the adherence of PMN to fibrinogen (a ligand for the beta 2 integrin CD11b/CD18) and to gelatin. In a dose-dependent manner (IC50 = 2 nM), NECA inhibited the adherence of FMLP-treated PMN to fibrinogen- but not gelatin-coated plates. In contrast, CPA (A1) promoted adherence of stimulated PMN to gelatin-(EC50 = 13 pM) but not fibrinogen-coated plates. Theophylline (10 microM), an adenosine receptor antagonist, reversed the inhibition by NECA (0.3 microM) of stimulated neutrophil adherence to fibrinogen. These observations not only confirm the presence of A1 and A2 receptors on PMN but also suggest two opposing roles for adenosine in inflammation. Occupancy of A1 receptors promotes neutrophil adherence to endothelium and chemotaxis (a proinflammatory role) whereas occupancy of A2 receptors inhibits adherence and generation of toxic oxygen metabolites (an antiinflammatory role)
— id: 9751, year: 1992, vol: 148, page: 2201, stat: Journal Article,

The effect of macrophage colony-stimulating factor on haemopoietic recovery after autologous bone marrow transplantation
Khwaja A; Yong K; Jones HM; Chopra R; McMillan AK; Goldstone AH; Patterson KG; Matheson C; Ruthven K; Abramson SB; et al
1992 Jun;81(2):288-295, British journal of haematology
Macrophage colony-stimulating factor (M-CSF) is active in the late stages of monocyte maturation, activates mature monocyte-macrophages and enhances their production of various other cytokines. We have examined the effects of a 21 d course of escalating doses of M-CSF purified from human urine (hM-CSF) on recovery following autologous bone marrow transplantation (ABMT) in 20 patients with malignant lymphomas. Four patients were treated at each dose level of 4, 8, 16, 32 and 64 x 10(6) U/m2/d and results compared to 46 concurrent controls. There was no significant difference in recovery to an absolute neutrophil count (ANC) of 0.5 x 10(9)/l (median 20 d in hM-CSF group versus 22 in controls) or in recovery of platelets to 50 x 10(9)/l (32 d versus 39 d, 0.05 less than P less than 0.1); hM-CSF patients received a median of 81 platelet units following ABMT (controls 112 units, P = NS). hM-CSF patients had a median of 5.5 d with fever greater than 37.5 degrees C (control 8, P = NS), received parenteral antibiotics for 14.5 d (control 17, P = NS) and had a 50% incidence of bacteraemia (control 48%). hM-CSF treated patients were discharged by a median of day 29 following transplantation (control 33, P less than 0.05). Platelet and neutrophil recovery correlated significantly with the number of marrow mononuclear cells (MNC) reinfused in the hM-CSF group (P = 0.05 and P = 0.014 respectively) but not in controls. Subgroup analysis showed that hM-CSF patients receiving greater than 2 x 10(8) MNC/kg body weight reached an ANC of 0.5 x 10(9)/l by a median of day 16.5 (control 18.5, NS), became platelet transfusion independent by day 17 (control 29, P less than 0.05) and reached a platelet count of 50 x 10(9)/l by day 21 (control 40, P less than 0.05). No significant toxicity attributable to hM-CSF treatment was seen. These results suggest that hM-CSF accelerates platelet recovery following ABMT and that relatively large marrow innocula are required to see this effect
— id: 9748, year: 1992, vol: 81, page: 288, stat: Journal Article,

CARDIAC RISK-FACTORS IN PATIENTS WITH SYSTEMIC LUPUS-ERYTHEMATOSUS (SLE)
KITSIS, EA; BELMONT, HM; SKOVRON, ML; ORNSTEIN, H; MCCULLAGH, E; PETER, JB; ABRAMSON, SB
1992 SEP ;35(9):S108-S108, Arthritis & rheumatism
— id: 51847, year: 1992, vol: 35, page: S108, stat: Journal Article,

Neuropeptides and inflammation. A somatostatin analog as a selective antagonist of neutrophil activation by substance P
Kolasinski SL; Haines KA; Siegel EL; Cronstein BN; Abramson SB
1992 Apr;35(4):369-375, Arthritis & rheumatism
OBJECTIVE. Substance P and somatostatin are neuropeptides found in peripheral sensory nerves. In vitro, these have opposing effects on inflammatory cells. We compared the effects of these peptides on the activation of neutrophils. METHODS. Neutrophils were isolated from healthy volunteers, and chemotaxis, superoxide anion generation, aggregation, and changes in cytosolic calcium and GTPase activity were measured in the presence of substance P, somatostatin, and the chemoattractant FMLP. RESULTS. Substance P was an effective chemoattractant, 20% as potent as FMLP at equimolar concentrations. Substance P also stimulated GTPase activity in neutrophil plasma membranes. Somatostatin did not activate neutrophils; however, it effectively inhibited neutrophil chemotaxis and GTPase activity provoked by substance P, but not by FMLP. CONCLUSIONS. These studies demonstrate that substance P can effectively stimulate chemotaxis, possibly via effects on a GTP-binding protein distinct from that triggered by FMLP, and that somatostatin is a selective antagonist of substance P. The biochemical specificities of these peptides on cells may modulate neurogenic inflammation at the local level
— id: 9750, year: 1992, vol: 35, page: 369, stat: Journal Article,

NITRIC-OXIDE DERIVATIVE S-NITROSOGLUTATHIONE INHIBITS T-CELL PROLIFERATION AND INDUCES ACCUMULATION OF CYCLIC GUANOSINE 3,5'-MONOPHOSPHATE
MERRYMAN, PF; CLANCY, RM; HE, X; ABRAMSON, SB
1992 APR ;40(2):A262-A262, Clinical research
— id: 51993, year: 1992, vol: 40, page: A262, stat: Journal Article,

INTRAVASCULAR NEUTROPHIL (PMN) ACTIVATION IN SLE - DISSOCIATION BETWEEN INCREASED CD11B/CD18 (CR3) AND DECREASED L-SELECTIN (LS) EXPRESSION ON NEUTROPHILS (PMNS)
MOLAD, Y; BUYON, J; ANDERSON, DC; ABRAMSON, SB; CRONSTEIN, BN
1992 SEP ;35(9):S192-S192, Arthritis & rheumatism
— id: 51849, year: 1992, vol: 35, page: S192, stat: Journal Article,

Quantitative electroencephalography. A new approach to the diagnosis of cerebral dysfunction in systemic lupus erythematosus
Ritchlin CT; Chabot RJ; Alper K; Buyon J; Belmont HM; Roubey R; Abramson SB
1992 Nov;35(11):1330-1342, Arthritis & rheumatism
OBJECTIVE. Neuropsychiatric manifestations are common in patients with systemic lupus erythematosus (SLE), but accurate diagnosis is often difficult. We conducted a prospective study to determine the utility of neurometric quantitative electroencephalography (QEEG) as an indicator of cerebral dysfunction in SLE patients. METHODS. Fifty-two SLE patients were divided into 4 groups based on the results of neuropsychiatric evaluations. These included patients with objective evidence of neuropsychiatric SLE (NPSLE), patients with neuropsychiatric symptoms, patients with no evidence of NPSLE, and patients with a prior history of NPSLE. All QEEG findings were compared with data in an age-regressed normative database and with findings in an independent sample of normal subjects. RESULTS. QEEG sensitivity was 87%, and specificity was 75%. QEEG results were abnormal in 74% of the SLE patients with neuropsychiatric symptoms and in 28% of the patients with no evidence of active NPSLE. QEEG profiles varied as a function of the severity and type of neuropsychiatric manifestation present. Within this patient population, QEEG was more sensitive than magnetic resonance imaging, computed tomography scanning, or conventional EEG. CONCLUSION. Neurometric QEEG may be a sensitive indicator of cerebral dysfunction in patients with NPSLE and can differentiate patients with diverse neuropsychiatric manifestations. When combined with a careful clinical history and evaluation, QEEG provides information that may be useful for the early detection of NPSLE and for serial evaluation of disease activity and treatment efficacy
— id: 9743, year: 1992, vol: 35, page: 1330, stat: Journal Article,

Therapy with and mechanisms of nonsteroidal anti-inflammatory drugs
Abramson S
1991 Jun;3(3):336-340, Current opinion in rheumatology
Nonsteroidal anti-inflammatory drugs have anti-inflammatory, analgesic, and antipyretic properties. Although most nonsteroidal anti-inflammatory drugs inhibit prostaglandin synthesis, these agents also have important pharmacologic actions unrelated to their effects on prostaglandins. Among these properties is the ability to inhibit the release of mediators of inflammation from neutrophils and macrophages. These effects are due to the ability of nonsteroidal anti-inflammatory drugs to intercalate into the lipid bilayer of the plasma membrane and thereby disrupt protein-protein and protein-lipid interactions critical for cell responses (eg, calcium translocations, membrane phospholipid turnover). Our data, for example, indicate that nonsteroidal anti-inflammatory drugs exert direct inhibitory actions at the regulatory GTP protein (G protein) within the plasma membrane. This exhibit examines the evidence for diverse mechanisms of action of nonsteroidal anti-inflammatory drugs including effects directed at the G protein as well as new evidence that nonsteroidal anti-inflammatory drugs regulate the expression of the cyclooxygenase enzyme at the level of gene transcription
— id: 14005, year: 1991, vol: 3, page: 336, stat: Journal Article,

Nonsteroidal antiinflammatory drugs
Abramson SB
1991 ;624:40-44, Annals of the New York Academy of Sciences
— id: 9757, year: 1991, vol: 624, page: 40, stat: Journal Article,

Acute reversible hypoxemia in systemic lupus erythematosus
Abramson SB; Dobro J; Eberle MA; Benton M; Reibman J; Epstein H; Rapoport DM; Belmont HM; Goldring RM
1991 Jun 1;114(11):941-947, Annals of internal medicine
OBJECTIVE: To determine the frequency of unexplained reversible hypoxemia in patients with systemic lupus erythematosus and to assess the relation between hypoxemia and elevated plasma levels of complement split products. DESIGN: Cohort study. SETTING: Inpatient and outpatient facilities of the New York University Medical Center/Bellevue Hospital and the Hospital for Joint Diseases. PATIENTS: Case patients were 22 patients hospitalized with disease exacerbation and no evidence of parenchymal lung disease on chest roentgenogram. Four patients with stable disease were followed in the outpatient clinic, and five healthy normal volunteers served as controls. MEASUREMENTS: Plasma levels of complement split products (C3a, factor Bb fragment), alveolar-arterial (A-a) Po2 gradients, and pulmonary function were measured. MAIN RESULTS: Nine episodes of hypoxemia or hypocapnia (mean A-a gradient, 30.4 +/- 4.8 mm Hg) or both (despite normal chest roentgenogram results) were noted in six hospitalized patients (group 1). Gas exchange improved within 72 hours of steroid therapy (mean A-a gradient, 11.6 +/- 4.3 mm Hg; P less than 0.01). These patients had an elevated initial mean C3a level (938.4 +/- 246.8 ng/mL) that decreased within 72 hours (407.8 +/- 80.9 ng/mL; P less than 0.01), concomitant with improved oxygenation. Ventilation-perfusion scans, obtained for four of six group 1 patients, excluded pulmonary emboli. Four hospitalized patients (group 2) had a normal A-a gradient (mean, 7.5 +/- 2.7 mm Hg). The mean C3a level of this group (358.3 +/- 39.2 ng/mL) was lower than that of group 1 (P less than 0.05). Four patients with stable disease (group 3) had a mean A-a gradient and a mean C3a level of 3.3 +/- 2.7 mm Hg and 237.8 +/- 105.7 ng/mL, respectively, similar to values found in five normal volunteers, in whom the mean A-a gradient was 3.7 +/- 1.7 mm Hg and the mean C3a level was 124.8 +/- 9.2 ng/mL. CONCLUSION: A syndrome of reversible hypoxemia, unassociated with parenchymal lung disease, is unexpectedly common in acutely ill, hospitalized patients with systemic lupus erythematosus. The pathogenesis of this syndrome is unclear, although the data are compatible with the hypothesis that hypoxemia may be related to pulmonary leukoaggregation
— id: 9755, year: 1991, vol: 114, page: 941, stat: Journal Article,

Non-steroidal anti-inflammatory drugs: effects on a GTP binding protein within the neutrophil plasma membrane
Abramson SB; Leszczynska-Piziak J; Haines K; Reibman J
1991 Jun 1;41(11):1567-1573, Biochemical pharmacology
Sodium salicylate and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit neutrophil functions via unknown mechanisms. To examine their site of action in the neutrophil we have studied discrete events within the plasma membrane which depend upon the normal function of a GTP binding protein (G protein). We demonstrated that sodium salicylate and piroxicam inhibit neutrophil activation in response to stimuli which require signal transduction via a G protein (e.g. formyl-methionine-leucine-phenylalanine) but have no effect on stimuli which do not (e.g. phorbol myristate acetate, ionomycin). NSAIDs blocked the ADP-ribosylation of the pertussis toxin substrate in human neutrophils. This effect was associated with the capacity of NSAIDs to block pertussis toxin-dependent inhibition of neutrophil functions. Finally, NSAIDs inhibited the binding of GTP gamma S, a stable analog of GTP, to purified neutrophil membrane preparations. The data indicate that salicylate and other NSAIDs interact with a G protein in the neutrophil plasmalemma and thereby uncouple post-receptor signaling events
— id: 9756, year: 1991, vol: 41, page: 1567, stat: Journal Article,

Arachidonic acid as a second messenger. Interactions with a GTP-binding protein of human neutrophils
Abramson SB; Leszczynska-Piziak J; Weissmann G
1991 Jul 1;147(1):231-236, Journal of immunology
Arachidonic acid (20:4) and other cis-unsaturated fatty acids exert direct effects on a variety of cells, effects that do not depend on the metabolism of fatty acids via cyclooxygenase or lipoxygenase pathways. In these studies arachidonic acid and other cis-unsaturated fatty acids (but not trans-unsaturated or saturated fatty acids) increased the specific binding of the nonhydrolyzable analog of GTP, [35S]GTP gamma S, to purified neutrophil membrane preparations and elicited superoxide anion generation from intact neutrophils. There was a positive correlation (r = 0.70) between the capacity of fatty acids to increase nucleotide binding and to elicit the respiratory burst. Scatchard plot analysis of binding at equilibrium demonstrated an increase in the number of available GTP binding sites in the presence of 50 microM arachidonic acid. Nonsteroidal antiinflammatory agents interfered with the arachidonic acid effect on [35S]GTP gamma S binding. ADP-ribosylation of the pertussis toxin substrate Gi alpha within the plasmalemma-reduced specific [35S]GTP gamma S binding and blocked arachidonate-dependent enhancement of binding. Moreover, pertussis toxin treatment of intact neutrophils inhibited arachidonic acid-induced superoxide anion generation. The data indicate that arachidonic acid directly activates a GTP binding protein in the neutrophil plasma membrane and may thereby act as a second messenger in signal transduction
— id: 9754, year: 1991, vol: 147, page: 231, stat: Journal Article,

ENDOTHELIAL DEFENSES AGAINST ATTACK BY HUMAN NEUTROPHILS - NITRIC-OXIDE INHIBITS NEUTROPHIL FUNCTION
CLANCY, RM; ABRAMSON, SB
1991 APR ;39(2):A225-A225, Clinical research
— id: 51607, year: 1991, vol: 39, page: A225, stat: Journal Article,

The prostaglandin paradox: additive inhibition of neutrophil function by aspirin-like drugs and the prostaglandin E1 analog misoprostol
Kitsis EA; Weissmann G; Abramson SB
1991 Oct;18(10):1461-1465, Journal of rheumatology
Nonsteroidal antiinflammatory drugs (NSAID) are thought to act in part by inhibiting prostaglandin H (PGH) synthase which diminishes release of inflammatory prostaglandins (PG). Paradoxically, PG of the E series also have antiinflammatory properties. We therefore studied the combined effects of NSAID and PGE1 on neutrophil activation. Incubation of neutrophils with a PGE1 analog, misoprostol (miso; 1 microM; 5 min, 37 degrees), reduced superoxide anion generation in response to the chemoattractant fmet-leu-phe (FMLP) to 70.7 +/- 7% of control (p less than 0.01). Piroxicam (10 microM) independently reduced FMLP dependent superoxide anion generation to 63.7 +/- 7.4% (p less than 0.01) of control. Addition of miso to piroxicam reduced superoxide anion production to 37.4 +/- 1.9%, an inhibition that exceeded that observed with either drug alone. Similarly, the addition of miso enhanced the inhibitory effects of indomethacin and sodium salicylate on superoxide anion generation, and of all 3 NSAID on other neutrophil functions (degranulation, aggregation and global rises in cytosolic calcium). Miso (1 microM) and NSAID, alone or in combination, did not inhibit superoxide anion generation in response to the calcium ionophore A23187 or phorbol myristate acetate, agents that bypass G protein depending signaling pathways, and that do not induce a rise in cytosolic cyclic AMP (cAMP). Therefore, our data clearly show that miso at micromolar concentrations, augments the inhibitory effects of NSAID on neutrophil activation via a mechanism dependent upon signal transduction across the plasma membrane
— id: 9753, year: 1991, vol: 18, page: 1461, stat: Journal Article,

THE CHEMOATTRACTANT FAMILY - ANTAGONISM OF SUBSTANCE-P, BUT NOT OTHER CHEMOATTRACTANTS, BY SOMATOSTATIN
KOLASINSKI, SL; HAINES, KA; SIEGEL, EL; CRONSTEIN, BN; ABRAMSON, SB
1991 APR ;39(2):A258-A258, Clinical research
— id: 51609, year: 1991, vol: 39, page: A258, stat: Journal Article,

Low molecular weight GTP-binding proteins in human neutrophil granule membranes
Philips MR; Abramson SB; Kolasinski SL; Haines KA; Weissmann G; Rosenfeld MG
1991 Jan 15;266(2):1289-1298, Journal of biological chemistry
Degranulation of neutrophils involves the differential regulation of the exocytosis of at least two populations of granules. Low molecular weight GTP-binding proteins (LMW-GBPs) have been implicated in the regulation of vesicular traffic in the secretory pathways of several types of cells. In the present study we identify distinct subsets of LMW-GBPs associated with the membranes of neutrophil-specific and azurophilic granules. Ninety-four percent of total [35S]guanosine 5'-(3-O-thio)triphosphate (GTP gamma S) binding activity was equally distributed between the plasma membrane and cytosol with the remaining 6% localized in the granules. In contrast, the cytosol contained only 10% of the total GTPase activity while the specific granules accounted for 13%. [alpha-32P]GTP binding to proteins transferred to nitrocellulose revealed LMW-GBPs in all fractions except the azurophilic granules. The specific granules contained three out of four bands which were found in the plasma membrane; these ranged from 20 to 23 kDa and all were resistant to alkaline extraction. Photoaffinity labeling with [alpha-32P]8-azido-GTP in the presence of micromolar Al3+ identified proteins of 25 and 26 kDa unique to azurophilic granules; these could not be labeled with [alpha-32P]8-azido-ATP and could be extracted by acidic but not alkaline pH. Botulinum C3-mediated [32P]ADP-ribosylation identified proteins of 16, 20, and 24 kDa both in plasma membranes and those of specific granules. An anti-ras monoclonal antibody, 142-24E5, recognized a 20-kDa protein localized to the plasma and specific granule membranes which could not be extracted by alkaline pH, was not a substrate for botulinum C3 ADP-ribosyltransferase, and was translocated from specific granules to plasma membrane after exposure of neutrophils to phorbol myristate acetate. We conclude that neutrophil-specific and azurophilic granules contain distinct subsets of LMW-GBPs which are uniquely situated to regulate the differential exocytosis of these two compartments
— id: 8314, year: 1991, vol: 266, page: 1289, stat: Journal Article,

Mechanisms of action of nonsteroidal anti-inflammatory drugs and therapeutic considerations
Abramson SB
1990 Fall;50(2):107-115, Bulletin of the Hospital for Joint Diseases Orthopaedic Institute
Nonsteroidal anti-inflammatory drugs (NSAIDs) have anti-inflammatory, analgesic, and antipyretic properties. Although most NSAIDs inhibit prostaglandin synthesis, these agents also have important pharmacologic actions unrelated to their effects on prostaglandins. This review examines the evidence for diverse mechanisms of action of NSAIDs and their use in sports injuries
— id: 9761, year: 1990, vol: 50, page: 107, stat: Journal Article,

Nonsteroidal antiinflammatory drugs exert differential effects on neutrophil function and plasma membrane viscosity. Studies in human neutrophils and liposomes
Abramson SB; Cherksey B; Gude D; Leszczynska-Piziak J; Philips MR; Blau L; Weissmann G
1990 Feb;14(1):11-30, Inflammation
Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit neutrophil functions via mechanisms separate from their capacity to inhibit prostaglandin synthesis. We have studied discrete events in the process of signal transduction: NSAIDs but not a related analgesic drug (acetaminophen), inhibited aggregation in response to the chemoattractants f-Met-Leu-Phe (FMLP), leukotriene B4, and C5a. NSAIDs, but not acetaminophen, inhibited binding of radiolabeled FMLP to purified neutrophil membranes. Gpp(NH)p, a GTPase insensitive analog of GTP, also inhibited the binding of FMLP but, paradoxically, enhanced superoxide anion generation and lysozyme release. The inhibition of ligand binding by NSAIDs did not correlate with their capacity to inhibit FMLP-induced increments in diacylglycerol (DG): piroxicam, but not salicylate effectively inhibited appearance of label ([3H]arachidonate, [14C]glycerol) in DG. Finally, NSAIDs exerted differential effects on the viscosity of neutrophil plasma membranes and multilamellar vesicles (liposomes): membrane viscosity was increased by piroxicam and indomethacin, decreased by salicylate, and unaffected by acetaminophen. Thus, the different effects of NSAIDs on discrete pathways are not due to their shared capacity to reduce ligand binding but rather to a capacity to uncouple postreceptor signaling events that depend upon the state of membrane fluidity
— id: 9760, year: 1990, vol: 14, page: 11, stat: Journal Article,

Therapy and mechanisms of nonsteroidal anti-inflammatory drugs, and pain management, acupuncture, and rehabilitation
Abramson SB; Kieran O; Lee M
1990 Jun;2(3):473-480, Current opinion in rheumatology
— id: 9759, year: 1990, vol: 2, page: 473, stat: Journal Article,

TRANSLOCATION OF HUMAN NEUTROPHIL GTP BINDING-PROTEIN FROM PLASMA-MEMBRANE TO CYTOSOL FOLLOWS EXPOSURE TO CHEMOATTRACTANT OR PHORBOL ESTER
Abramson, SB; Leszczynskapiziak, JM; Philips, MR
1990 Apr;38(2):A369-A369, Clinical research
— id: 31962, year: 1990, vol: 38, page: A369, stat: Journal Article,

Constitutive and induced phosphorylation of the alpha- and beta-chains of the CD11/CD18 leukocyte integrin family. Relationship to adhesion-dependent functions
Buyon JP; Slade SG; Reibman J; Abramson SB; Philips MR; Weissmann G; Winchester R
1990 Jan 1;144(1):191-197, Journal of immunology
We sought to determine whether the activation event which renders the CD11/CD18 leukocyte integrin/Leu-CAM glycoproteins capable of promoting cell to cell adhesion was associated with the induced posttranslational modification of phosphorylation. In neutrophils, two species of alpha-chains, a predominant CD11b 165-kDa subunit and a minor 150-kDa CD11c subunit were found to be constitutively phosphorylated. However, the 95-kDa CD18 common beta-chain was not phosphorylated in resting cells but became strongly phosphorylated in cells incubated with PMA. The beta-chain was phosphorylated in a dose-related manner within 1 min of the addition of PMA, reached maximal intensity between 4 to 10 min, and remained fully phosphorylated at 30 min. The similarities of the kinetics of homotypic aggregation induced by PMA to the time course of phosphorylation suggest that phosporylation may be relevant to at least this type of Leu-CAM-dependent adhesion. In contrast, in the presence of FMLP which induces aggregation with different kinetics than PMA, no phosphorylation of the common beta-chain was observed over a time interval of from 30 s to 10 min further emphasizing the apparent differences in the two modes of activation to an adhesive state. The phosphorylated species on neutrophils were readily detected by immunoprecipitation with each CD18 mAb and most but not all CD11b mAb which otherwise precipitated 125I-labeled CD11b species suggesting that the CD11b alpha-chain labelled with 32P may differ slightly from the 125I-labeled species in terms of its recognition by certain CD11b mAb. In mononuclear cells, similar constitutive phosphorylation of the CD11a and CD11c alpha-chains was observed that remained unchanged in the presence of either FMLP or PMA. As was demonstrated in neutrophils, phosphorylation of the CD18 beta-chains of mononuclear cells was not constitutive but was induced in the presence of PMA and not FMLP. Taken together these data suggest the existence of specific recognition sites on beta-chains for a regulatory kinase-phosphatase system
— id: 9762, year: 1990, vol: 144, page: 191, stat: Journal Article,

THE OPPOSING EFFECTS OF ADENOSINE A1 AND A2 RECEPTOR OCCUPANCY ON STIMULATED NEUTROPHIL (PMN) ADHERENCE
Cronstein, BN; Levin, RI; Hirschhorn, R; Weissmann, G; Philips, MR; Abramson, SB
1990 Apr;38(2):A417-A417, Clinical research
— id: 31966, year: 1990, vol: 38, page: A417, stat: Journal Article,

Cocaine and its derivatives blunt neutrophil functions without influencing phosphorylation of a 47-kilodalton component of the reduced nicotinamide-adenine dinucleotide phosphate oxidase
Haines KA; Reibman J; Callegari PE; Abramson SB; Philips MR; Weissmann G
1990 Jun 15;144(12):4757-4764, Journal of immunology
Cocaine and its derivatives blunted responses of neutrophils (cell/cell aggregation, up-regulation of the receptor for C3bi (CR3, CD11b/CD18), generation of superoxide anion (O2-) and degranulation to various stimuli. The order of potency of these agents was the same as that for local anesthesia: tetracaine greater than bupivacaine greater than cocaine greater than lidocaine. Neutrophil aggregation elicited by the chemoattractant FMLP (10(-7) M) was inhibited by cocaine (10 mM) to 13.6 +/- 6% of control (p less than 0.002); the IC50 was approximately 4 mM. Cocaine and the other local anesthetics not only inhibited the upregulation of CR3 and O2- generation, but also blocked degranulation of cytochalasin B-treated cells. Cocaine (10 mM) reduced beta-glucuronidase and lysozyme secretion to 4.3 +/- 0.7 and 13 +/- 2.2% controls, respectively; its IC50 was 4 mM. Local anesthetics added after ligand/receptor engagement (FMLP) interrupted aggregation and halted generation of O2-. Moreover, local anesthetics rapidly inhibited aggregation, O2- generation, and degranulation elicited by PMA (1 microgram/ml) or the Ca ionophore A23187 (10 microM): the effects of cocaine could therefore not be attributed to unique actions at the FMLP receptor. Peak levels of intracellular Ca2+ ([Ca]i) at 5 to 10 s, and levels of [Ca]i 120 s after FMLP in Fura 2-loaded cells were significantly lower in cells treated with lidocaine, findings that could be explained by enhanced 45Ca2+ efflux from neutrophils. In cells loaded with bis(carboxyethyl)carboxyfluorescine (pH indicator) local anesthetics failed to affect the initial FMLP-induced (0 to 15 s) drop of pHi but inhibited the later (120 s) realkalinization of the cytosol (lidocaine, bupivacaine). Most remarkably, autoradiographs of SDS gels prepared from stimulated, 32P-labeled neutrophils treated with local anesthetics showed no difference from resting cells, either with respect to patterns of phosphorylation and dephosphorylation or their kinetics. Labeling of a 47-kDa protein, a component of the reduced nicotinamide-adenine dinucleotide phosphate-oxidase system, was unchanged. The effects of local anesthetics, which blunt neutrophil responses without affecting protein phosphorylation, suggest that protein phosphorylation is an insufficient signal for neutrophil activation. Inasmuch as cocaine and its derivatives affect cell functions at sites distal to activation of protein kinase C, these agents should prove useful in uncoupling protein phosphorylation from functional responses
— id: 9758, year: 1990, vol: 144, page: 4757, stat: Journal Article,

THE PROSTAGLANDIN PARADOX - ADDITIVE INHIBITION OF NEUTROPHIL FUNCTION BY ASPIRIN-LIKE DRUGS AND PROSTAGLANDINS (MISOPROSTOL)
Kitsis, E; Gude, D; Weissmann, G; Abramson, S
1990 Apr;38(2):A317-A317, Clinical research
— id: 31959, year: 1990, vol: 38, page: A317, stat: Journal Article,

LOCALIZATION OF LOW-MOLECULAR-WEIGHT GTP BINDING-PROTEINS IN MEMBRANES OF HUMAN NEUTROPHIL GRANULES
Philips, MR; Rosenfeld, MG; Abramson, SB; Kolasinski, SL; Haines, KA; Weissmann, G
1990 Apr;38(2):A351-A351, Clinical research
— id: 32065, year: 1990, vol: 38, page: A351, stat: Journal Article,

FALSE POSITIVE SEROREACTIVITY TO BORRELIA-BURGDORFERI IN RHEUMATIC DISEASE - THE VALUE OF IMMUNOBLOT ANALYSIS
Weiss, NL; Philips, MR; Sadock, VA; Sigal, LH; Merryman, PF; Abramson, SB
1990 Apr;38(2):A277-A277, Clinical research
— id: 31954, year: 1990, vol: 38, page: A277, stat: Journal Article,

ARACHIDONATE (20-4) AND DOCOSAHEXANOATE (22-6) AS DIRECT MESSENGERS OF INFLAMMATION - EFFECT ON G-PROTEINS IN MARINE SPONGE AGGREGATION
Weissmann, G; Sands, PJ; Haines, KA; Abramson, SB; Leszczynska, JM
1990 Apr;38(2):A596-A596, Clinical research
— id: 31977, year: 1990, vol: 38, page: A596, stat: Journal Article,

The mechanisms of action of nonsteroidal antiinflammatory drugs
Abramson S; Weissmann G
1989 Sep-Oct;7 Suppl 3:S163-S170, Clinical & experimental rheumatology
In mammalian species and in the oldest of multicellular animal forms, NSAIDs inhibit cell activation, apparently in the absence of effects on PG biosynthesis. Thus, an alternative hypothesis can be proposed to account for the antiinflammatory effects of these drugs. Clearly, at low doses aspirin and most of the newer NSAIDs inhibit the biosynthesis of PGs from arachidonic acid, and stable PGs have been shown to mediate fever, hyperalgesia, vasodilation (edema), and several interleukin-1-dependent responses. At high doses, however, aspirin, sodium salicylate, and the newer NSAIDs (at antiinflammatory doses) inhibit non-PG-dependent processes, such as the activity of a variety of enzymes, proteoglycan synthesis by chondrocytes, transmembrane ion fluxes, and chemoattractant binding. These effects are most likely due to the capacity of aspirin-like drugs to insert into the lipid bilayer of plasma membranes, where they disrupt normal signaling events and protein-protein interactions. The ability of NSAIDs to thereby inhibit the activation of inflammatory cells such as the neutrophil may contribute to the antiinflammatory properties of this class of drugs
— id: 10514, year: 1989, vol: 7 Suppl 3, page: S163, stat: Journal Article,

Therapy and mechanisms of nonsteroidal anti-inflammatory drugs
Abramson SB
1989 Jun;1(1):61-67, Current opinion in rheumatology
— id: 9763, year: 1989, vol: 1, page: 61, stat: Journal Article,

The mechanisms of action of nonsteroidal antiinflammatory drugs
Abramson SB; Weissmann G
1989 Jan;32(1):1-9, Arthritis & rheumatism
— id: 9765, year: 1989, vol: 32, page: 1, stat: Journal Article,

PHOSPHORYLATION OF THE ALPHA-CHAINS AND BETA-CHAINS OF THE CD11/CD18 INTEGRIN FAMILY - CONSTITUTIVE AND ACTIVATED STATES
BUYON, JP; REIBMAN, J; ABRAMSON, SB; PHILIPS, M; SLADE, SG; WEISSMANN, G; WINCHESTER, RJ
1989 APR ;37(2):A425-A425, Clinical research
— id: 51439, year: 1989, vol: 37, page: A425, stat: Journal Article,

NEUTROPHIL ACTIVATION - PROTEIN-I OF N-GONORRHEA DEMONSTRATES A PHOSPHATIDYLCHOLINE-SPECIFIC PHOSPHOLIPASE-C IN NEUTROPHILS
Haines, KA; Reibman, J; Abramson, SB; Blake, M; Weissmann, G
1989 Apr;37(2):A564-A564, Clinical research
— id: 31713, year: 1989, vol: 37, page: A564, stat: Journal Article,

Periodic organization of the contractile apparatus in smooth muscle revealed by the motion of dense bodies in single cells
Kargacin GJ; Cooke PH; Abramson SB; Fay FS
1989 Apr;108(4):1465-1475, Journal of cell biology
To study the organization of the contractile apparatus in smooth muscle and its behavior during shortening, the movement of dense bodies in contracting saponin skinned, isolated cells was analyzed from digital images collected at fixed time intervals. These cells were optically lucent so that punctate structures, identified immunocytochemically as dense bodies, were visible in them with the phase contrast microscope. Methods were adapted and developed to track the bodies and to study their relative motion. Analysis of their tracks or trajectories indicated that the bodies did not move passively as cells shortened and that nearby bodies often had similar patterns of motion. Analysis of the relative motion of the bodies indicated that some bodies were structurally linked to one another or constrained so that the distance between them remained relatively constant during contraction. Such bodies tended to fall into laterally oriented, semirigid groups found at approximately 6-microns intervals along the cell axis. Other dense bodies moved rapidly toward one another axially during contraction. Such bodies were often members of separate semirigid groups. This suggests that the semirigid groups of dense bodies in smooth muscle cells may provide a framework for the attachment of the contractile structures to the cytoskeleton and the cell surface and indicates that smooth muscle may be more well-ordered than previously thought. The methods described here for the analysis of the motion of intracellular structures should be directly applicable to the study of motion in other cell types
— id: 9764, year: 1989, vol: 108, page: 1465, stat: Journal Article,

NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) INHIBIT ARACHIDONIC-ACID (AA)-INDUCED INCREASES OF GTP GAMMA-S BINDING TO HUMAN NEUTROPHIL (PMN) MEMBRANES
Leszczynskapiziak, J; Kitsis, E; Abramson, S
1989 Apr;37(2):A587-A587, Clinical research
— id: 31715, year: 1989, vol: 37, page: A587, stat: Journal Article,

Complement split products and the pathogenesis of SLE
Abramson SB; Weissmann G
1988 Dec 15;23(12):45-56, Hospital practice (office edition)
— id: 9766, year: 1988, vol: 23, page: 45, stat: Journal Article,

NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) INHIBIT NEUTROPHIL (PMN) FUNCTIONS VIA EFFECTS AT THE G-PROTEIN OF THE PLASMA- MEMBRANE
Abramson, S; Haines, K; Leszczynska, J; Reibman, J; Weissmann, G
1988 Apr;36(3):A548-A548, Clinical research
— id: 31506, year: 1988, vol: 36, page: A548, stat: Journal Article,

LUPUS PSYCHOSIS AND ANTI-RIBOSOMAL-P PROTEIN ANTIBODIES
Belmont, HM; Abramson, S
1988 Feb 4;318(5):323-324, New England journal of medicine
— id: 31551, year: 1988, vol: 318, page: 323, stat: Journal Article,

Dissociation between increased surface expression of gp165/95 and homotypic neutrophil aggregation
Buyon JP; Abramson SB; Philips MR; Slade SG; Ross GD; Weissmann G; Winchester RJ
1988 May 1;140(9):3156-3160, Journal of immunology
Whether homotypic neutrophil aggregation depends on the quantitative increase of gp165/95 molecules (Mac 1, CR3) recruited to the cell surface during activation was studied using mAb of the CD11b group that recognize distinct epitopes encoded by the alpha-subunit of this glycoprotein. After the addition of antibody MN41, neutrophils did not aggregate in response to a chemoattractant, FMLP. Blockade of preexisting surface gp165/95 by mAb MN41, followed by removal of the excess antibody from the mixture, was used to show that the molecules of gp165/95 newly expressed in response to stimulation by a chemoattractant were incapable of effectively mediating the induced cell-cell interactions of aggregation. Flow cytometry studies confirmed that binding of unlabeled antibody MN41 did not block further increases in surface expression of gp165/95 after stimulation with FMLP. These data suggest that molecules of gp165/95 exhibit two functionally distinct forms, one, present on the surface of freshly isolated neutrophils, that becomes competent to mediate the aggregation response upon activation by a stimulus and a second form that can be translocated to the cell surface by the stimulus but is greatly diminished if not lacking in the ability to participate in that aggregation event
— id: 9768, year: 1988, vol: 140, page: 3156, stat: Journal Article,

Surface expression of Gp 165/95, the complement receptor CR3, as a marker of disease activity in systemic Lupus erythematosus
Buyon JP; Shadick N; Berkman R; Hopkins P; Dalton J; Weissmann G; Winchester R; Abramson SB
1988 Jan;46(1):141-149, Clinical immunology & immunopathology
Complement-derived peptides capable of activating neutrophils appear in plasma during flares of systemic lupus erythematosus (SLE). One possible consequence of such activation is an increased expression of the surface adhesion promoting heterodimer gp165/95 (the complement receptor CR3). The quantity of gp165/95 was measured by indirect immunofluorescence using a monoclonal antibody of the CD11b group. Mol, directed to the alpha chain. Eighty-three percent of 26 patients with SLE expressed gp165/95 on their neutrophil surface to a greater extent than normals. The highest levels of surface gp165/95 were found in patients with the most severe disease, who also had the highest levels of the circulating anaphylatoxin C3a (mean = 560 ng/ml versus 147 ng/ml in controls). There was a negative correlation between expression of gp165/95 and absolute neutrophil count. Five individuals followed serially demonstrated an increase in surface gp165/95 during disease flares which returned to normal with clinical improvement. These data support the hypothesis that the neutrophils of patients with active SLE recruit increased numbers of gp165/95 molecules to their surface in respose to complement activation; these activated neutrophils bearing increased numbers of adhesion promoting gp165/95 may contribute to endothelial injury in SLE
— id: 9770, year: 1988, vol: 46, page: 141, stat: Journal Article,

DETERMINATION OF PLASMA COMPLEMENT SPLIT PRODUCTS (CSP) IN LUPUS IS THE MOST SENSITIVE PREDICTOR OF DISEASE-ACTIVITY
Buyon, J; Tamerius, J; Kolb, W; Morrow, P; Winchester, R; Weissmann, G; Abramson, S
1988 Apr;36(3):A531-A531, Clinical research
— id: 31505, year: 1988, vol: 36, page: A531, stat: Journal Article,

DIFFERENTIAL PHOSPHORYLATION OF THE ALPHA-CHAINS AND BETA- CHAINS OF THE LFA FAMILY GP165/95, P150/95 AND LFA-1
Buyon, JP; Abramson, SB; Slade, SG; Philips, M; Reibman, J; Weissmann, G; Winchester, RJ
1988 Sep;36(5):A799-A799, Clinical research
— id: 31447, year: 1988, vol: 36, page: A799, stat: Journal Article,

Increased levels of plasma anaphylatoxins in systemic lupus erythematosus predict flares of the disease and may elicit vascular injury in lupus cerebritis
Hopkins P; Belmont HM; Buyon J; Philips M; Weissmann G; Abramson SB
1988 May;31(5):632-641, Arthritis & rheumatism
We measured levels of complement anaphylatoxin split products, C3a and C5a, in the circulation of patients with systemic lupus erythematosus (SLE). In 23 SLE patients who were followed serially, the mean C3a value was 179 ng/ml during stable disease and 550 ng/ml during a disease flare. In 10 patients, C3a levels predicted disease activity, with the C3a value rising from a mean of 183 ng/ml at a time of stable disease to a mean of 242 ng/ml 1-2 months prior to a clinical exacerbation of disease. The mean C3a level in 5 patients with acute dysfunction of the central nervous system (CNS) was 1,297 ng/ml, which is significantly higher than that observed in patients with active disease but without CNS involvement (P less than 0.01). C5a levels were also significantly elevated in 4 patients with acute CNS disease. Pathologic specimens from 2 patients who died during an acute lupus flare revealed neutrophils occluding the cerebral and intestinal vessels. Fluorescein angiography in a patient with CNS lupus revealed vasoocclusive retinopathy. In 5 of 7 SLE patients who were pregnant, C3a levels were elevated, with a group mean value of 310 ng/ml. There was a negative correlation (r = -0.59) between C3a and C3 levels in pregnant patients with SLE, and this finding is consistent with complement activation as the cause of decreasing C3 levels. We suggest that serial measurements of C3a can predict flares of disease in lupus patients and can demonstrate complement activation during pregnancy in women with SLE. In addition, release of C3a and C5a (mediators of inflammation) into the circulation may elicit vascular injury, particularly in patients with lupus cerebritis
— id: 9769, year: 1988, vol: 31, page: 632, stat: Journal Article,

Up-regulation of the iC3b receptor (CR3) is neither necessary nor sufficient to promote neutrophil aggregation
Philips MR; Buyon JP; Winchester R; Weissmann G; Abramson SB
1988 Aug;82(2):495-501, Journal of clinical investigation
The iC3b receptor (CR3) is required for neutrophil adhesive functions, including homotypic aggregation. Because stimuli that enhance neutrophil adhesion also induce up-regulation of surface CR3, it is widely held that these two responses are causally related. We have dissociated CR3 display (immunofluorescence) from CR3 function (aggregation). Neutrophils isolated at 4 degrees C and rewarmed to 37 degrees C up-regulated surface CR3 twofold, but did not aggregate. The kinetics of FMLP-induced CR3 up-regulation were discordant with those of aggregation. In the absence of extracellular divalent cations, CR3 expression increased twofold after exposure to FMLP, but neutrophils did not aggregate. FMLP elicited 3.5-fold more aggregation than the ionophore A23187, yet less than one-half as much CR3 up-regulation. 3 mM sodium salicylate inhibited aggregation 55 +/- 4%, but had no effect on CR3 up-regulation. Conversely, 1 mM tetracaine completely inhibited CR3 up-regulation, while significantly enhancing aggregation. Neutroplasts expressed CR3, but did not up-regulate the receptor; in contrast, FMLP induced CR3-dependent aggregation of neutroplasts. We conclude that, although constitutive surface CR3 is required for neutrophil aggregation, the up-regulation of CR3 is neither necessary nor sufficient to promote cell-cell adhesion
— id: 9767, year: 1988, vol: 82, page: 495, stat: Journal Article,

Complement activation and vascular injury in systemic lupus erythematosus
Abramson S; Belmont HM; Hopkins P; Buyon J; Winchester R; Weissmann G
1987 Jun;14 Suppl 13:43-46, Journal of rheumatology. Supplement
The deposition of immune complexes within blood vessel walls results in the potential for complement activation and the release of chemotactic factors, such as fragments of C5 (C5fr). The generation of C5fr results in the intravascular aggregation of neutrophils with subsequent leukostatic occlusion of the pulmonary arterioles. The generation of C5fr may contribute to the pathogenesis of adult respiratory distress syndrome and other diseases. Studies were undertaken to determine the role of circulating complement derived peptides and intravascular neutrophil activation in systemic lupus erythematosus
— id: 59685, year: 1987, vol: 14 Suppl 13, page: 43, stat: Journal Article,

NONSTEROIDAL ANTIINFLAMMATORY AGENTS (NSAIDS), BUT NOT ACETAMINOPHEN, DISRUPT SIGNAL TRANSDUCTION WITHIN THE NEUTROPHIL(PMN)PLASMALEMMA
Abramson, S; Cherksey, B; Veiro, D; Ludewig, R; Weissmann, G
1987 Mar 5;46(4):1389-1389, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 31256, year: 1987, vol: 46, page: 1389, stat: Journal Article,

NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) DISRUPT G-PROTEIN DEPENDENT SIGNAL TRANSDUCTION AT THE NEUTROPHIL (PMN) PLASMALEMMA
Abramson, S; Gude, D; Weissmann, G
1987 Apr;35(3):A639-A639, Clinical research
— id: 31201, year: 1987, vol: 35, page: A639, stat: Journal Article,

Pediatric AIDS
Amodio, J B; Abramson, S; Berdon, W E; Levy, J
1987 Jan;22(1):66-76, Seminars in roentgenology
— id: 68210, year: 1987, vol: 22, page: 66, stat: Journal Article,

Cystic fibrosis in childhood: pulmonary, paranasal sinus, and skeletal manifestations
Amodio, J B; Berdon, W E; Abramson, S; Baker, D
1987 Apr;22(2):125-135, Seminars in roentgenology
— id: 68208, year: 1987, vol: 22, page: 125, stat: Journal Article,

DISSOCIATION BETWEEN THE PHENOMENON OF GP165/95 (CR3) MEDIATED GRANULOCYTE AGGREGATION AND THE QUANTITY OF GP165/95 EXPRESSED ON THE CELL-SURFACE - EVIDENCE FOR 2 FUNCTIONALLY DISTINCT FORMS OF GP165/95
Buyon, JP; Phillips, M; Dalton, J; Abramson, S; Weissmann, G; Winchester, R
1987 Apr;35(3):A469-A469, Clinical research
— id: 31369, year: 1987, vol: 35, page: A469, stat: Journal Article,

COCAINE DERIVATIVES BLUNT NEUTROPHIL RESPONSES
Callegari, P; Abramson, S; Philips, M; Haines, K; Reibman, J; Weissmann, G
1987 Apr;35(3):A613-A613, Clinical research
— id: 31199, year: 1987, vol: 35, page: A613, stat: Journal Article,

AGGREGATION OF HUMAN-NEUTROPHILS IN RESPONSE TO CHEMOATTRACTANT BEARS NO RELATIONSHIP TO DISPLAY OF COMPLEMENT RECEPTOR (CR3)
Philips, M; Buyon, J; Hopkins, P; Gude, D; Winchester, R; Abramson, S; Weissmann, G
1987 Mar 1;46(3):405-405, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 31260, year: 1987, vol: 46, page: 405, stat: Journal Article,

UP-REGULATION OF IC3B RECEPTORS IS NEITHER NECESSARY NOR SUFFICIENT FOR AGGREGATION OF NEUTROPHILS BY A CHEMOATTRACTANT
Philips, M; Buyon, J; Winchester, R; Weissmann, G; Abramson, S
1987 Apr;35(3):A486-A486, Clinical research
— id: 31193, year: 1987, vol: 35, page: A486, stat: Journal Article,

Non-steroidal anti-inflammatory drugs: how do they work?
Weissmann G; Korchak H; Ludewig R; Edelson H; Haines K; Levin RI; Herman R; Rider L; Kimmel S; Abramson S
1987 ;8(1):6-17, European journal of rheumatology & inflammation
Current dogma holds that non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibition of the synthesis and release of prostaglandins. However, NSAIDs also inhibit the activation of neutrophils, which provoke inflammation by releasing products other than prostaglandins. We now report that NSAIDs (for example, indomethacin, piroxicam) inhibit activation of neutrophils by inflammatory stimuli such as C5-derived peptides and leukotriene B4 even when cyclooxygenase products generated in suspensions of stimulated neutrophils (prostaglandin E and thromboxanes) are present. Sodium salicylate (3mM) greatly inhibited aggregation of neutrophils but had no effect on aggregation of platelets or production of thromboxane induced by arachidonate. Sodium salicylate and other NSAIDs also inhibit calcium movements (45Ca uptake, changes in fluorescence of chlortetracycline and Quin-2). Aspirin, sodium salicylate, indomethacin, and piroxicam also enhanced the post-stimulation rise in intracellular cyclic AMP. NSAIDs therefore inhibit early steps in neutrophil enhance intracellular levels of cyclic AMP
— id: 59687, year: 1987, vol: 8, page: 6, stat: Journal Article,

SURFACE EXPRESSION OF CR3 ON NEUTROPHILS (PMN) AS A MARKER OF DISEASE-ACTIVITY IN SYSTEMIC LUPUS-ERYTHEMATOSUS (SLE)
ABRAMSON, S; BUYON, J; SHADDICK, N; BERKMAN, R; HOPKINS, P; DALTON, J; WEISSMANN, G; WINCHESTER, R
1986 APR ;34(2):A614-A614, Clinical research
— id: 41405, year: 1986, vol: 34, page: A614, stat: Journal Article,

NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) INHIBIT NEUTROPHIL (PMN) FUNCTION VIA EFFECTS ON SIGNAL TRANSDUCTION AT THE PLASMALEMMA
ABRAMSON, S; LUDEWIG, R; CHERKSEY, B; YOKOTA, S; WEISSMANN, G
1986 APR ;34(2):A614-A614, Clinical research
— id: 41404, year: 1986, vol: 34, page: A614, stat: Journal Article,

Complement activation during systemic lupus erythematosus. C3a and C5a anaphylatoxins circulate during exacerbations of disease
Belmont HM; Hopkins P; Edelson HS; Kaplan HB; Ludewig R; Weissmann G; Abramson S
1986 Sep;29(9):1085-1089, Arthritis & rheumatism
To determine whether activated complement components appear in the circulation of patients with systemic lupus erythematosus (SLE), we measured C5a and C3a by radioimmunoassay. Mean C5a concentration in the plasma of acutely ill SLE patients was 46.0 ng/ml, compared with 17.1 ng/ml in normal controls (P less than 0.01). Mean C3a concentration in patients with severe disease was 526 ng/ml, compared with 134 ng/ml in controls (P less than 0.01). In patients with moderately active SLE, the mean C3a concentration, but not the mean C5a concentration, was also elevated. In addition, C3a was elevated in 15 or 21 patients with active SLE, whereas low levels of C3 or C4 were noted in only 7 of these 21 patients. We conclude that the measurement of complement-derived anaphylatoxins may be useful in the management of patients with SLE. In addition, we suggest that these circulating mediators may contribute to the pathogenesis of vascular injury in patients with the disease
— id: 59691, year: 1986, vol: 29, page: 1085, stat: Journal Article,

"Missing" femoral condyle: an unusual sequela to neonatal osteomyelitis and septic arthritis
Singson, R D; Berdon, W E; Feldman, F; Denton, J R; Abramson, S; Baker, D H
1986 Nov;161(2):359-361, Radiology
Growth deformities of the distal femur and unusual gait disturbances were observed in four girls who had had neonatal osteomyelitis and septic arthritis. In each case apparent absence or hypoplasia of one of the femoral condyles, as seen on plain radiographs, was associated with marked genu varum or genu valgum. Arthrography showed the apparently missing condyle to be present in a cartilaginous form, with preservation of the articular surfaces. Based on these findings, surgical treatment was limited to corrective osteotomy
— id: 68503, year: 1986, vol: 161, page: 359, stat: Journal Article,

Modes of action of aspirin-like drugs
Abramson S; Korchak H; Ludewig R; Edelson H; Haines K; Levin RI; Herman R; Rider L; Kimmel S; Weissmann G
1985 Nov;82(21):7227-7231, Proceedings of the National Academy of Sciences of the United States of America
Current dogma holds that nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibition of the synthesis and release of prostaglandins. However, NSAIDs also inhibit the activation of neutrophils, which provoke inflammation by releasing products other than prostaglandins. We now report that NSAIDs (e.g., indomethacin, piroxicam) inhibit activation of neutrophils by inflammatory stimuli, such as C5-derived peptides and leukotriene B4, even when cyclooxygenase products generated in suspensions of stimulated neutrophils (prostaglandin E and thromboxanes) are present. Sodium salicylate (3 mM) greatly inhibited aggregation of neutrophils but had no effect on aggregation of platelets or production of thromboxane induced by arachidonate. Sodium salicylate and other NSAIDs also inhibit calcium movements (45Ca uptake, changes in fluorescence of chlortetracycline and quin-2). Aspirin, sodium salicylate, indomethacin, and piroxicam also enhanced the poststimulation increase in intracellular cyclic AMP. NSAIDs therefore inhibit early steps in neutrophil activation as reflected by their capacity to inhibit movements of Ca and to enhance intracellular levels of cyclic AMP
— id: 59701, year: 1985, vol: 82, page: 7227, stat: Journal Article,

Hyperalgesic pseudothrombophlebitis. New syndrome in male homosexuals
Abramson SB; Odajnyk CM; Grieco AJ; Weissmann G; Rosenstein E
1985 Feb;78(2):317-320, American journal of medicine
Five male homosexuals, four of whom had Kaposi's sarcoma, presented with painful swelling of the lower extremity. The overlying skin was erythematous and exquisitely tender. Deep vein thrombosis was strongly suspected in all patients. Venography, however, revealed no evidence of venous occlusion. This condition, which in this report is termed the hyperalgesic pseudothrombophlebitis syndrome, appears to be another unusual manifestation of the acquired immune deficiency syndrome. It should be considered among the entities known to mimic deep vein thrombosis and must be recognized in order to prevent unnecessary anticoagulation in these patients.
— id: 9771, year: 1985, vol: 78, page: 317, stat: Journal Article,

LUPUS CRISIS - C3A DESARG AND LIPOXYGENASE PRODUCTS APPEAR IN PLASMA
Abramson, S; Belmont, HM; Ludewig, R; Kimmel, S; Haines, K; Weissmann, G
1985 ;33(2):A503-A503, Clinical research
— id: 30925, year: 1985, vol: 33, page: A503, stat: Journal Article,

SALMONELLA BACTEREMIA IN SYSTEMIC LUPUS-ERYTHEMATOSUS - 8-YEAR EXPERIENCE AT A MUNICIPAL HOSPITAL
ABRAMSON, S; KRAMER, SB; RADIN, A; HOLZMAN, R
1985 ;28(1):75-79, Arthritis & rheumatism
— id: 41162, year: 1985, vol: 28, page: 75, stat: Journal Article,

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) - EFFECTS ON NEUTROPHIL (PMN) ACTIVATION MEDIATED NOT BY CYCLOOXYGENASE INHIBITION BUT BY AN EFFECT ON ADENYLATE-CYCLASE (AC)
Abramson, S; Ludewig, R; Korchak, H; Weissmann, G
1985 ;33(2):A278-A278, Clinical research
— id: 30918, year: 1985, vol: 33, page: A278, stat: Journal Article,

Circulating hydroxy fatty acids in familial Mediterranean fever
Aisen PS; Haines KA; Given W; Abramson SB; Pras M; Serhan C; Hamberg M; Samuelsson B; Weissmann G
1985 Feb;82(4):1232-1236, Proceedings of the National Academy of Sciences of the United States of America
Episodes of fever, serositis, and arthritis in familial Mediterranean fever (FMF) suggested circulating mediators of acute inflammation (e.g., neutrophil activation). The mean serum neutrophil-aggregating activity of 51 FMF patients was 2.5 +/- 0.2 cm2/min, compared to 1.0 +/- 0.1 cm2/min in 20 normal controls (P less than 0.0002). Lipid extracts of FMF sera retained neutrophil-aggregating activity and had UV absorbance peaks at 269 and 279 nm, indicating the presence of lipids with a conjugated triene structure. Chromatography of extracts yielded peaks that were coeluted with reference dihydroxyicosatetraenoic acids, had UV absorbance peaks at 259, 269, and 279 nm, and possessed neutrophil-aggregating activity. The presence of leukotriene B4 was excluded by chromatography following methyl-esterification. Monohydroxy compounds identified in FMF extracts by gas chromatography/mass spectrometry included 5-hydroxyicosatetraenoic acid, and 9- and 13-hydroxyoctadecadienoic acids. Hydroxy acids were present in 19 of 31 FMF sera and absent in extracts of sera from 8 patients with active systemic lupus erythematosus, 7 with fever from infection, and 12 normal controls. The finding of circulating mono- and dihydroxy fatty acids in FMF suggests that defects in the formation or elimination of these compounds might play a role in the pathogenesis of FMF.
— id: 9772, year: 1985, vol: 82, page: 1232, stat: Journal Article,

Pure human pancreatic juice directly enhances uptake of cobalamin by guinea pig ileum in vivo
Carmel R; Hollander D; Gergely HM; Renner IG; Abramson SB
1985 Jan;178(1):143-150, Proceedings of the Society for Experimental Biology & Medicine
Although pancreatic enzymes clearly degrade R binder, a nonintrinsic factor binder, the full scope of the pancreatic role in cobalamin absorption remains the subject of debate. Therefore the direct effect of pure human pancreatic juice (PPJ) on ileal cobalamin absorption in the absence of intrinsic factor was studied. PPJ significantly enhanced cobalamin uptake in guinea pig ileal loop perfused in vivo. It did not do so in the jejunum. This PPJ activity in the ileum was further stimulated by enteropeptidase and inhibited by aprotinin. The intestinal mucosa remained intact during our study by morphologic and inulin clearance criteria and behaved normally with respect to intrinsic factor and nonintrinsic factor binders. Since no intrinsic factor was present in the perfusate, PPJ must directly enhance cobalamin uptake by the ileum, perhaps promoting cobalamin attachment to receptor sites for subsequent transport by intrinsic factor. PPJ thus seems to affect cobalamin absorption at several levels. Previous studies have established its interaction with luminal R binders and with bile. The findings now indicate that pancreatic juice may have an additional, more direct role in promoting cobalamin absorption in the ileum.
— id: 9774, year: 1985, vol: 178, page: 143, stat: Journal Article,

Influence of nutritional status on circulatory ribonuclease C levels in patients with cancer
Chlebowski RT; Abramson SB; Bateman JR; Weiner JM; Renner IG
1985 Jan 15;55(2):427-431, Cancer
The influence of a variety of clinical and biochemical parameters on the activities in serum of ribonuclease (RNAse) selective for polycytidylic acid (RNAse C) were examined in 90 adult patients with cancer. The clinical data base determined on each patient included: RNAse C level, carcinoembryonic antigen (CEA) level, age, sex, race, presence (or absence of metastases, type of cancer, site of metastasis, renal function blood urea nitrogen [BUN], creatinine), hepatic function (bilirubin, alkaline phosphatase), and nutritional status (percent ideal body weight, percent weight loss, and albumin). Common tumor types studied included: colon (21), lung (18), breast (15), and hepatocellular carcinoma (10). For comparison, 175 nonmalignant control patients were studied to establish the normal range for RNAse. In patients with cancer, RNAse levels were increased in 57% and CEA levels were above 10 ng/dl in 36%. Although patients with BUN greater than 25 mg/dl or creatinine greater than 1.5 mg/dl were not entered on the study, nonetheless, RNAse was significantly (P less than 0.05) associated with both BUN and creatinine. Nutritional status also had an important influence on RNAse levels as both percent weight loss and percent ideal body weight were significantly (P less than 0.05) associated with circulatory RNAse: weight loss resulted in higher RNAse levels. These results account in part for the increased RNAse levels seen in those malignant conditions such as pancreatic and lung cancer commonly associated with weight loss in advanced stage. The possibility that circulatory RNAse C determination will provide a sensitive means for assessing nutritional status in cancer patients will require prospective evaluation.
— id: 9773, year: 1985, vol: 55, page: 427, stat: Journal Article,

The inactivation of the polymorphonuclear leukocyte by non-steroidal anti-inflammatory drugs
Abramson S; Edelson H; Kaplan H; Given W; Weissmann G
1984 Jun;8 Suppl:S103-S108, Inflammation
When human neutrophils (PMNs) are activated by appropriate stimuli, they aggregate, generate superoxide anion (O2-) and secrete lysosomal enzymes. Pre-incubation of PMNs in vitro with the cyclo-oxygenase (COx) inhibitor piroxicam (50 microM) before stimulation with the chemotactic peptide f-met-leu-phe (FMLP, 10(-7)M) inhibited all of these responses. The COx inhibitor ibuprofen inhibited FMLP-induced aggregation and lysozyme secretion, leaving O2- generation unaffected. Binding of 3H-FMLP was inhibited by piroxicam. When the plant lectin concanavalin A (Con-A, 30 micrograms/ml) or the tumor promoter phorbol myristate acetate (PMA, 50 micrograms/ml) was used as a stimulus, ibuprofen had no effect on PMN response, while piroxicam inhibited only O2- generation. To determine whether such inhibition might also occur in vivo, we tested neutrophil aggregation and O2- generation in response to FMLP in 26 normal subjects. These subjects were then administered therapeutic doses of piroxicam (20 mg/day), ibuprofen (2400 mg/day) or indomethacin (100 mg/day), and neutrophil functions were retested after 3 days. Piroxicam inhibited FMLP-induced aggregation by 31% (5.2 cm2/min versus 3.6 cm2/min, P less than 0.004) and O2- generation by 35% (15.8 nmol cytochrome c reduced versus 10.2 nmol, P less than 0.002). Ibuprofen inhibited FMLP-induced aggregation by 44% (5.2 versus 3.0, P less than 0.03) but had no effect on O2- production. Indomethacin inhibited FMLP-induced aggregation (6.4 versus 2.9, P less than 0.01) but had no effect on O2- generation.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 59714, year: 1984, vol: 8 Suppl, page: S103, stat: Journal Article,

Inhibition of neutrophil activation by nonsteroidal anti-inflammatory drugs
Abramson S; Edelson H; Kaplan H; Ludewig R; Weissmann G
1984 Oct 15;77(4B):3-6, American journal of medicine
Nonsteroidal anti-inflammatory drugs are thought to prevent inflammation in rheumatoid arthritis by inhibiting prostaglandin synthesis. This observation does not explain, however, why nonsteroidal anti-inflammatory drugs are able to control inflammation caused by other mediators. To determine whether nonsteroidal anti-inflammatory drugs also exert an effect on neutrophil activation, in vitro and in vivo studies were undertaken. Aggregation, superoxide anion generation, and lysosomal enzyme release were assessed. The nonsteroidal anti-inflammatory drugs were found to inhibit these neutrophil responses, but the patterns of inhibition varied from drug to drug. These findings suggest that nonsteroidal anti-inflammatory drugs may have direct effects on neutrophil activation that are independent of their shared inhibition of prostaglandin synthesis
— id: 59706, year: 1984, vol: 77, page: 3, stat: Journal Article,

A serum-free culture system for studying solute exchanges in the choroid plexus
Agnew WF; Alvarez RB; Yuen TG; Abramson SB; Kirk D
1984 Sep;20(9):712-722, In vitro
Organ cultures of choroid plexus tissues from the lateral ventricle of juvenile rats have been maintained for periods up to 7 wk in a chemically defined, serum-free media. Of several media and various supplements evaluated, the best growth and survival was obtained with the Pasadena Foundation for Medical Research-4 media supplemented with three hormones: epidermal growth factor, insulin, and hydrocortisone. Autoradiographic studies demonstrated that the epithelial cells incorporated [3H]leucine and [3H]thymidine indicating active protein and DNA synthesis, respectively. The organ cultures were characterized by bulbous, vesicular outgrowths from the choroidal villi explants. The fluid-filled lumina of the vesicles reached diameters of 900 microns and were easily accessed by micropipettes. The walls of the vesicles were composed of single layers of epithelial cells in which the ultrastructural features in the in vivo tissue were well maintained. The in vivo polarity (apical end toward the media and basilar end of the cells toward the luminal cavity) was also maintained. This morphologically stable in vitro system seems to be a promising model for investigation of secretory mechanisms of choroidal tissue.
— id: 9775, year: 1984, vol: 20, page: 712, stat: Journal Article,

BIOLOGICALLY-ACTIVE LIPOXYGENASE PRODUCTS IN THE SERA OF PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER (FMF)
AISEN, P; HAINES, K; GIVEN, W; ABRAMSON, S; PRAS, M; WEISSMANN, G
1984 ;32(2):A363-A363, Clinical research
— id: 40975, year: 1984, vol: 32, page: A363, stat: Journal Article,

DEMONSTRATION OF CIRCULATING C5 FRAGMENTS AND NOVEL LIPID NEUTROPHIL AGGREGANTS IN ACTIVE SYSTEMIC LUPUS-ERYTHEMATOSUS
EDELSON, HS; KAPLAN, HB; GIVEN, WP; AISEN, P; LUDWIG, R; WEISSMANN, G; ABRAMSON, SB
1984 ;32(2):A462-A462, Clinical research
— id: 40976, year: 1984, vol: 32, page: A462, stat: Journal Article,

Generation of C5-derived peptides and other immune reactants in the sera of patients with systemic lupus erythematosus
Given WP; Edelson HS; Kaplan HB; Aisen P; Weissmann G; Abramson SB
1984 Jun;27(6):631-637, Arthritis & rheumatism
Activated complement components and immune complexes cause neutrophil aggregation in vitro and in vivo. We have previously demonstrated that sera of patients with active systemic lupus erythematosus (SLE) provoke the aggregation of normal neutrophils in vitro. In this study the serum or plasma of 4 such patients was fractionated on Sephadex G-75. In 3 patients neutrophil aggregating activity (NAA) was detectable in fractions which coeluted with reference C5-derived peptides (estimated molecular radius of 17,000). The activity of these fractions was inhibitable by antibodies to human C5. All patients also had activity that coeluted with reference immune complexes. In addition, material of apparent molecular radius under 12,000 that contributed to the neutrophil aggregating activity of SLE sera was detected. In separate experiments increased levels of C5a desarg were demonstrated during active disease by means of radioimmunoassay. These findings suggest that multiple neutrophil aggregants circulate during the course of active SLE. The formation of intravascular leukoaggregates may contribute to endothelial injury in this disease.
— id: 9776, year: 1984, vol: 27, page: 631, stat: Journal Article,

Effects of non-steroidal anti-inflammatory agents on human neutrophil functions in vitro and in vivo
Kaplan HB; Edelson HS; Korchak HM; Given WP; Abramson S; Weissmann G
1984 Feb 1;33(3):371-378, Biochemical pharmacology
Human blood neutrophils exposed to appropriate stimuli aggregate, degranulate and generate superoxide anion (O2-). These responses are anteceded by mobilization of membrane-associated calcium, monitored as a decrease in fluorescence of cells preloaded with chlortetracycline (CTC). We studied the effects, both in vitro and in vivo, of non-steroidal anti-inflammatory agents (aspirin, indomethacin, ibuprofen and piroxicam) on these neutrophil responses to three stimuli: a chemoattractant, N-formyl-methionyl-leucyl-phenylalanine (FMLP); a tumor promotor, phorbol myristate acetate (PMA); and a lectin, concanavalin A (Con A). The effects of these drugs were compared with those of two polyenoic inhibitors of arachidonate metabolism: eicosatrienoic acid (ETI) and eicosatetraynoic acid (ETYA). The pattern of inhibition of neutrophil functions varied both with inhibitor and the nature of the stimulus. Thus, aspirin, piroxicam, ETYA and ETI inhibited neutrophil aggregation, degranulation, and O2- generation in response to FMLP, whereas ibuprofen inhibited only aggregation and degranulation and indomethacin only inhibited aggregation. None of the agents inhibited aggregation or degranulation induced by PMA or Con A: only piroxicam inhibited O2- generation in response to PMA or Con A. ETI and ibuprofen inhibited decrements of CTC fluorescence induced by FMLP, but whereas ETI inhibited the CTC response to PMA or Con A, ibuprofen was without effect. The agents had varying effects on binding of the stimulus [( 3H]FMLP, [3H]Con A), but these did not correlate with neutrophil responses to the ligands. Neutrophils from subjects taking therapeutic doses of ibuprofen, indomethacin, or piroxicam showed profiles of inhibited responses to FMLP similar to those observed with these agents in vitro. These data suggest that, although non-steroidal anti-inflammatory agents may inhibit discrete neutrophil functions both in vitro and in vivo, their effects do not duplicate those of polyenoic inhibitors of arachidonate metabolism. Moreover, since the susceptibility of neutrophils differed not only with respect to each inhibitor, but also to the stimulus, it is unlikely that all neutrophil responses are necessarily linked by a common pathway that is blocked by inhibitors of arachidonic acid metabolism
— id: 59719, year: 1984, vol: 33, page: 371, stat: Journal Article,

Mesotrypsin: a new inhibitor-resistant protease from a zymogen in human pancreatic tissue and fluid
Rinderknecht H; Renner IG; Abramson SB; Carmack C
1984 Apr;86(4):681-692, Gastroenterology
We have isolated and identified a new zymogen in human pancreatic tissue and fluid. It is secreted as a minor component of pancreatic juice and resembles the two known trypsinogen variants in many properties. Its electrophoretic mobility and isoelectric pH lie between those of the cationic and anionic trypsinogen variants, and we propose the name 'mesotrypsinogen' for the new enzyme precursor. It is activated by enteropeptidase or trypsin, and the free enzyme possesses a substrate specificity similar to that of the trypsins. Its pH optimum is at 8.2, and it appears to require Ca2+ for full enzymatic activity. The molecular weight of the new enzyme is approximately 25,000, similar to that of the known trypsin variants. Its stability resembles that of anionic trypsin extending over a pH range of 4-8.5. Activity is lost gradually at pH 2. The enzyme is inactivated rapidly by diisopropylfluorophosphate, but in contrast to the trypsins, it reacts only slowly with tosyllysine chloromethylketone. Immunologically, it is different from the cationic trypsin variant with which it does not cross-react. The most remarkable property of mesotrypsin is its almost total resistance to biological trypsin inhibitors, such as pancreatic trypsin inhibitor, soybean, lima bean, ovomucoid inhibitor, alpha 1-antitrypsin, etc. It is capable of activating trypsinogen in the presence of excess pancreatic trypsin inhibitor and thus inducing activation of other pancreatic zymogens, but it also possesses the ability to degrade trypsinogen rapidly to inert products. The physiological or pathophysiological role of this unique enzyme remains to be explored.
— id: 9777, year: 1984, vol: 86, page: 681, stat: Journal Article,

THE CELLULAR EFFECTS OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAID) CANNOT BE DUE TO INHIBITION OF PROSTAGLANDIN (PG) RELEASE
WEISSMANN, G; KORCHAK, H; ABRAMSON, S; KIMMEL, S; ROBERTS, C; WILKENFELD, C; RIDER, L; RICH, A; DUNHAM, P
1984 ;32(2):A566-A566, Clinical research
— id: 40985, year: 1984, vol: 32, page: A566, stat: Journal Article,

The neutrophil in rheumatoid arthritis: its role and the inhibition of its activation by nonsteroidal antiinflammatory drugs
Abramson S; Edelson H; Kaplan H; Given W; Weissmann G
1983 Aug;13(1 Suppl 1):148-153, Seminars in arthritis & rheumatism
The activation of the polymorphonuclear leukocyte (PMN) in rheumatoid arthritis produces toxic products that include lysosomal enzymes, stable prostaglandins, and leukotrienes and causes the release of superoxide anion. These products produce the inflammatory response, damage cell membranes, and degrade hyaluronic acid. The inhibition of prostaglandin synthetase by NSAIDs does not, by itself, account for their effectiveness in preventing inflammation in rheumatoid arthritis. In vivo and in vitro experiments were conducted to determine if NSAIDs also exert an effect on neutrophil activation. The NSAIDs tested inhibited discrete PMN functions dependent upon the stimulus tested. The antiinflammatory effects of NSAIDs cannot be entirely explained by their inhibition of prostaglandin synthetase and may, in part, be due to other direct effects upon inflammatory cell activation
— id: 59729, year: 1983, vol: 13, page: 148, stat: Journal Article,

Neutrophil aggregation induced by sera from patients with active systemic lupus erythematosus
Abramson SB; Given WP; Edelson HS; Weissmann G
1983 May;26(5):630-636, Arthritis & rheumatism
Activated complement components and immune complexes cause neutrophil (PMN) aggregation in vitro and in vivo, as in dialysis-induced neutropenia and adult respiratory distress syndrome. To investigate the possible role of PMN aggregation in systemic lupus erythematosus (SLE), we studied the capacity of 59 sera from 53 patients to induce aggregation of normal PMN in vitro. Neutrophil aggregating activity (NAA) was present in the sera of 26 of 28 patients with active SLE. The mean NAA in this group was significantly greater than that found in 13 patients with inactive SLE, 20 patients with rheumatoid arthritis, and 17 normal controls. In patients with SLE there was a positive correlation between disease severity and the quantitative measure of NAA. NAA did not correlate with serum C3 or C4 nor with the presence or absence of circulating immune complexes. High levels of NAA were particularly characteristic of central nervous system lupus. These data suggest that the formation of intravascular leukoaggregates may contribute to morbidity in SLE.
— id: 9778, year: 1983, vol: 26, page: 630, stat: Journal Article,

NEUTROPHILS FROM SUBJECTS GIVEN CONVENTIONAL DOSES OF NON-STEROIDAL ANTI-INFLAMMATORY AGENTS (NSAIA) FAIL TO AGGREGATE AND GENERATE SUPEROXIDE ANION (O-2-.) IN RESPONSE TO IMMUNE-COMPLEXES AND CHEMOATTRACTANT
ABRAMSON, S; EDELSON, H; KAPLAN, H; GIVEN, W; FREED, R; WEISSMANN, G
1983 ;31(2):A414-A414, Clinical research
— id: 40684, year: 1983, vol: 31, page: A414, stat: Journal Article,

Symposia : rheumatoid arthritis : immune mechanism and antiinflammatory drugs
Abramson, Steven
New York : Grune & Stratton, 1983,
— id: 235, year: 1983, vol: , page: , stat: ,

Characterization of pure human pancreatic juice: cobalamin content, cobalamin-binding proteins and activity against human R binders of various secretions
Carmel R; Abramson SB; Renner IG
1983 Feb;64(2):193-205, Clinical science (London, 1979)
— id: 9781, year: 1983, vol: 64, page: 193, stat: Journal Article,

Activation of the alternative pathway of complement by monosodium urate crystals
Fields TR; Abramson SB; Weissmann G; Kaplan AP; Ghebrehiwet B
1983 Feb;26(2):249-257, Clinical immunology & immunopathology
Monosodium urate crystals (MSU) have been shown to activate the alternative pathway of complement in a dose- and time-dependent fashion at 37 degrees C. Activation was maximal upon addition of 10-20 mg/ml monosodium urate crystals to C2-deficient human serum (C2D) or normal human serum containing 5 mM MgEGTA. Immunoelectrophoretic analysis of such treated sera demonstrated cleavage of C3 and factor B. Incubation of highly purified C3 and factor B with 10 mg/ml MSU did not, however, affect their immunoelectrophoretic pattern, suggesting that cleavage of either factor B or C3 in serum requires an intact alternative complement pathway. The fluid-phase control proteins, Factor H and Factor I, were not found to be diminished upon incubation of C2D serum or NHS containing MgEGTA with MSU. Thus activation appeared to be surface dependent and not a consequence of control protein depletion. It was also found, in agreement with earlier observations, that the classical complement pathway is activated, with concomitant depletion of C1 and C4. We conclude that MSU crystals activate both the classical and alternative pathways, and that such activation may participate in the pathogenesis of gouty arthritis.
— id: 9780, year: 1983, vol: 26, page: 249, stat: Journal Article,

NEUTROPHIL AGGREGATION IN SYSTEMIC LUPUS-ERYTHEMATOSUS (SLE) - EVIDENCE FOR A NEW, LOW-MOLECULAR WEIGHT FACTOR
GIVEN, W; EDELSON, H; KAPLAN, H; FREED, R; ABRAMSON, S
1983 ;31(2):A449-A449, Clinical research
— id: 40685, year: 1983, vol: 31, page: A449, stat: Journal Article,

Production of acute hemorrhagic pancreatitis in the dog using venom of the scorpion, Buthus quinquestriatus
Pantoja JL; Renner IG; Abramson SB; Edmondson HA
1983 May;28(5):429-439, Digestive diseases & sciences
Acute hemorrhagic pancreatitis has been produced in dogs by two separate intraarterial injections (20 and 10 micrograms/kg) of venom from the scorpion Buthus quinquestriatus. Morphological changes related to the development of the disease were detectable by electron and light microscopy at 1 and 3 hr, respectively, following the injection of venom. Six hours following venom injection, widespread areas of hemorrhage and fat necrosis were observed on the surface of the pancreas and adjacent mesenteries. By 24 hr, areas of fat necrosis more than 1 cm in diameter were present on the surface of the pancreas. No free protease was found in pure pancreatic juice collected at 3, 6, 24, and 96 hr after the injection of Buthus quinquestriatus venom. Amylase concentrations in serum increased to a maximum sevenfold above the basal level at 6-8 hr after injection. Since acute hemorrhagic pancreatitis occurred both with and without pancreatic duct cannulation, it is likely that the pathological process is independent of any venom effect on papillary sphincter tone. The morphological characteristics of the experimental disease appear similar to those observed at autopsy in acute hemorrhagic pancreatitis in humans.
— id: 9779, year: 1983, vol: 28, page: 429, stat: Journal Article,

Effects of scorpion and rattlesnake venoms on the canine pancreas following pancreaticoduodenal arterial injections
Renner IG; Pantoja JL; Abramson SB; Douglas AP; Russell FE; Koch MK
1983 ;21(3):405-420, Toxicon
Three scorpion venoms caused a transitory decrease in the rate of fluid secretion and increases in the concentration, in pancreatic juice, of total protein and individual enzymes. Protein and enzyme elevations 4-7 fold over the basal levels were produced by the venom of Tityus bahiensis and 6-7 fold by venoms from Tityus serrulatus and Buthus quinquestriatus. Although these increases were smaller than those stimulated by the C-terminal octapeptide of cholecystokin (OP-CCK; 8-9 fold), the secretory responses were of longer duration, so that the total output of protein caused by each of the three venoms was significantly greater than that observed with OP-CCK. Although electron microscopy revealed evidence of widespread degeneration of acinar cells at 1 hr and more extensive damage at 2 hr following injection of scorpion venom, no free protease was detected in pancreatic secretion collected during this period. The scorpion venoms also caused hypersecretion of viscid saliva. In contrast, rattlesnake venom, had no detectable effect on salivation, pancreatic secretion or morphology of the pancreas.
— id: 9782, year: 1983, vol: 21, page: 405, stat: Journal Article,

FORMATION OF LEUKOTRIENES (LT) AND HYDROXY-ACIDS BY HUMAN-LEUKOCYTES EXPOSED TO MONOSODIUM URATE (MSU)
SERHAN, CN; LUNDBERG, U; ABRAMSON, S; SAMUELSSON, B; WEISSMANN, G
1983 ;31(2):A521-A521, Clinical research
— id: 40691, year: 1983, vol: 31, page: A521, stat: Journal Article,

Superoxide anion generation by human neutrophils exposed to monosodium urate
Abramson S; Hoffstein ST; Weissmann G
1982 Feb;25(2):174-180, Arthritis & rheumatism
We studied the capacities of naked and protein-coated monosodium urate (MSU) crystals to stimulate superoxide anion (O(2)) release by human polymorphonuclear leukocytes (PMN). Uncoated MSU estimated significant O(2) production by cytochalasin B-treated PMN. Precoating MSU with IgG caused an increase in mean O(2) production, whereas precoating heated MSU with serum or plasma inhibited O(2) release. Unheated MSU crystals, which activate complement to a greater extent than heated crystals, also provoked O(2) generation, an effect again abrogated by precoating with serum but not with plasma. Coincubation of unheated MSU and plasma resulted in an enhancement of O(2) generation. The results of these experiments support the hypothesis that adsorbed proteins modulate the phlogistic potential of MSU and that the surface activation of humoral mediators contributes to the local inflammatory response
— id: 59757, year: 1982, vol: 25, page: 174, stat: Journal Article,

Ribonuclease C and pancreatic secretory proteins in the peripheral circulation before and after pancreatectomy for pancreatic cancer
Abramson SB; Rinderknecht H; Renner IG
1982 Oct;27(10):889-896, Digestive diseases & sciences
— id: 9783, year: 1982, vol: 27, page: 889, stat: Journal Article,

NEUTROPHIL AGGREGATION INDUCED BY SERA FROM PATIENTS WITH ACTIVE SYSTEMIC LUPUS-ERYTHEMATOSUS (SLE) AND NECROTIZING VASCULITIS
Abramson, S; Given, W; Edelson, H; Febbraio, J; Weissmann, G
1982 ;30(2):A468-A468, Clinical research
— id: 30425, year: 1982, vol: 30, page: A468, stat: Journal Article,

The release of inflammatory mediators from neutrophils
Abramson S; Weissmann G
1981 Apr-Jun;11(2):91-99, Ricerca in clinica e in laboratorio = Research in clinic & laboratory
Human polymorphonuclear leukocytes exposed to phagocytic stimuli undergo a series of cellular reactions designed to eliminate foreign invaders such as bacteria, viruses, or fungi. The responses of human granulocytes to the stimuli of phagocytosis are initiated at the cell surface and proceed in the following sequence: a. ligand binding to surface receptors; b. membrane hyperpolarization; c. O2- generation by a surface oxidase and 1O2 metabolism; d. generation of thromboxanes and prostaglandins; e. lysosomal enzyme secretion. These events, known as 'stimulus-secretion coupling', result in the secretion of toxic substances which, though intended to end up in the phagocytic vacuole, may escape to the extracellular space where they initiate inflammation
— id: 59771, year: 1981, vol: 11, page: 91, stat: Journal Article,

MONOSODIUM URATE (MSU) CRYSTAL-INDUCED INFLAMMATION - COMPLEMENT (C) ACTIVATION AND SUPEROXIDE ANION GENERATION O-2.(-)
ABRAMSON, S; HOFFSTEIN, ST; WEISSMANN, G
1981 ;29(2):A584-A584, Clinical research
— id: 40229, year: 1981, vol: 29, page: A584, stat: Journal Article,

DO IMMUNOGLOBULINS OR COMPLEMENT MEDIATE LYSOSOMAL ENZYME- RELEASE AND SUPEROXIDE ANION (O2) GENERATION BY NEUTROPHILS EXPOSED TO MONOSODIUM URATE (MSU) CRYSTALS
Abramson, S; Weissmann, G; Hoffstein, S
1980 ;28(2):A338-A338, Clinical research
— id: 28006, year: 1980, vol: 28, page: A338, stat: Journal Article,

alpha-Amylase of human pure pancreatic juice: effects of pancreatic disease and the occurrence of variant forms in pancreatic juice from healthy volunteers
Renner IG; Abramson SB; Douglas AP
1979 Dec 17;99(3):259-266, Clinica chimica acta
Pure pancreatic juice (PPJ) from healthy human volunteers and from patients with pancreatic or liver disease was subjected to isoelectric focussing (IEF) and assayed for alpha-amylase activity. In PPJ from most normals, a single predominant form of amylase was found, comprising congruent to 83% of the total activity recovered, and having pIapp congruent to pH 6.8. In PPJ from six normals, variant principal forms of amylase were found at pH congruent to 6.4 or pH congruent to 7.3, in addition to the peak at pH 6.8. IEF patterns of PPJ from individuals with pancreatic or liver disease were indisquishable from patterns obtained with PPJ from the control group of healthy volunteers.
— id: 9784, year: 1979, vol: 99, page: 259, stat: Journal Article,