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ID PMID Title PublicationDate abstract
12564836 Receptor activator for nuclear factor kappaB ligand and osteoprotegerin: regulators of bon 2002 Nov The discovery of receptor activator for nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) as the fundamental factors in controlling osteoclast formation and activation has led to a greater understanding of bone biology over the past few years. Here we discuss the role of these molecules in immunology and skeletal remodelling and assess their involvement in diseases of bones and joints, including rheumatoid arthritis, Paget's disease, post-menopausal osteoporosis and malignant bone diseases. OPG has been identified as a potential anabolic agent for treating conditions in which there is net bone loss and is currently in Phase I clinical trials. This review examines the current evidence indicating that OPG increases bone mass, and discusses other possible beneficial effects of OPG, such as inhibition of tumour growth and relief from bone cancer pain. OPG can be measured in human serum, and numerous studies have suggested that increased or decreased serum concentrations of this molecule can indicate the existence of remodelling disorders. Here we discuss how abnormal serum OPG concentrations could potentially be used to indicate imbalances of bone resorption and formation. The possible applications of serum OPG concentration as a marker for non-skeletal disease conditions are also considered.
12525382 Bioenergetics of immune cells to assess rheumatic disease activity and efficacy of glucoco 2003 Feb OBJECTIVE: To investigate whether activity and glucocorticoid treatment of rheumatic diseases are reflected by selected parameters of cellular energy metabolism of peripheral blood mononuclear cells (PBMC). METHODS: PBMC were obtained from 30 healthy volunteers, 28 patients (16 inactive; 12 active) with rheumatoid arthritis, systemic lupus erythematosus, vasculitis, or other autoimmune diseases, and five patients with infectious diseases. Patients with active rheumatic diseases were examined before and 4-5 days after starting, restarting, or increasing the dose of glucocorticoids. Cellular oxygen consumption (as a measure of ATP production), bioenergetic ability to be stimulated, and major ATP consuming processes were measured amperometrically with a Clark electrode. RESULTS: A normal value for oxygen consumption of 3.84 (SEM 0.1) (all data in nmol O(2)/min/10(7) cells) independent of sex was found. In patients with inactive disease the respiration rate was slightly higher, but was significantly increased in active patients to 4.82 (SEM 0.33) (p<0.001). PBMC from active patients showed a significantly lower bioenergetic response to a mitogenic stimulus than controls (p<0.05). In stimulated cells from active patients there was a significant reduction in cation transport and protein synthesis. All parameters above were almost normalised within 4-5 days upon optimised treatment with glucocorticoids. For comparison, PBMC from patients with active infectious diseases also showed an increased respiration rate; their response to mitogenic stimulation was even higher. CONCLUSIONS: This study shows for the first time that parameters describing the cellular function of PBMC in bioenergetic terms are suitable for (a) describing semiquantitatively the activity of a rheumatic disease and (b) assessing the therapeutic effect on the disease.
12452846 Autoantibodies against small nucleolar ribonucleoprotein complexes and their clinical asso 2002 Dec Sera from patients suffering from systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) have been shown to contain reactivities to nuclear components. Autoantibodies specifically targeting nucleolar antigens are found most frequently in patients suffering from SSc or SSc overlap syndromes. We determined the prevalence and clinical significance of autoantibodies directed to nucleolar RNA-protein complexes, the so-called small nucleolar ribonucleoprotein complexes (snoRNPs). A total of 172 patient sera with antinucleolar antibodies were analysed by immunoprecipitation. From 100 of these patients clinical information was obtained by chart review. Autoantibodies directed to snoRNPs were detected not only in patients suffering from SSc and primary Raynaud's phenomenon (RP), but also in patients suffering from SLE, rheumatoid arthritis (RA) and myositis (PM/DM). Antibodies against box C/D small snoRNPs can be subdivided in antifibrillarin positive and antifibrillarin negative reactivity. Antifibrillarin-positive patient sera were associated with a poor prognosis in comparison with antifibrillarin negative (reactivity with U3 or U8 snoRNP only) patient sera. Anti-Th/To autoantibodies were associated with SSc, primary RP and SLE and were found predominantly in patients suffering from decreased co-diffusion and oesophagus motility and xerophthalmia. For the first time autoantibodies that recognize box H/ACA snoRNPs are described, identifying this class of snoRNPs as a novel autoantigenic activity. Taken together, our data show that antinucleolar patient sera directed to small nucleolar ribonucleoprotein complexes are found frequently in other diseases than SSc and that categorization of diagnoses and clinical manifestations based on autoantibody profiles seems particularly informative in patient sera recognizing box C/D snoRNPs.
12195370 Association of symptomatic acute human parvovirus B19 infection with human leukocyte antig 2002 Aug 15 To determine the effect of the major histocompatibility complex on the development of symptoms during acute human parvovirus B19 infection, we compared human leukocyte antigen (HLA) class I and II alleles in 36 patients with symptomatic acute B19 infection with those in >900 control subjects from northwestern England. The frequency of each of HLA-DRB1*01 (P=.016), DRB1*04 (P=.007), and DRB1*07 (P<.0001) alleles was significantly higher in parvovirus B19 patients than in control subjects. In the parvovirus group, 63.9% carried the rheumatoid arthritis-associated shared epitope sequence, compared with 45% of control subjects (odds ratio [OR], 2.2; 95% confidence interval [CI], 0.97-4.8; P=.04), and carriage was associated with fatigue during the acute phase (OR, 4.2; 95% CI, 0.8-23.9; P=.047). All symptomatic parvovirus-associated HLA-DRB1 molecules carry a neutrally charged glutamine at position 10 and a positively charged lysine at position 12 of the first hypervariable region. HLA-B49 was associated with parvovirus infection independently of HLA-DRB1*01, DRB1*04, and DRB1*07.
12072047 Preliminary evidence that an endogenous retroviral long-terminal repeat (LTR13) at the HLA 2002 Jun OBJECTIVE: Addison's disease is associated with particular haplotypes of the human leucocyte antigen (HLA) region [DQA1*0501-DQB1*0201 (DQ2) and DQA1*0301-DQB1*0302 (DQ8)]. This locus harbours several human endogenous retroviral (HERV) long-terminal repeats (LTR). LTRs within the HLA region have been shown to confer additional susceptibility to type 1 diabetes and rheumatoid arthritis. DESIGN: We investigated the role of LTR3 and LTR13, both of which are located adjacent to the DQB1 gene, in Addison's disease. PATIENTS: Eighty-seven patients and 160 controls were genotyped for HLA-DQA, -DQB, and the presence or absence of LTR3 and LTR13. RESULTS: Significantly more patients' HLA alleles than those of controls carried the LTR13 insertion (19.0% vs. 10.6%, P = 0.0143), whereas there was only a trend for LTR3 (allele-wise chi-squared test: P = 0.0941). Both, LTR3 and LTR13 are in strong linkage disequilibrium with DQ8, which itself was significantly more frequent in patients than in controls (29.9% vs. 15.0%, P = 0.0089). However, significantly more alleles of DQ8+ patients than of DQ8+ controls carried the LTR13 insertion (44.2% vs. 18.8%, P = 0.0119), whereas we did not observe any difference for LTR3 in the DQ8+ subset (30.5 vs. 23.1%, P = 0.9416). CONCLUSIONS: We have found preliminary evidence that the endogenous retroviral element DQ-LTR13, but not LTR3, is associated with Addison's disease. LTR13 appears to enhance HLA-DQ8 mediated disease risk. This retroviral insertion therefore might represent a novel susceptibility factor in Addison's disease, but these findings need to be confirmed in a larger data set.
11996936 AUUUA motifs in the 3'UTR of human glucocorticoid receptor alpha and beta mRNA destabilize 2002 Jun An association between a gene polymorphism of the human glucocorticoid receptor (hGR) gene and rheumatoid arthritis has recently been suggested. This polymorphism contains an A to G mutation in the 3'UTR of exon 9beta, which encodes the 3'UTR of the mRNA of the hGRbeta isoform. The hGRbeta isoform can act as a dominant negative inhibitor of hGRalpha, and therefore may contribute to glucocorticoid resistance. The A to G mutation is located in an AUUUA motif, which is known to destabilize mRNA. In the present study, the importance of the mutation in this AUUUA motif was further characterized and mutations in other AUUUA motifs in the 3'UTR of hGRbeta and hGRalpha mRNA were studied. hGRbeta and hGRalpha expression vectors, carrying mutations in one AUUUA motif or all AUUUA motifs were transiently transfected into COS-1 cells. Each transfected vector was analyzed for the mRNA expression level, the mRNA turnover rate and the protein expression level. The naturally occurring mutation in the 3'UTR of hGRbeta mRNA increased mRNA stability and protein expression. Mutation of two other AUUUA motifs in the 3'UTR of hGRbeta, or mutation of all four AUUUA motifs resulted in a similar effect. Mutation of the most 5' AUUUA motif did not alter hGRbeta mRNA expression or mRNA stability. Mutation of all 10 AUUUA motifs in the 3'UTR of hGRalpha mRNA increased hGRalpha mRNA expression and mRNA stability as well as expression of the receptor protein level. Thus, the naturally occurring mutation in an AUUUA motif in the 3'UTR of hGRbeta mRNA results not only in increased mRNA stability, but also in increased receptor protein expression, which may contribute to glucocorticoid resistance. A similar role is suggested for two other AUUUA motifs in the 3'UTR of hGRbeta mRNA and for the 10 AUUUA motifs that are present in the 3'UTR of hGRalpha.
11891230 Mannose-binding lectin (MBL) mutants are susceptible to matrix metalloproteinase proteolys 2002 May 17 Mannose-binding lectin (MBL) plays a critical role in innate immunity. Point mutations in the collagen-like domain (R32C, G34D, or G37E) of MBL cause a serum deficiency, predisposing patients to infections and diseases such as rheumatoid arthritis. We examined whether MBL mutants show enhanced susceptibility to proteolysis by matrix metalloproteinases (MMPs), which are important mediators in inflammatory tissue destruction. Human and rat MBL were resistant to proteolysis in the native state but were cleaved selectively within the collagen-like domain by multiple MMPs after heat denaturation. In contrast, rat MBL with mutations homologous to those of the human variants (R23C, G25D, or G28E) was cleaved efficiently without denaturation in the collagen-like domain by MMP-2 and MMP-9 (gelatinases A and B) and MMP-14 (membrane type-1 MMP), as well as by MMP-1 (collagenase-1), MMP-8 (neutrophil collagenase), MMP-3 (stromelysin-1), neutrophil elastase, and bacterial collagenase. Sites and order of cleavage of the rat MBL mutants for MMP-2 and MMP-9 were: Gly(45)-Lys(46) --> Gly(51)-Ser(52) --> Gly(63)-Gln(64) --> Asn(80)-Met(81) which differed from that of MMP-14, Gly(39)-Leu(40) --> Asn(80)-Met(81), revealing that the MMPs were not functionally interchangeable. These sites were homologous to those cleaved in denatured human MBL. Hence, perturbation of the collagen-like structure of MBL by natural mutations or by denaturation renders MBL susceptible to MMP cleavage. MMPs are likely to contribute to MBL deficiency in individuals with variant alleles and may also be involved in clearance of MBL and modulation of the host response in normal individuals.
20641534 N-4-[(18)F]Fluorobenzoyl-c(RGDyK). 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell-cell and cell-matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents and the agonists as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most of the cyclic RGD peptides are monomeric and composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (IC(50), 7-40 nM) but not to α(v)β(5) (IC(50), 600-4,000 nM) or α(IIb)β(3) (IC(50), 700-5,000 nM) integrin. [(18)F]FB-c(RGDyK) was synthesized to study in vivo biodistribution of the tracer in tumor-bearing mice. [(18)F]FB-c(RGDyK) was found to have high accumulation in tumors, but it also had a high tumor washout and biliary excretion into the gallbladder and intestines (12). A dimeric analog was also synthesized as [(18)F]FB-E[c(RGDyK)](2), which was shown to have higher tumor uptake than the monomer and predominantly renal excretion (13).
15518340 UL16 binding proteins. 2004 According to present concepts, innate immunity plays an important role in tumor surveillance and immune modulation. The state of NK cells depends on the balance between inhibitory and activating signals from corresponding receptors. As one of the activating receptors, NKG2D recognises some self ligands such as MICA/B in human and Rae1 in mice, which is dissimilar to those toll-like receptors that recognise some pathogen-derived ligands. NKG2D is expressed not only on NK cells, but on gammadelta T cells, CD8+ alphabeta T cells in normal individuals and CD4+ alphabeta T cells in rheumatoid arthritis patients and plays a different role on respective cells. Whereas NKG2D can only function as a costimulatory receptor on CD8+ alphabeta T cells under the domination of alphabeta TCR in spite of a deficiency of costimulatory molecule CD28, NKG2D can directly activate NK cells even in the presence of inhibitory signals from MHC-I and corresponding receptor complexes. Experiments in mice have identified that alternative splicing produces two distinct NKG2D polypeptides that associate differentially with the DAP10 and DAP12 signaling subunits and that differential expression of these isoforms and of signaling proteins determines whether NKG2D only functions as a costimulatory receptor in the adaptive immune system (CD8+ T cells) or as both a primary recognition unit and a costimulatory receptor in the innate immune system (natural killer cells and macrophages). This review summarizes the research achievements in a new ligand family (UL16 binding proteins) of NKG2D in human and shows the possible prospects of ULBP function and application.
15327398 Wegener's granulomatosis is associated with organ-specific antiendothelial cell antibodies 2004 Sep BACKGROUND: Antiendothelial cell antibodies (AECA), usually detected using human umbilical vein endothelial cells (HUVEC), are frequently observed in systemic vasculitis, but their pathogenic role is unclear. Heterogeneity of endothelial cells necessitates use of clinically relevant endothelial cells for elucidation of the role of AECA in systemic vasculitis involving small blood vessels of specific organs. METHODS: Human endothelial cells were isolated from normal tissue specimens from the nose, kidney, lung, liver, and umbilical vein. Using flow cytometry, AECA were detected against both unstimulated and cytokine-stimulated [tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)] endothelial cells. Functional capacity of AECA was determined by complement fixation assay. Sera from patients with Wegener's granulomatosis (16), limited Wegener's granulomatosis (8), renal limited disease (4), microscopic polyangiitis (MPA) (5), rheumatoid arthritis (10), and systemic lupus erythematosus (SLE) (9), and from healthy controls (20) were analyzed. RESULTS: Compared with controls (1) Wegener's granulomatosis is significantly associated with noncytotoxic AECA that selectively bind surface antigens on unstimulated nasal, kidney, and lung endothelial cells; (2) binding of Wegener's granulomatosis AECA to kidney and nasal endothelial cells in particular was lost upon treatment with IFN-gamma and TNF-alpha; (3) the two cytokines per se were cytotoxic (30%) to nasal and lung endothelial cells and lysis was further increased (60%) by addition of systemic vasculitis serum; and (4) Wegener's granulomatosis serum caused agglutination of cytokine-stimulated nasal endothelial cells. CONCLUSION: Based on these findings we suggest that AECA may be one factor involved in the initiation of Wegener's granulomatosis. Antigen identification and elucidation of the pathogenic roles of AECA and inflammatory cytokines in systemic vasculitis using these cells will be particularly important.
23115808 (99m)Tc-Labeled rituximab, a chimeric murine/human anti-CD20 monoclonal antibody. 2004 Rituximab is a chimeric murine/human monoclonal antibody (mAb) that targets the CD20 antigen (also known as membrane-spanning 4-domains, subfamily A, member 1; or MS4A1), which is expressed on 95% of the transformed B-cells that participate in the pathogenesis of non-Hodgkin lymphomas (NHL; diffused large-B cell, low-grade, or the follicular types), a hematological malignancy, and autoimmune diseases such as rheumatoid arthritis (RA), granulomatosis with polyangiitis (Wegener's granulomatosis), and microscopic polyangiitis. The CD20 antigen is not expressed on any other hematopoietic cells and is not shed for circulation into the plasma or internalized by the cells (1). Therefore, the CD20 antigen is considered to be an excellent target for the treatment of the various B-lymphocyte, cell-based diseases such as those mentioned above. The United States Food and Drug Administration has approved the use of rituximab for the treatment of NHL and the other diseases mentioned above. The exact mechanism of action of rituximab has been discussed by Maloney (2). Although much is known about the pathogenesis of the different forms of NHL at the molecular level, the prognosis for an individual suffering from this disease is based on the morphological and histological information obtained with invasive methods used on the patients (3). As an alternative to the invasive methods, noninvasive procedures, such as imaging with radiolabeled agents using single-photon emission computed tomography (SPECT) or positron emission tomography, are attractive options to screen for patients who can benefit the most from an anti-cancer treatment, and the same imaging technique(s) can be used to monitor and assess the efficacy of a treatment (4). Rituximab was labeled with (99m)Tc ([(99m)Tc]rituximab) and used with SPECT for the imaging of NHL (1) and several inflammatory autoimmune diseases such as RA, Behcet’s disease, sarcoidosis, and others, in humans (5).
21473028 (111)In-Labeled recombinant gelonin toxin-B lymphocyte stimulator protein fusion protein. 2004 The B lymphocyte stimulator (BLyS; for other synonyms see Summary Table above) is a glycoprotein belonging to the tumor necrosis factor cytokine family and promotes the survival, proliferation, and differentiation of the B cells (2). Three different receptors on the B cells (for details, see Wen et al. (2)) are known to bind BLyS; among these, the B cell–activating factor receptor shows the strongest affinity for this cytokine. Although BLyS is overexpressed on B cells of individuals suffering from autoimmune diseases such as lupus, rheumatoid arthritis, etc., the BLyS receptors are known to be expressed on the membrane surface of several types of cancerous tumor cells [PubMed]. Because of its specificity of binding to B cells, BLyS-derived fusion toxins such as the gelonin (Gel)-BLyS fusion protein has been studied by investigators to selectively target and treat B cell malignancies (3-6). Gel is an N-glycosidase type I ribosome-inactivating plant toxin that lacks a cell binding or a cell internalization domain and is almost non-toxic to intact cells (2, 7). However, mammalian cells can internalize the toxin in association with a carrier, at which point Gel is lethal to the cells because it inhibits protein synthesis completely within 3–4 days of internalization and release within the cell. Recently a recombinant Gel (rGel)-BLyS fusion protein (rGel/BLyS) was constructed by linking rGel to the N-terminus of BLyS, and rGel/BLys was labeled with (111)In using diethylenetriamine pentaacetic acid (DTPA) to produce the radionuclide chelator [(111)In]-DTPA-rGel/BLyS (2). The biodistribution and tumor-imaging characteristics of [(111)In]-DTPA-rGel/BLyS were then studied in severe combined immunodeficient (SCID) mice bearing B cell lymphoma tumors (2).
15652280 Cheongyeolsaseuptang inhibits production of TNF-alpha, IL-6 and IL-8 as well as NF-kappa B 2005 Feb 10 Traditional Korean medicine, Cheongyeolsaseuptang (CYSST) has been widely applied as a treatment of rheumatoid arthritis (RA) in Korea. However, its effect in experimental models remains unknown. Recent reports suggest that in patients with RA, synovial mast cells increase in number and show signs of activation and production of cytokines. In this study, we investigated the effect of CYSST on production of cytokines by activated human mast cell line, HMC-1. When CYSST (1mg/ml) was added, the production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8 was significantly inhibited about 37, 33.6, and 48%, respectively on phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187-stimulated HMC-1 cells. In addition, CYSST inhibited PMA plus A23187-induced activation of nuclear factor-kappaB. These findings may help understanding the mechanism of action of this medicine leading to control activated mast cells on inflammatory condition like RA.
15485592 Omega-3 fatty acids and inflammation. 2004 Nov Dietary omega-3 (n-3) fatty acids have a variety of anti-inflammatory and immune-modulating effects that may be of relevance to atherosclerosis and its clinical manifestations of myocardial infarction, sudden death, and stroke. The n-3 fatty acids that appear to be most potent in this respect are the long-chain polyunsaturates derived from marine oils, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and this review is restricted to these substances. A variety of biologic effects of EPA and DHA have been demonstrated from feeding studies with fish or fish oil supplements in humans and animals. These include effects on triglycerides, high-density lipoprotein cholesterol, platelet function, endothelial and vascular function, blood pressure, cardiac excitability, measures of oxidative stress, pro- and anti-inflammatory cytokines, and immune function. Epidemiologic studies provide evidence for a beneficial effect of n-3 fatty acids on manifestations of coronary heart disease and ischemic stroke, whereas randomized, controlled, clinical feeding trials support this, particularly with respect to sudden cardiac death in patients with established disease. Clinically important anti-inflammatory effects in man are further suggested by trials demonstrating benefits of n-3 fatty acids in rheumatoid arthritis, psoriasis, asthma, and inflammatory bowel disorders. Given the evidence relating progression of atherosclerosis to chronic inflammation, the n-3 fatty acids may play an important role via modulation of the inflammatory processes.
15363379 Plantarflexion opening wedge medial cuneiform osteotomy for correction of fixed forefoot v 2004 Aug BACKGROUND: Flatfoot presents as a wide spectrum of foot deformities that include varying degrees of hindfoot valgus, forefoot abduction, and forefoot varus. Medial displacement calcaneal osteotomy, lateral column lengthening, and subtalar fusion can correct heel valgus, but may not adequately correct the fixed forefoot varus component. The purpose of this study was to determine the effectiveness of plantarflexion opening wedge medial cuneiform (Cotton) osteotomy in the correction of forefoot varus. METHODS: Sixteen feet (15 patients) had plantarflexion opening wedge medial cuneiform osteotomies to correct forefoot varus associated with flatfoot deformities from several etiologies, including congenital flatfoot (six feet, average age 37 years), tarsal coalition (five feet, average age 15 years), overcorrected clubfoot deformity (two feet, ages 17 years and 18 years), skewfoot (one foot, age 15 years), chronic posterior tibial tendon insufficiency (one foot, 41 years), and rheumatoid arthritis (one foot, age 56 years). RESULTS: Standing radiographs showed an average improvement in the anterior-posterior talo-first metatarsal angle of 7 degrees (9 degrees preoperative, 2 degrees postoperative). The talonavicular coverage angle improved an average of 15 degrees (20 degrees preoperative, 5 degrees postoperative). The lateral talo-first metatarsal angle improved an average of 14 degrees (-13 degrees preoperative, 1 degree postoperative). Correcting for radiographic magnification, the distance from the mid-medial cuneiform to the floor on the lateral radiograph averaged 40 mm preoperatively and 47 mm postoperatively (average improvement 7 mm). All patients at followup described mild to no pain with ambulation. There were no nonunions or malunions. CONCLUSIONS: Opening wedge medial cuneiform osteotomy is an important adjunctive procedure to correct the forefoot varus component of a flatfoot deformity. Advantages of this technique in comparison to first tarsometatarsal arthrodesis include predictable union, preservation of first ray mobility, and the ability to easily vary the amount of correction. Because of the variety of hindfoot procedures done in these patients, the degree of hindfoot correction contributed by the cuneiform osteotomy alone could not be determined. We have had excellent results without major complications using this technique.
15293995 Design, synthesis, and biological evaluation of new cyclic disulfide decapeptides that inh 2004 Aug 12 The transcription factor activator protein-1 (AP-1) is an attractive target for the treatment of immunoinflammatory diseases, such as rheumatoid arthritis. Using the three-dimensional (3D) X-ray crystallographic structure of the DNA-bound basic region leucine zipper (bZIP) domains of AP-1, new cyclic disulfide decapeptides were designed and synthesized that demonstrated AP-1 inhibitory activities. The most potent inhibition was exhibited by Ac-c[Cys-Gly-Gln-Leu-Asp-Leu-Ala-Asp-Gly-Cys]-NH2 (peptide 2) (IC50 = 8 microM), which was largely due to the side chains of residues 3-6 and 8 of the peptide, as shown by an alanine scan. To provide structural information about the biologically active conformation of peptide 2, the structures of peptide 2 derived from molecular dynamics simulation of the bZIP-peptide 2 complex with explicit water molecules were superimposed on the solution structures derived from NMR measurements of peptide 2 in water. These showed a strong structural similarity in the backbones of residues 3-7 and enabled the construction of a 3D pharmacophore model of AP-1 binding compounds, based on the chemical and structural features of the amino acid side chains of residues 3-7 in peptide 2.
15252091 Preoperative factors associated with improvements in shoulder function after humeral hemia 2004 Jul BACKGROUND: The relationship between the characteristics of the shoulder that can be determined before humeral hemiarthroplasty and the functional improvement after surgery is not known. The goal of this study was to test the hypothesis that the functional outcome of this procedure correlated significantly with factors that are identifiable preoperatively. METHODS: The study group included seventy-one shoulders in sixty-eight patients undergoing hemiarthroplasty, performed by the same surgeon, for diagnoses other than acute fracture. The mean age of the patients was sixty-one years (range, thirty to eighty-three years). The results were characterized in terms of the change in self-assessed shoulder function and general health status at an average of forty-nine months (range, twenty-four to 142 months) after surgery. RESULTS: The preoperative absence of erosion of the glenoid was associated with greater improvement in shoulder function and level of comfort after hemiarthroplasty (p < 0.001). Shoulders that had not had previous surgery had greater functional improvement than did those that had previous surgery (p = 0.012). Shoulders with an intact rotator cuff showed significantly (p < 0.5) greater improvement in the ability to lift weight above shoulder level after hemiarthroplasty (p <0.5). With regard to diagnoses, shoulders with rheumatoid arthritis, capsulorrhaphy arthropathy, and cuff tear arthropathy had the least functional improvement, whereas those with osteonecrosis (p = 0.0004) and with primary (p = 0.02) and secondary degenerative joint disease (p = 0.03) had the greatest improvement. Patient age and gender did not significantly affect the outcome. CONCLUSIONS: These results suggest that the functional improvement following humeral hemiarthroplasty is related to factors that are identifiable before surgery. These data may be of benefit in preoperative discussions with patients who have a shoulder disorder and are considering treatment with hemiarthroplasty.
15190675 Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases. 2004 Inflammatory processes associated with the over-production of cytokines, particularly of TNF-alpha, accompany numerous neurodegenerative diseases, such as Alzheimer's disease, in addition to numerous systemic conditions, exemplified by rheumatoid arthritis and erythema nodosum leprosum (ENL). TNF-alpha has been validated as a drug target with Remicade and Enbrel available as prescription medications. Both, however, are large macromolecules, require injection and have limited brain access. The classical drug, thalidomide is being increasingly used in the clinical management of a wide spectrum of diseases. As its clinical value in treating ENL derives from its TNF-alpha inhibitory activity, thalidomide was chosen for structural modification for the discovery of novel and more potent isosteric analogues with appropriate lipophilicity to insure high brain penetration. TNF-alpha inhibitory activity was evaluated against lipopolysacharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) in cell culture, whose viability was quantified to differentiate reductions in TNF-alpha secretion from that associated with cellular toxicity. Specific analogues potently inhibited TNF-alpha secretion, compared to thalidomide. This involved a post-transcriptional mechanism, as they decreased TNF-alpha mRNA stability via its 3'-untranslated region (UTR), as determined by luciferase activity in stably transfected cells with and without the 3'-UTR of human TNF-alpha.
15142523 Autoimmunity through cytokine-induced dendritic cell activation. 2004 May We propose a model where autoimmunity can be viewed as a dynamic system driven by opposite vectors IFN-alpha/beta and TNF. These cytokines drive differentiation of distinct types of DCs, TNF-DCs, or IFN-DCs, which present different antigens leading to distinct autoimmune responses. When balanced, both cytokines synergize in protective immunity. When one of the cytokines prevails, autoimmunity occurs, Type I interferons (IFN-alpha/beta) playing a major role in systemic lupus erythematosus (SLE) and TNF playing a major role in rheumatoid arthritis. This model complements the Type 1/Type 2 paradigm. Therefore, immunity can be viewed as a dynamic system driven by two sets of opposite vectors: IFN-alpha/beta/TNF and IFN-gamma/IL-4.
15139785 Reversal of chronic obstructive pulmonary disease-associated weight loss : are there pharm 2004 Poor nutritional status is associated with an increased incidence of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). While a number of factors have been shown to produce tissue catabolism, no single mechanism has been clearly identified as a primary cause for weight loss in patients with severe COPD. Without a clear understanding of the aetiology of weight loss, therapeutic strategies to reverse this process have historically been unsuccessful. A review of recent studies allows consideration of a model of mechanisms of weight loss. This model includes multiple pathways that may be activated singly or simultaneously to cause loss of weight, specifically lean body mass. These include energy imbalances, elevated levels of cytokines, tissue hypoxia and the effects of cocorticosteroid therapy. To date, interventional studies that have looked at newer pharmacotherapies such as growth hormone and anabolic steroids in patients with COPD who are losing weight have not demonstrated reversal of weight loss or improvement in nutritional status. Currently, early identification of patients at risk for weight loss and aggressive nutritional supplementation coupled with an exercise programme has demonstrated the greatest benefit. However, with increasing understanding of the mechanisms that may be implicated, new targets for therapies are being identified. Of particular research interest are molecules such as leukotrienes, hormones, tumour necrosis factor-alpha and acute-phase proteins, which are noted to be elevated in some patients with COPD-associated weight loss. Currently, inhibitors to some of these inflammatory substances are used therapeutically in other chronic illnesses such as rheumatoid arthritis and cancer cachexia. Future research may investigate their usefulness in COPD and direct new therapies that target the processes contributing to weight loss in these patients.