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ID PMID Title PublicationDate abstract
18437285 Tumor necrosis factor-alpha inhibits chondrogenic differentiation of synovial fibroblasts 2008 We previously reported that synovial fibroblast-like cells (SFs) can be differentiated into chondrocytes through activin receptor-like kinase (ALK) 3 activation. The aim of this study was to clarify the effect and signaling pathways of tumor necrosis factor (TNF)-alpha on the chondrogenic differentiation of SFs. Primary SFs from patients with rheumatoid arthritis (RA) were treated with recombinant human bone morphogenetic protein-2 or transduced with a constitutively active mutant of the ALK3 gene (ALK3CA) with or without TNF-alpha, and then cultured in pellets. Expression of chondrocyte-specific genes was analyzed by real-time polymerase chain reaction or by histological analysis. Inhibitors of mitogen-activating protein kinase (MAPK) pathways or adenovirus vectors carrying a dominant-negative mutant of the IkappaB kinase 2 gene (AxIKK2DN) were used to analyze the signaling pathways of TNF-alpha. Expression of chondrocyte-specific genes was induced in SFs either by rhBMP-2 treatment or by ALK3CA transduction, which was strongly suppressed by TNF-alpha treatment. TNF-alpha markedly increased the p38 MAPK pathways in SFs, and inhibition of p38 MAPK activation partially restored the inhibitory effect of TNF-alpha on the chondrogenic differentiation of SFs. Combination therapy BMP-2 and anti-TNF-alpha agents especially targeting p38 MAPK might be a good approach to stimulating neochondrogenesis in the damaged joints in RA.
18270859 Rituximab in treatment-resistant autoimmune blistering skin disorders. 2008 Feb Autoimmune blistering diseases are associated with autoantibodies to desmosomal (pemphigus group) or hemidesmosomal proteins (autoimmune subepidermal blistering disorders) that are essential for the structural integrity of the epidermis and dermoepidermal junction. Treatment is usually based on systemic glucocorticosteroids, which are often combined with additional immunosuppressants such as azathioprine and mycophenolate mofetil or immunomodulators including dapsone, antibiotics, and intravenous immunoglobulins. These interventions are sometimes not sufficient to induce remission and/or may be associated with intolerable adverse events. In such situations, the anti-CD20 antibody rituximab has been successfully applied in recent years. Rituximab transitorily depletes CD20-positive B lymphocytes from the circulation. It has been employed in more than 1 million patients with CD20-positive non-Hodgkin's lymphoma and severe side effects were only rarely observed. Subsequently, the B cell-modulating effect of rituximab has encouraged its use in a variety of autoimmune diseases, including more than 40 patients with pemphigus. In addition, a few patients with bullous pemphigoid, mucous membrane pemphigoid, and epidermolysis bullosa acquisita have received rituximab. In the majority of these patients, clinical remission was induced; however, serious adverse events were considerable higher compared to both patients with non-Hodgkin's lymphoma or nonbullous autoimmune disorders like lupus erythematosus, dermatomyositis, and rheumatoid arthritis.
18220957 TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. 2007 Dec There is an increasing interest in ligands of nucleic acid-sensing Toll-like receptors (TLR), especially TLR7 and TLR9, for pharmacological intervention in various diseases. The TLR7 agonist imiquimod is currently used as a topical treatment for genital warts caused by human papillomavirus (HPV), actinic keratosis (AK) and superficial basal cell carcinoma. Oligodeoxynucleotides (ODN) TLR9 agonists are currently in clinical trials for use in lung cancer, as anti-viral therapy, as adjuvants and as immune modulators in asthma and allergies. TLR7/9 antagonists, such as the anti-malaria drugs chloroquine, hydroxychloroquine and quinacrine, have been used since the 1950s to treat immune-mediated inflammatory disorders (IMID) such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjögren's syndrome. However, the use of these anti-malarials in IMID is limited due to the side effects or suboptimal efficacy. Pre-clinical animal models as well as genetic linkage studies have indicated that TLR7/9 play a pivotal role in the aforementioned as well as other IMID such as multiple sclerosis (MS), inflammatory bowl disease (IBD)/colitis and psoriasis. Recent evidence has suggested that selective, specific antagonists for TLR7 and/or 9 might be more beneficial in certain diseases, such as SLE. Thus, the use of suppressive ODN or novel small molecule TLR7/9 inhibitors with a larger safety window and differentiated selectivity may potentially have significant clinical utility in these IMID. Herein, we review efforts to develop novel TLR7/9 antagonists and the rationale for the use of such therapeutics in a variety of IMID.
18094520 Comparison of the clinical features of Japanese patients with primary biliary cirrhosis in 2007 Nov BACKGROUND: In Asia there are few reports considering time intervals in the examination of clinical features of primary biliary cirrhosis (PBC). Therefore, we tried to compare the characteristics of patients with PBC in two different years. METHODS: In two fiscal years (1999 and 2004), 9,761 and 13,142 patients with symptomatic PBC were registered to receive public financial aid from the Ministry of Health, Labour and Welfare of Japan, respectively. For the present study, clinical data from 2,127 patients in 1999 and 6,423 ones in 2004 were available. We compared the data in the two different years, including sex, age, major symptoms, and laboratory data. RESULTS: Male/female ratios were the same figure (0.13 for 1999 and 2004). The median age was significantly older in 2004 than in 1999 (59 years for 1999, 63 years for 2004, respectively, p<0.01). Jaundice and esophageal varices were found significantly less frequent in 2004 than in 1999 (p<0.01 for each item). Levels of total bilirubin,gamma-glutamyl transpeptidase (gamma-GTP), total cholesterol, and immunoglobulin M were significantly lower in 2004 than in 1999 (p< 0.02 for total bilirubin, and p<0.01 for other each item). The positive rate of antimitochondrial antibodies was significantly higher in 1999 than in 2004 (87.0% for 1999, 83.5% for 2004, respectively, p<0.01)). Complicated autoimmune diseases such as Sjögren's syndrome, rheumatoid arthritis, and chronic thyroiditis were found significantly more frequent in 2004 than in 1999 (p<0.01 for each item). CONCLUSIONS: Among the patients with PBC in 2004, an increase in median age, and lower levels of laboratory data such as gamma-GTP have been found compared to 1999. These results may show an accumulation of patients with better prognosis and the recent medical progress in controlling patients with PBC.J Epidemiol 2007; 17: 210-214.
18080123 Celecoxib inhibits production of MMP and NO via down-regulation of NF-kappaB and JNK in a 2008 Jun The purpose of this study was to examine the effects of celecoxib on matrix metalloproteinases (MMP-1 and MMP-3), nitric oxide (NO), and the phosphorylation of nuclear factor-kappaB (NF-kappaB) and three mitogen-activated protein kinases (MAPKs), (p38, JNK and ERK) in human articular chondrocytes from normal, osteoarthritis, and rheumatoid arthritis cartilages. Celecoxib at 100 nM reduced the IL-1beta-induced productions of MMP-1, MMP-3, iNOS, and NO, whereas indomethacin at 100 nM showed no effect. The additional stimulation of prostaglandin E2 (PGE2) failed to restore those productions, while the production of PGE2 were reduced by 1 and 10 microM but not 100 nM of celecoxib. The inhibitors of NF-kappaB, JNK and p38, but not ERK, decreased IL-1beta-enhanced MMP-1, MMP-3 and NO production, respectively, and 100 nM celecoxib down-regulated the phosphorylation of NF-kappaB and JNK but has no effect on either p38 or ERK. Celecoxib has inhibitory effects on MMP-1, MMP-3 and NO productions, suggesting the protective roles directly on articular chondrocytes. Despite the COX-2 selectivity, celecoxib affects those productions via not PGE2 but NF-kappaB and JNK MAPK.
18060614 [An unusual cause of recurrent chest pain in a highly trained recreational athlete]. 2007 Dec ANAMNESIS: Here, the case of a 48-year-old highly trained patient without classic myocardial risk factors is described who reported on frequent and recurrent angina pectoris. In a previous examination, the test for cardiac troponin T (cTnT) was slightly positive, however, cardiac examination including myocardial perfusion scintigraphy and coronary catheterization was without pathologic findings. Worth mentioning in the past medical history was a rheumatoid arthritis with persistent Raynaud's symptoms and hemoglobin as well as hematocrit levels in the upper normal range. EXAMINATIONS AND COURSE OF EVENTS: The patient reported that symptoms would occur most likely during long-term endurance exercise. Therefore, a bicycle ergometry with 180 W and open ending was performed. After 1.55 h, the patient complained of severe angina pectoris. The ECG showed massive ST segment elevations in II, III, and aVF (Figure 2). However, coronary catheterization showed no major stenosis or occlusion. Nevertheless, cTnT increased to 0.979 ng/ml. (Therefore, the reason for the symptomatic ST elevation was believed to be a myocardial tissue damage due to coronary vasospasm and the patient received an antivasospastic medication (amlodipine, atorvastatin, and acetylsalicylic acid [ASS]). After 6 months, the patient had a relapse during moderate physical activity. The ECG showed an ST segment depression in V(4) and V(5) while markers for myocardial tissue damage including cTnT were negative. A coronary CT angiography was performed that revealed a subtotal stenosis of the proximal LAD (Fig ure 3), which was successfully treated by angioplasty with subsequent stenting. In the course of further examinations, a polycythemia vera (JAK2-V617 mutation) was diagnosed as the cause for the high hemoglobin and hematocrit levels. Since then, the patient was without further events under a medication consisting of ASS, atorvastatin, candesartan, and intermittent phlebotomy. CONCLUSION: Although a relative weighting is difficult, it can be assumed that the combined effects of a polycythemia- associated hypercoagulability, an increased reagibility of the coronary arteries (aggravated by physical stress) as well as a hemoconcentration following prolonged exercise, could account for symptomatic recurrent minor thrombotic coronary events as well as the subtotal occlusion of the LAD. Obviously, this could not be prevented by a healthy lifestyle, regular physical activity, and the absence of classic coronary risk factors.
18059103 Frequency of abnormal thyroid function tests in Kuwaiti Arabs with autoimmune diseases. 2008 OBJECTIVES: The purpose of this study was to examine the frequencies of abnormal thyroid function tests and serum thyroid autoantibodies in healthy Kuwaitis and those with autoimmune diseases. SUBJECTS AND METHODS: Serum concentrations of sensitive thyrotropin, and free thyroxine were measured in 577 apparently healthy controls, 177 patients with rheumatoid arthritis (RA), 60 with systemic lupus erythematosus (SLE) and 25 with primary Sjogren's syndrome (pSS) using the immunochemiluminescent assay method on IMMULITE 1000. Serum microsomal and thyroglobulin autoantibodies were also measured by passive hemagglutination assay. For analysis of the thyroid function tests, the subjects were classified into five categories: normal, subclinical hypothyroidism, overt hypothyroidism, euthyroid sick syndrome and biochemical hyperthyroidism. RESULTS: Subclinical hypothyroidism was seen in 1.7% of healthy controls, 10.2% of RA, 13.3% of SLE, and 16% of pSS patients. Among RA patients, the frequency of subclinical hypothyroidism in females (11.4%) was significantly higher than among males (5.4%; p < 0.01). In SLE and pSS patients, all those with subclinical hypothyroidism were females. Overt hypothyroidism was seen in 1.4% of controls, 10.2% of RA, 8.3% of SLE, and 4% of pSS patients. Biochemical hyperthyroidism was seen in 0.2% of controls, 4.5% of RA, 5% of SLE and none of pSS patients. The euthyroid sick syndrome was seen in 0.4% of controls, 13.6% of RA, 16.7% of SLE and in none of pSS patients. Thyroid autoantibodies were present in 3.1% of controls, 12.4% of RA, 18.3% of SLE, and 12% of pSS patients. CONCLUSION: Our data show that abnormal thyroid function tests and thyroid autoantibodies occur frequently in Kuwaitis with autoimmune diseases. Therefore, ordering these tests in these diseases is recommended.
17186568 The pharmacological properties of anisodamine. 2007 Mar Anisodamine is a naturally occurring atropine derivative that has been isolated, synthesized and characterized by scientists in the People's Republic of China. Like atropine and scopolamine, anisodamine is a non-specific cholinergic antagonist exhibiting the usual spectrum of pharmacological effects of this drug class. It appears to be less potent and less toxic than atropine and displays less CNS toxicity than scopolamine. Anisodamine has been shown to interact with and disrupt liposome structure which may reflect its effects on cellular membranes. Experimental evidence implicates anisodamine as an anti-oxidant that may protect against free radical-induced cellular damage. Its cardiovascular properties include depression of cardiac conduction and the ability to protect against arrhythmia induced by various agents. Anisodamine is a relatively weak alpha(1) adrenergic antagonist which may explain its vasodilating activity. Its anti-thrombotic activity may be a result of inhibition of thromboxane synthesis. The T(1/2) of anisodamine in humans is about 2-3 h. Numerous therapeutic uses of anisodamine have been proposed including treatment of septic shock, various circulatory disorders, organophosphorus (OP) poisoning, migraine, gastric ulcers, gastrointestinal colic, acute glomerular nephritis, eclampsia, respiratory diseases, rheumatoid arthritis, obstructive jaundice, opiate addiction, snake bite and radiation damage protection. The primary therapeutic use of anisodamine has been for the treatment of septic shock. Several mechanisms have been proposed to explain its beneficial effect though most mechanisms are based upon the assumption that anisodamine ultimately acts by an improvement of blood flow in the microcirculation. Preliminary studies suggest another important therapeutic use of anisodamine is for the treatment of OP poisoning. Additional research is needed to delineate further the clinical usefulness of anisodamine relative to other anti-muscarinic drugs such as atropine and scopolamine.
17140435 Testing the proficiency to distinguish locations with elevated plantar pressure within and 2006 Dec 1 BACKGROUND: Identification of locations with elevated plantar pressures is important in daily foot care for patients with rheumatoid arthritis, metatarsalgia and diabetes. The purpose of the present study was to evaluate the proficiency of podiatrists, pedorthists and orthotists, to distinguish locations with elevated plantar pressure in patients with metatarsalgia. METHODS: Ten podiatrists, ten pedorthists and ten orthotists working in The Netherlands were asked to identify locations with excessively high plantar pressure in three patients with forefoot complaints. Therapists were instructed to examine the patients according to the methods used in their everyday clinical practice. Regions could be marked through hatching an illustration of a plantar aspect. A pressure sensitive platform was used to quantify the dynamic bare foot plantar pressures and was considered as 'Gold Standard' (GS). A pressure higher than 700 kPa was used as cut-off criterion for categorizing peak pressure into elevated or non-elevated pressure. This was done for both patient's feet and six separate forefoot regions: big toe and metatarsal one to five. Data were analysed by a mixed-model ANOVA and Generalizability Theory. RESULTS: The proportions elevated/non-elevated pressure regions, based on clinical ratings of the therapists, show important discrepancies with the criterion values obtained through quantitative plantar pressure measurement. In general, plantar pressures in the big toe region were underrated and those in the metatarsal regions were overrated. The estimated method agreement on clinical judgement of plantar pressures with the GS was below an acceptable level: i.e. all intraclass correlation coefficient's equal or smaller than .60. The inter-observer agreement for each discipline demonstrated worrisome results: all below .18. The estimated mutual agreements showed that there was virtually no mutual agreement between the professional groups studied. CONCLUSION: Identification of elevated plantar pressure through clinical evaluation is difficult, insufficient and may be potentially harmful. The process of clinical plantar pressure screening has to be re-evaluated. The results of this study point towards the merit of quantitative plantar pressure measurement for clinical practice.
16859308 Exploration of a binding mode of benzothiazol-2-yl acetonitrile pyrimidine core based deri 2006 Jul C-Jun N-terminal kinase (JNK) is a therapeutic target for inhibitors which may provide clinical benefit in the pathogenesis of rheumatoid arthritis (RA) as well as in various apoptosis-related disorders. The benzothiazol-2-yl acetonitrile derivatives, recently reported by Pascale et al. (J. Med. Chem. 2005, 48, 4596-4607), are the first generation JNK inhibitors of this class. To understand inhibitory mechanisms and elucidate pharmacophoric properties of these derivatives molecular docking and 3D-QSAR studies were performed on a set of 44 compounds. Ligand Fit module of Cerius2 (4.9) was employed to locate the binding orientations of all the compounds within the JNK-3 ATP binding site. A good correlation (r2=0.810) between the calculated binding free energies (-PMF score) and the experimental inhibitory activities suggests that the identified binding conformations of these potential inhibitors are reliable. Based on the binding conformations, robust and highly predictive 3D-QSAR models were developed with conventional r2 0.886 and 0.802, full cross-validation r2 0.980 and 0.788, and predictive r2 0.965 and 0.968 for MFA and MSA, respectively. The interaction mode was demonstrated taking into consideration inhibitor conformation, hydrogen bonding, and electrostatic interaction. The 3D-QSAR model built in this study will provide clear guidelines for a novel inhibitor design based on the benzothiazole derivatives against JNK-3 for the treatment of inflammatory disorders.
16755239 The incidence of fibromyalgia and its associated comorbidities: a population-based retrosp 2006 Jun BACKGROUND: The epidemiology of fibromyalgia is poorly defined. The incidence of fibromyalgia has not been determined using a large population base. Previous studies based on prevalence data demonstrated that females are 7 times more likely to have fibromyalgia than males and that the peak age for females is during the childbearing years. OBJECTIVE: We have calculated the incidence rate of fibromyalgia in a large, stable population and determined the strength of association between fibromyalgia and 7 comorbid conditions. METHODS: We conducted a retrospective cohort study of a large, stable health insurance claims database (62,000 nationwide enrollees per year). Claims from 1997 to 2002 were examined using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to identify fibromyalgia cases (ICD code 729.1) and 7 predetermined comorbid conditions. RESULTS: A total of 2595 incident cases of fibromyalgia were identified between 1997 and 2002. Age-adjusted incidence rates were 6.88 cases per 1000 person-years for males and 11.28 cases per 1000 person-years for females. Females were 1.64 times (95% confidence interval = 1.59-1.69) more likely than males to have fibromyalgia. Patients with fibromyalgia were 2.14 to 7.05 times more likely to have one or more of the following comorbid conditions: depression, anxiety, headache, irritable bowel syndrome, chronic fatigue syndrome, systemic lupus erythematosus, and rheumatoid arthritis. CONCLUSION: Females are more likely to be diagnosed with fibromyalgia than males, although to a substantially smaller degree than previously reported, and there are strong associations for comorbid conditions that are commonly thought to be associated with fibromyalgia.
16697465 A human monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF. 2007 Feb The pro-inflammatory cytokine GM-CSF is aberrantly produced in many autoimmune and chronic inflammatory human diseases. GM-CSF neutralization by antibodies has been shown to have a profound therapeutic effect in animal models of rheumatoid arthritis, inflammatory lung diseases, psoriasis and multiple sclerosis. Moreover, the absence of GM-CSF in null mutant mice ameliorates or prevents certain of these diseases. Here we describe the biophysical and biological properties of a human anti-GM-CSF IgG1 antibody designated MT203, which was derived by phage display guided selection. MT203 bound with picomolar affinity to an epitope on human and macaque GM-CSF involved in high-affinity receptor interaction. As a consequence, the antibody potently prevented both GM-CSF-induced proliferation of TF-1 cells with a sub-nanomolar IC50 value and the production of the chemokine IL-8 by U937 cells. MT203 neutralized equally well recombinant (r) human (h) GM-CSF from Escherichia coli and yeast, and also normally glycosylated GM-CSF secreted by human lung epithelial cells in response to IL-1beta stimulation. Furthermore, MT203 significantly reduced both survival and activation of peripheral human eosinophils as may be required for effective treatment of inflammatory lung diseases. The antibody did not show a detectable loss of neutralizing activity after 5 days in human serum at 37 degrees C. Based on its favorable properties, MT203 has been selected for development as a novel anti-inflammatory human monoclonal antibody with therapeutic potential in a multitude of human autoimmune and inflammatory diseases.
16571614 Lymphoid interstitial pneumonia: clinical features, associations and prognosis. 2006 Aug Lymphoid interstitial pneumonia (LIP) is rare and its clinical course incompletely described. The aim of this study was to examine the clinical features, associations and prognosis of surgical lung biopsy-proven LIP. The study group consisted of 15 subjects encountered over a 14-yr period. The majority of subjects were females (n = 11) and the mean age was 47 yrs (range 17-78 yrs). Underlying systemic immune disorders were frequent, including Sjögren's syndrome (n = 8), rheumatoid arthritis, systemic lupus erythematosus, polymyositis, common variable immunodeficiency and dysproteinaemia. Only three patients were classified as "idiopathic". Presenting symptoms were dominated by dyspnoea and cough. Restrictive physiology, reduced diffusion capacity (62.5+/-18.4% predicted) and bronchoalveolar lavage lymphocytosis (30.5+/-29.1% pred) were noted. Thirteen patients received corticosteroid therapy. Of the nine whose response could be assessed, four showed clinical improvement and four were stable. Overall, median survival was 11.5 yrs. Of the seven patients who died, respiratory problems were the primary cause of death in three. Conversion to lymphoma was not identified. In conclusion, histopathological lymphoid interstitial pneumonia is commonly associated with immune system dysregulation, with idiopathic lymphoid interstitial pneumonia being extremely rare. Clinical stability or improvement with corticosteroids can be expected; however, survival remains impaired.
16511916 Quinacrine but not chloroquine inhibits PMA induced upregulation of matrix metalloproteina 2006 Mar OBJECTIVE: Macrophages play an important role in rheumatoid arthritis (RA). RA is a disease characterized by the successive accumulation of leukocytes resulting in subsequent destruction of affected joints. Activation of matrix metalloproteinases (MMP) is essential for many physiological as well as many pathological events owing to the essential role of MMP in cell migration. We analyzed the effectiveness of quinacrine as an inhibitor of MMP activation in leukocytes and investigated the mode of action. METHODS: Leukocytes were isolated and treated with quinacrine with or without phorbol myristic acetate (PMA). ELISA and RT-PCR were used to monitor production of MMP-1, MMP-2, MMP-3, and MMP-8 at the mRNA and protein level. RESULTS: Quinacrine suppressed PMA induced MMP-1 release in mononuclear cells (MNC) in a dose- and time-dependent manner. RT-PCR showed that quinacrine downregulated induced as well as noninduced steady-state mRNA levels of MMP-1, MMP-2, and MMP-8, but had no effect on MMP-3. The observed inhibition was not due to effects of quinacrine on phospholipase A2 (PLA2) activity. Adding exogenous arachidonic acid to reconstitute the blocked PLA2 signaling pathways did not result in restoration of PMA induced mRNA transcription. CONCLUSION: Inhibition of MMP by quinacrine might, in part, account for its reported immunosuppressive action. Synthesizing more potent derivatives of quinacrine may be a means of suppressing undesired MMP activation.
16459351 Alterations in the phenotype and function of immune cells in ovariectomy-induced osteopeni 2006 Apr BACKGROUND: Within the last few years, much evidence has been presented on the involvement of the immune system in certain types of bone loss, such as activated T cells in rheumatoid arthritis and in periodontitis. Estrogen deficiency induces bone loss; however, how this deficiency affects the immune system has not been sufficiently studied. METHODS: To evaluate the effects of estrogen withdrawal on the status and functionality of the immune system, mice were ovariectomized or sham-operated, and 5 weeks after surgery, when osteopenia had developed, several parameters were analysed in spleen and in bone marrow. We analysed bone turnover, cell phenotype by flow cytometry, cell function by cell proliferation assays, and the expression of several genes related to the process. RESULTS: Five weeks after ovariectomy, augmented osteoclastogenesis persisted in the bone marrow. In addition, the ovariectomized mice had more B-cells and CD3+ T-cells expressing the receptor activator of NF-kappaB ligand (CD3+/RANKL+). The ovariectomized mice had lower serum alkaline phosphatase activity, a normal amount of T cells, lower percentages of CD11b+ and CD51+ cells in the bone marrow, and a lower serum interferon-gamma level compared with sham-operated controls. CONCLUSIONS: The data suggest that, 5 weeks after ovariectomy, bone turnover remains imbalanced, with increased osteoclastogenesis and a decreased rate of bone formation. Moreover, there is an increase in B-cell formation, with normal and decreased percentages of T cells and myelomonocytic cells (CD11b+), respectively, in the bone marrow. Decreased serum interferon-gamma levels could be involved in the increased osteoclastogenesis found in the present work.
18607537 IL-8 and p53 are inversely regulated through JNK, p38 and NF-kappaB p65 in HepG2 cells dur 2008 Jul OBJECTIVE: It is reported that Nuclear factor-kappaB (NF-kappaB) activation is dysregulated in chronic inflammatory diseases like psoriasis, rheumatoid arthritis and cancer, resulting in an over expression of pro-inflammatory cytokines and an inhibition of apoptosis. We studied NF-kappaB activation and the induction of interleukin 8 (IL-8) and p53 gene expression in an interleukin 1beta (IL-1beta) stimulated HepG2 cell line. METHODS: NF-kappaB induced IL-8 and p53 protein production was studied using specific siRNA, an IkappaB kinase 2 inhibitor, and mitogen activated protein kinase (MAPK) inhibitors. Results were analyzed by different techniques including Western blotting and ELISA. RESULTS: IL-1beta induced both the IL-8 and p53 mRNA expression and protein production of IL-8, but not p53. Knockdown of NF-kappaB p65 expression with siRNA strongly reduced IL-8 production and significantly induced protein levels of p53. An IkappaB kinase 2 inhibitor, sc514, also strongly reduced IL-8 and significantly induced p53 protein levels. Using three MAPK inhibitors we showed that p38 MAPK and JNK dependent mechanisms are involved in the regulation of the IL-8 and p53 protein expression. CONCLUSION: Our results indicate that IL-8 and p53 protein expression is regulated through inverse activation of the p38 MAPK and the JNK pathways and the NF-kappaB p65 expression.
20641579 (99m)Tc-Glucosamino-Asp-cyclo(Arg-Gly-Asp-D-Phe-Lys). 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. The 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 the 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. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied 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 cyclic RGD peptides are 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) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Jung et al. (13) reported the development of glucosamino (99m)Tc-D-c(RGDfK) that contains N-D-glucosamine as a sugar moiety for imaging α(v)β(3) receptors during tumor angiogenesis.
18836936 A case of lower lid ulcer secondary to reverse migration of silicone punctal plug. 2008 Silicone punctal plugs are effective and relatively safe method of managing keratoconjunctivitis sicca. We present a case where a silicone punctal plug migrated to cause aseptic necrosis of the surrounding tissue leading to a lid ulcer.
17557869 Specific testing for "isolated" anti-52 kDa SSA/Ro antibodies during standard anti-extract 2007 Jun AIM: To ascertain whether specific testing for "isolated" anti-52 kDa SSA/Ro antibodies (a-SSA/Ro52) during standard anti-extractable nuclear antigen (ENA) testing is clinically useful. METHODS: 1438 consecutive sera submitted for anti-ENA testing over 1 year were evaluated for a-SSA/Ro52 using various assays. RESULTS: 7 of 1438 (0.48%) patients were found to have a-SSA/Ro52 without SSA/Ro60 antibodies. Subsequent testing detected a further five patients. Clinical follow-up was possible in 10/12 patients. 2 of these 10 patients had evidence of primary Sjögren's syndrome (SS) and one had systemic lupus erythematosus (SLE), with sicca symptoms and abnormal Schirmer's tests. Five other patients had sicca symptoms, of which four had abnormal Schirmer's tests. CONCLUSIONS: "Isolated" anti-52 kDa SSA/Ro antibodies were detected in approximately 0.5% of standard anti-ENA requests, in which their presence was generally not associated with underlying SS or SLE. In view of the increased testing complexity and costs in detecting and confirming these antibodies, specific testing for isolated a-SSA Ro52 antibodies during standard anti-ENA testing seems to be of limited clinical value in a non-obstetric population.
18645441 Pseudomonas aeruginosa eyelid necrosis associated with Felty syndrome. 2008 Jul We describe a case of left upper eyelid necrosis due to Pseudomonas aeruginosa in a patient with Felty syndrome. This is a rare but potentially serious condition. In our patient, medical management and reconstructive surgery achieved a good outcome.