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ID PMID Title PublicationDate abstract
18485558 Astaxanthin inhibits cytotoxic and genotoxic effects of cyclophosphamide in mice germ cell 2008 Jun 27 Cyclophosphamide (CP), an alkylating agent used in the treatment of several cancers as well as an immunosuppressant in rheumatoid arthritis. It is used against several cancers due to its broad spectrum efficacy, but at the same time possesses unwanted risks for occupational exposure as well as therapy related toxicities to patients. The present study was aimed to investigate the protective effect of astaxanthin (AST) a red carotenoid pigment on CP induced germ cell toxicity in male mice. CP was administered intraperitoneally (i.p.) at the dose of 50, 100 and 200mg/kg body weight to mice (20-25 g) once in a week for a period of five weeks. AST was given at the dose of 25mg/kg per oral (p.o.) for five consecutive days in a week for five weeks. The animals were sacrificed one week after the last injection of CP. The protective effect of AST against CP induced male germ cell toxicity was evaluated using body weight, testes and epididymis weight, sperm count, sperm head morphology, sperm comet assay, histology of testes and TUNEL assay. AST treatment significantly improved the testes weight, sperm count and sperm head morphology as compared to only CP treated animals. The result of comet assay showed that AST treatment significantly restored the sperm DNA damage induced by CP. Further, AST treatment showed protection against CP induced testicular toxicity as evident from testes histology and TUNEL assay. The present results indicate the chemoprotective potential of AST against CP induced germ cell toxicity in mice.
18427724 Effect of alendronate on glucocorticoid-induced osteoporosis in Japanese women with system 2008 Glucocorticoids-induced osteoporosis is a serious problem for patients with systemic autoimmune disease requiring relatively long-term glucocorticoid treatment. Effectiveness of alendronate for the prevention of glucocorticoids-induced osteoporosis was evaluated in comparison with that of alfacalcidol in Japanese women with autoimmune disease excluding rheumatoid arthritis. Loss of bone mass was evaluated with bone mineral density (BMD) of lumber vertebrae, bone resorption was with urinary N-telopeptide for type I collagen (NTX), and bone formation was with serum bone-specific alkaline phosphatase (B-ALP). A total of 33 patients who were treated with oral glucocorticoids (>or=5 mg/day of prednisolone equivalence) for more than 6 months were randomized into two groups; alendronate group (n = 17) received 5 mg/day of alendronate, and alfacalcidol group (n = 16) received 1.0 mug/day of alfacalcidol for 24 months with glucocorticoids. The dose of alendronate was the maximal dose approved in Japan. BMD had tendency to decrease with alfacalcidol, while increase with alendronate. The difference in BMD change between the two groups was significant by 4.3% at 18 months and by 4.2% at 24 months (both P < 0.05). Bone resorption was significantly reduced only with alendronate; NTX was decreased by 28 to 35% at 6 to 24 months (P < 0.05), but not changed with alfacalcidol at 24 months. The bone formation was found to be unchanged according to the B-ALP measured between the two groups. In conclusion, the treatment of 5 mg alendronate daily is more effective than alfacalcidol for preventing the glucocorticoid-induced osteoporosis by the mechanism of reducing bone resorption in Japanese women with systemic autoimmune disease.
18273033 Association of LILRA2 (ILT1, LIR7) splice site polymorphism with systemic lupus erythemato 2008 Apr Leukocyte immunoglobulin-like receptors (LILRs) are inhibitory, stimulatory or soluble receptors encoded within the leukocyte receptor complex. Some LILRs are extensively polymorphic, and exhibit evidence for balancing selection and association with disease susceptibility. LILRA2 (LIR7/ILT1) is an activating receptor highly expressed in inflammatory tissues, and is involved in granulocyte and macrophage activation. In this study, we examined the association of LILRA2 and adjacently located LILRA1 with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and microscopic polyangiitis (MPA). Polymorphism screening detected a LILRA2 SNP (rs2241524 G>A) that disrupts splice acceptor site of intron 6. Case-control association studies on 273 Japanese SLE, 296 RA, 50 MPA and 284 healthy individuals revealed increase of genotype A/A in SLE (12.1%, odds ratio (OR) 1.82, 95% confidence interval (CI) 1.02-3.24, P=0.041) and in MPA (16.0%, OR 2.52, 95% CI 1.07-5.96, P=0.049) compared with healthy individuals (7.0%). The risk allele caused an activation of a cryptic splice acceptor site that would lead to a novel LILRA2 isoform lacking three amino acids in the linker region (Delta 419-421). Flow cytometry indicated that this isoform was expressed on the surface of monocytes. These findings suggested that LILRA2 Delta 419-421 isoform encoded by the splice site SNP may play a role in SLE and MPA.
18270925 [Drug-induced alveolitis associated with infliximab/azathioprine therapy]. 2008 Apr BACKGROUND: TNF-alpha is known to play a decisive role as a pro-inflammatory cytokine in several autoimmune conditions. Its neutralisation by TNF-alpha antagonists such as infliximab (Remicade), a chimeric monoclonal anti-TNF-alpha antibody, may be beneficial in patients with active disease. These anticytokine drugs have been approved and are being increasingly used in the therapy of rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriatic arthropathy and generalised psoriasis after established treatments have failed. Whenever therapy options are few, TNF-alpha antagonists are regarded as an effective, relatively safe and generally well-tolerated alternative, even if there is no detailed knowledge of their safety profile and possible long-term adverse events. In the respiratory tract an increased risk of viral, (myco-)bacterial, fungal and opportunistic infections has been observed. Furthermore, rare cases of severe fibrosing alveolitis in patients with concomitant immunosuppressant therapy or underlying lung disease have been reviewed recently. CASE: We present a case of drug-induced alveolitis following infliximab and azathioprine for the treatment of severe, generalised psoriasis and atopic eczema without pre-existing lung disease. Withdrawal of both drugs achieved clinical and functional stabilisation, and the addition of prednisolone resulted in a rapid improvement. CONCLUSION: As the pathophysiology of the pulmonary insult is unknown and since there are potentially serious adverse effects, we advise caution and close screening before and after initiation of TNF-alpha blockade, especially in patients with an underlying lung disease or with a combination of pneumotoxic agents.
18178718 CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through define 2008 Mar Recruitment of leukocytes to inflammatory sites is crucial in the pathogenesis of chronic inflammatory diseases. The aim of this study was to investigate if activation of CB2 cannabinoid receptors would modulate the chemotactic response of human monocytes. Human monocytes treated with the CB2 agonist JWH-015 for 12-18 h showed significantly reduced migration to chemokines CCL2 and CCL3, associated with reduced mRNA and surface expression of their receptors CCR2 and CCR1. The induction of ICAM-1 in response to IFN-gamma was inhibited by JWH-015. Moreover, JWH-015 cross-desensitized human monocytes for migration in response to CCL2 and CCL3 by its own chemoattractant properties. The CB2-selective antagonist SR-144528, but not the CB1 antagonist SR-147778, reversed JWH-015-induced actions, whereas the CB2 agonist JWH-133 mimicked the effects of JWH-015. The investigation of underlying pathways revealed the involvement of phosphatidylinositol 3-kinase/Akt and ERK1/2 but not p38 MAPK. In conclusion, selective activation of CB2 receptors modulates chemotaxis of human monocytes, which might have crucial effects in chronic inflammatory disorders such as atherosclerosis or rheumatoid arthritis.
18177501 Switch-like genes populate cell communication pathways and are enriched for extracellular 2008 Jan 4 BACKGROUND: Recent studies have placed gene expression in the context of distribution profiles including housekeeping, graded, and bimodal (switch-like). Single-gene studies have shown bimodal expression results from healthy cell signaling and complex diseases such as cancer, however developing a comprehensive list of human bimodal genes has remained a major challenge due to inherent noise in human microarray data. This study presents a two-component mixture analysis of mouse gene expression data for genes on the Affymetrix MG-U74Av2 array for the detection and annotation of switch-like genes. Two-component normal mixtures were fit to the data to identify bimodal genes and their potential roles in cell signaling and disease progression. RESULTS: Seventeen percent of the genes on the MG-U74Av2 array (1519 out of 9091) were identified as bimodal or switch-like. KEGG pathways significantly enriched for bimodal genes included ECM-receptor interaction, cell communication, and focal adhesion. Similarly, the GO biological process "cell adhesion" and cellular component "extracellular matrix" were significantly enriched. Switch-like genes were found to be associated with such diseases as congestive heart failure, Alzheimer's disease, arteriosclerosis, breast neoplasms, hypertension, myocardial infarction, obesity, rheumatoid arthritis, and type I and type II diabetes. In diabetes alone, over two hundred bimodal genes were in a different mode of expression compared to normal tissue. CONCLUSION: This research identified and annotated bimodal or switch-like genes in the mouse genome using a large collection of microarray data. Genes with bimodal expression were enriched within the cell membrane and extracellular environment. Hundreds of bimodal genes demonstrated alternate modes of expression in diabetic muscle, pancreas, liver, heart, and adipose tissue. Bimodal genes comprise a candidate set of biomarkers for a large number of disease states because their expressions are tightly regulated at the transcription level.
18072935 A conserved hydrogen-bond network in the catalytic centre of animal glutaminyl cyclases is 2008 Apr 1 QCs (glutaminyl cyclases; glutaminyl-peptide cyclotransferases, EC 2.3.2.5) catalyse N-terminal pyroglutamate formation in numerous bioactive peptides and proteins. The enzymes were reported to be involved in several pathological conditions such as amyloidotic disease, osteoporosis, rheumatoid arthritis and melanoma. The crystal structure of human QC revealed an unusual H-bond (hydrogen-bond) network in the active site, formed by several highly conserved residues (Ser(160), Glu(201), Asp(248), Asp(305) and His(319)), within which Glu(201) and Asp(248) were found to bind to substrate. In the present study we combined steady-state enzyme kinetic and X-ray structural analyses of 11 single-mutation human QCs to investigate the roles of the H-bond network in catalysis. Our results showed that disrupting one or both of the central H-bonds, i.e., Glu(201)...Asp(305) and Asp(248)...Asp(305), reduced the steady-state catalysis dramatically. The roles of these two COOH...COOH bonds on catalysis could be partly replaced by COOH...water bonds, but not by COOH...CONH(2) bonds, reminiscent of the low-barrier Asp...Asp H-bond in the active site of pepsin-like aspartic peptidases. Mutations on Asp(305), a residue located at the centre of the H-bond network, raised the K(m) value of the enzyme by 4.4-19-fold, but decreased the k(cat) value by 79-2842-fold, indicating that Asp(305) primarily plays a catalytic role. In addition, results from mutational studies on Ser(160) and His(319) suggest that these two residues might help to stabilize the conformations of Asp(248) and Asp(305) respectively. These data allow us to propose an essential proton transfer between Glu(201), Asp(305) and Asp(248) during the catalysis by animal QCs.
18063312 Localization of S100A8 and S100A9 expressing neutrophils to spinal cord during peripheral 2008 Jan Investigation of hyperalgesia at the spinal transcriptome level indicated that carrageenan-induced inflammation of rat hind paws leads to a rapid but sustained increase in S100A8 and S100A9 expression, two genes implicated in the pathology of numerous inflammatory diseases including rheumatoid arthritis and gout. In situ hybridization revealed that the elevation occurred in neutrophils that migrate to the spinal cord vasculature during peripheral inflammation, not in spinal neurons or glial cells. Immunohistochemical analysis suggests, but does not prove, that these neutrophils abundantly release S100A8 and S100A9. Consistent with this, we detected an increase in ICAM and VCAM, both indicators of endothelial activation, a known trigger for secretion of S100A8 and S100A9. Migration of S100A8- and S100A9-expressing neutrophils to spinal cord is selective, since MCP-1- and CD68-expressing leukocytes do not increase in spinal cord vasculature during hind paw inflammation. Examination of many neutrophil granule mediators in spinal cord indicated that they are not regulated to the same degree as S100A8 and S100A9. Neutrophil migration also occurs in the vasculature of brain and pituitary gland during peripheral inflammation. Together, these findings suggest an interaction between a subpopulation of leukocytes and the CNS during peripheral tissue inflammation, as implied by an apparent release and possible diffusion of S100A8 and S100A9 through the endothelial blood-brain barrier. Although the present findings do not establish the neurophysiological or behavioral relevance of these observations to nociceptive processing, the data raise the possibility that selective populations of leukocytes may communicate the presence of disease or tissue damage from the periphery to cells in the central nervous system.
18060853 Prostaglandin E2 inhibits tumor necrosis factor-alpha RNA through PKA type I. 2008 Feb 1 Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that may contribute to the pathogenesis of septic shock, rheumatoid arthritis, cancer, and diabetes. Prostaglandins endogenously produced by macrophages act in an autocrine fashion to limit TNF-alpha production. We investigated the timing and signaling pathway of prostaglandin-mediated inhibition of TNF-alpha production in Raw 264.7 and J774 macrophages. TNF-alpha mRNA levels were rapidly modulated by PGE(2) or carbaprostacylin. PGE(2) or carbaprostacyclin prevented and rapidly terminated on-going TNF-alpha gene transcription within 15 min of prostaglandin treatment. Selective activation of PKA type I, but not PKA type II or Epac, with chemical analogs of cAMP was sufficient to inhibit LPS-induced TNF-alpha mRNA levels. The mechanisms by which prostaglandins limit TNF-alpha mRNA levels may underlie endogenous regulatory mechanisms that limit inflammation, and may have important implications for understanding chronic inflammatory disease pathogenesis.
18059282 PPAR-gamma regulates osteoclastogenesis in mice. 2007 Dec Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis. Although peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to inhibit osteoblast differentiation, its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR-gamma agonists, "such as thiazolidinediones-" a class of insulin-sensitizing drugs, have been reported to cause a higher rate of fractures in human patients. Here we have uncovered a pro-osteoclastogenic effect of PPAR-gamma by using a Tie2Cre/flox mouse model in which PPAR-gamma is deleted in osteoclasts but not in osteoblasts. These mice develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. These defects are the result of impaired osteoclast differentiation and compromised receptor activator of nuclear factor-kappaB ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR-gamma by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR-gamma functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis. Therefore, PPAR-gamma and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption.
17878796 A clinicoradiologic study of the shoulder in Apert syndrome. 2007 Oct To provide a comprehensive radiographic, clinical, and functional description of the shoulder in Apert syndrome. METHODS: A cohort of 9 Apert syndrome patients (ages, 9-27 years) followed at a tertiary care facility was included in this prospective study. Patients were clinically assessed with physical examination and completion of 2 validated functional assessment tools, the Shoulder Pain and Disability Index (SPADI) and American Academy of Orthopaedic Surgeons Pediatric Outcomes Data Collection Instrument (AAOS PODCI). Radiographs were obtained of both shoulders, and standardized-protocol magnetic resonance imaging was performed on the dominant shoulder of all participants. RESULTS: All patients had some degree of functional impairment attributable to their shoulder pathologic abnormality. Physical examination consistently revealed reduced forward flexion and abduction. Radiographic findings were similar to previous reports, with pervasive osseous dysplasia of the shoulder joint. Medial humeral head hypoplasia was seen in 8 of 9 patients and greater tuberosity overgrowth in 7 of 9 patients. Magnetic resonance imaging of the shoulder, not previously performed in a cohort of Apert patients, allowed better delineation of abnormalities seen radiographically such as a central glenoid cleft seen in 8 of 9 patients. It also revealed a new finding of inferior glenoid inclination (7/9 patients) that has not been described in the literature. Very few soft tissue or degenerative abnormalities were demonstrated. CONCLUSIONS: The findings of this study confirm that patients with Apert syndrome are functionally impaired by their shoulder pathologic abnormality, which may have a similar clinical impact as the more well-described hand and foot anomalies. The global functioning of patients with Apert syndrome is equivalent to patients with juvenile rheumatoid arthritis. The shoulder range of motion in Apert patients is decreased, most significantly in flexion and abduction. Radiographs confirmed previous imaging findings of glenohumeral dysplasia. The novel magnetic resonance imaging component demonstrated consistent inferior glenoid inclination, which may be a significant factor in their shoulder impairment. Magnetic resonance imaging revealed no significant soft tissue or degenerative abnormalities to account for their clinical disability. These findings have potential relevance in the surgical and clinical management of these patients. LEVEL OF EVIDENCE: Level IV.
17785287 Standardization of autoimmune diagnostics in Germany: activities of the German group in th 2007 Aug The German Regional Group of EASI was established during the annual Meeting of the German Society of Immunology in Kiel in September 2005. Since this initial informative meeting, an active core group of about a dozen rheumatologists, immunologists, and laboratory specialists has been generating starter projects. In general, these projects do focus on clinically associated diagnostic questions, and do integrate a variety of specialists with profound knowledge in several related subjects. The aims of the German EASI group are to contribute to the definition of standards and to improve patient care. Therefore, the group is establishing guidelines for the diagnosis of autoimmune diseases, to standardize and improve their quality, combining the experience of clinical and laboratory specialists. The diagnostic activities focus currently on systemic lupus erythematosus (SLE) and on rheumatoid arthritis. These activities include laboratory investigations and diagnosis through clinical manifestations. Standardized diagnostics cannot be based solely on vague symptoms and positive laboratory tests. In laboratory diagnostics, standardization and implementation of objective methods for the detection of autoantibodies has been identified as a central challenge. Here, immune fluorescence techniques and the evaluation of RibP are used as first parameters that could improve SLE diagnostics. Furthermore, guidelines and proposals from scientific medical organizations, and in particular from other national EASI groups will be adapted to the German health system. A cornerstone of implementation is the identification and logistic preparation of existing serum banks, the definition of gaps that should be bridged, and, particularly, the definition and collection of adequate control groups. Through these measures, the German EASI group will provide a standardized diagnostic model of autoimmune disorders throughout Europe starting in the field of rheumatology. Diagnostics may become more rational, efficient, faster, and cost-efficient. Patients with autoimmune rheumatic disorders will profit from receiving an earlier and more accurate diagnosis, which again will allow earlier therapeutic intervention and lead to a better long-term clinical outcome.
17336692 Interleukin-18 and the pathogenesis of inflammatory diseases. 2007 Jan Several autoimmune diseases are thought to be mediated in part by interleukin (IL)-18. Many are those with associated increased interferon-gamma (IFNgamma) levels such as systemic lupus erythematosus, macrophage activation syndrome, rheumatoid arthritis, Crohn's disease, psoriasis, and graft-versus-host disease. In addition, ischemia, including acute renal failure in human beings, appears to involve IL-18. Animal studies also support the concept that IL-18 is a key player in models of lupus erythematosus, atherosclerosis, graft-versus-host disease, and hepatitis. Unexpectedly, IL-18 plays a role in appetite control and the development of obesity. IL-18 is a member of the IL-1 family; IL-1beta and IL-18 are related closely, and both require the intracellular cysteine protease caspase-1 for biological activity. The IL-18 binding protein, a naturally occurring and specific inhibitor of IL-18, neutralizes IL-18 activities and has been shown to be safe in patients. Other options for reducing IL-18 activities are inhibitors of caspase-1, human monoclonal antibodies to IL-18, soluble IL-18 receptors, and anti-IL-18 receptor monoclonal antibodies.
17316606 The neuronal 5-HT3 receptor network after 20 years of research--evolving concepts in manag 2007 Mar 29 The 5-HT3 receptor is a pentameric ligand-gated cation channel which is found in the central and peripheral nervous system and on extraneuronal locations like lymphocytes, monocytes and fetal tissue. Five monomer subtypes, the 5-HT(3A-E) subunits, have been identified which show differences in the amino-terminal and the transmembrane region. The functional relevance of different receptor compositions is not yet clarified. 5-HT3 receptors are located predominantly in CNS regions that are involved in the integration of the vomiting reflex, pain processing, the reward system and anxiety control. The preferential localization on nerve endings is consistent with a physiological role of 5-HT3 receptors in the control of neurotransmitter release such as dopamine, cholecystokinin, glutamate, acetylcholine, GABA, substance P, or serotonin itself. 5-HT3-receptor agonists cause unpleasant effects like nausea and anxiety, and no clinical use has been considered. In contrast, the introduction of 5-HT3-receptor antagonists for chemotherapy-induced vomiting was extremely successful. After development of other gastrointestinal indications like postoperative vomiting and diarrhea-predominant irritable bowel syndrome recent research focuses on rheumatological indications such as fibromyalgia, rheumatoid arthritis and tendinopathies. Positive effects have also been observed for pain syndromes such as chronic neuropathic pain and migraine. These effects seem to be related to substance P-mediated inflammation and hyperalgesia. Furthermore, antiinflammatory and immunomodulatory properties have been observed for 5-HT3-receptor antagonists which might explain promising findings in systemic sclerosis and other immunological conditions. For all of these innovative indications the optimal dosing schedule is a crucial issue, since a bell-shaped dose-response curve has been observed repeatedly for 5-HT3-receptor antagonists, particularly in CNS effects.
17261796 Estrogens and autoimmune diseases. 2006 Nov Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors . Several physiological, pathological, and therapeutic conditions may change the serum estrogen milieu and/or peripheral conversion rate, including the menstrual cycle, pregnancy, postpartum period, menopause, being elderly, chronic stress, altered circadian rhythms, inflammatory cytokines, and use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. In particular, cortisol and melatonin circadian rhythms are altered, at least in rheumatoid arthritis (RA), and partially involve sex hormone circadian synthesis and levels as well. Abnormal regulation of aromatase activity (i.e., increased activity) by inflammatory cytokine production (i.e., TNF-alpha, IL-1, and IL-6) may partially explain the abnormalities of peripheral estrogen synthesis in RA (i.e., increased availability of 17-beta estradiol and possible metabolites in synovial fluids) and in systemic lupus erythematosus, as well as the altered serum sex-hormone levels and ratio (i.e., decreased androgens and DHEAS). In the synovial fluids of RA patients, the increased estrogen concentration is observed in both sexes and is more specifically characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, which is a mitogenic and cell proliferative endogenous hormone. Local effects of sex hormones in autoimmune rheumatic diseases seems to consist mainly in modulation of cell proliferation and cytokine production (i.e., TNF-alpha, Il-1, IL-12). In this respect, it is interesting that male patients with RA seem to profit more from anti-TNFalpha strategies than do female patients.
17220825 Steroid-induced ptosis: case studies and histopathologic analysis. 2008 Apr PURPOSE: The purpose of this study was to review patients who developed ptosis after subtenon's steroid injection and to study the mechanism of steroid-induced ptosis in an animal model. METHODS: Part 1. Twenty-two patients with uveitis who had received posterior subtenon's triamcinolone acetonide injections were retrospectively reviewed. Demographics, type of uveitis, type and number of surgeries, pre and postoperative marginal reflex distance (MRD1), and clinical outcomes were evaluated. Part 2. Study of rabbit levator muscle and aponeurosis histopathology after subtenon's triamcinolone injection was performed. RESULTS: Part 1. The average age was 44.6 years (range: 14-85 years) with a mean follow-up of 14 months. The most common causes of uveitis included uveitis after cataract extraction (five), pars planitis (three), multifocal choroiditis (three), and juvenile rheumatoid arthritis (three). The average time to documented onset of ptosis was 13.9 months (range: 0-49 months). In patients who received only one steroid injection, the average time to ptosis recorded was 2.7 months (range: 0-6 months). Seventeen patients underwent ptosis repair. Part 2. No ptosis was noted in the experimental and control groups. Histopathologic analysis of levator tissues revealed no significant difference in atrophy or degree of inflammation between experimental and control groups. CONCLUSIONS: Ptosis following subtenon's steroid injection ranged from mild to moderate and occurred a few months after steroid injection. Prior studies of muscles and periocular tissues exposed to corticosteroids demonstrated degenerative muscle changes; our studies revealed no histopathologic changes in the levator muscle or aponeurosis.
16968406 Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppre 2006 Oct Macrophages/monocytes and the proinflammatory mediators, such as tumour necrosis factor (TNF)-alpha, prostaglandin E(2) (PGE(2)), macrophage inflammatory protein (MIP)-1alpha and MIP-1alpha, play a critical role in the progression of immunological disorders including rheumatoid arthritis, Behçet's disease and Crohn's disease. In addition, the nicotinic acetylcholine receptor-alpha7 (alpha7nAChR) subunit is an essential regulator of inflammation. In this study, we evaluated the expression of the alpha7nAChR subunit on human peripheral monocytes and the effect of nicotine on the production of these proinflammatory mediators by activated monocytes. Fluorescein isothiocyanate (FITC)-labelled alpha-bungarotoxin demonstrated the cell surface expression of the alpha7nAchR subunit. Pretreatment with low-dose nicotine caused inhibition of TNF-alpha, PGE(2), MIP-1alpha and MIP-1alpha production, and mRNA expression of TNF-alpha, MIP-1alpha and MIP-1alpha and COX-2 in lipopolysaccharide (LPS)-activated monocytes. These suppressive effects of nicotine were caused at the transcriptional level and were mediated through alpha7nAChR. Nicotine suppressed the phosphorylation of I-kappaB, and then inhibited the transcriptional activity of nuclear factor-kappaB. These immunosuppressive effects of nicotine may contribute to the regulation of some immune diseases.
16855132 Sequence variants of the CRH 5'-flanking region: effects on DNA-protein interactions studi 2006 Jun Recently, studies in adult rheumatoid arthritis patients have shown an association with four single-nucleotide polymorphisms (SNPs) in the 3.7-kb regulatory region of human corticotropin-releasing hormone (hCRH) gene located at positions -3531, -3371, -2353, and -684 bp. Three of these novel polymorphisms are in absolute linkage disequilibrium, resulting in three combined alleles, named A1B1, A2B1, and A2B2. To study whether the described polymorphic nucleotide sequences in the 5' region of the hCRH gene interfere with binding of nuclear proteins, an electric mobility shift assay (EMSA) was performed. At position -2353 bp, a specific DNA protein complex was detected for the wild-type sequence only, possibly interfering with a binding site for the activating transcription factor 6 (ATF6). In contrast, no difference could be detected for the other SNPs. However, at position -684, a quantitative difference in protein binding due to cAMP incubation could be observed. To further investigate whether these SNPs in the CRH promoter are associated with an altered regulation of the CRH gene, we performed a luciferase reporter gene assay with transiently transfected rat pheochromocytoma cells PC12. Incubation with 8-Br-cAMP alone or in combination with cytokines enhanced significantly the promoter activity in PC12 cells. The promoter haplotypes studied exhibited a differential capacity to modulate CRH gene expression. In all our experiments, haplotype A1B1 showed the most pronounced influence on promoter activity. Taken together, our results demonstrate a differential binding capacity of nuclear proteins of the promoter polymorphisms resulting in a different gene regulation. Most probably the SNP at position -2,353 plays a major role in mediating these differences.
16799886 Oral dimethyl sulfoxide for systemic amyloid A amyloidosis complication in chronic inflamm 2006 May BACKGROUND: Amyloid A amyloidosis is an obstinate disease complication in chronic inflammatory disease, and there are few effective therapies. The objective of this study was to investigate the effect of oral dimethyl sulfoxide (DMSO) on amyloid A amyloidosis. METHODS: Fifteen secondary amyloid A amyloidosis patients (4 men, 11 women; age, 23-70 years) were treated with DMSO between 1995 and 2003. DMSO was administered orally in all patients at a dose of 3-20 g/day. The clinical symptoms together with the renal and gastrointestinal functions were evaluated before and after treatment. RESULTS: Among the 15 patients, amyloid A amyloidosis was a complication of rheumatoid arthritis (RA) in 10, of Crohn's disease in 4, and of Adult Still's disease in 1. Nine cases mainly involved the kidney, with renal dysfunction and proteinuria, five mainly involved the gastrointestinal tract, with protein-losing gastroenteropathy and intractable diarrhea, and one involved both gastrointestinal and renal amyloidosis. DMSO treatment was successful in 10 (66.7%) of the 15 patients (RA, 6/10; Crohn's disease, 4/4; Adult Still's disease, 0/1). Eight weeks of DMSO administration improved the renal function and proteinuria in five out of ten renal amyloidosis patients, but had no effect on those patients with severe and/or advanced renal dysfunction. With regard to gastrointestinal amyloidosis, gastrointestinal symptoms, including diarrhea and protein-losing gastroenteropathy, were improved in six patients. No serious side effects were encountered with the DMSO treatment. CONCLUSIONS: Oral administration of DMSO is an effective treatment for amyloid A amyloidosis, especially for gastrointestinal involvement and the early stage of renal dysfunction.
16717269 Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. 2006 May 23 BACKGROUND: Chronic noncancer pain (CNCP) is a major health problem, for which opioids provide one treatment option. However, evidence is needed about side effects, efficacy, and risk of misuse or addiction. METHODS: This meta-analysis was carried out with these objectives: to compare the efficacy of opioids for CNCP with other drugs and placebo; to identify types of CNCP that respond better to opioids; and to determine the most common side effects of opioids. We searched MEDLINE, EMBASE, CENTRAL (up to May 2005) and reference lists for randomized controlled trials of any opioid administered by oral or transdermal routes or rectal suppositories for CNCP (defined as pain for longer than 6 mo). Extracted outcomes included pain, function or side effects. Methodological quality was assessed with the Jadad instrument; analyses were conducted with Revman 4.2.7. RESULTS: Included were 41 randomized trials involving 6019 patients: 80% of the patients had nociceptive pain (osteoarthritis, rheumatoid arthritis or back pain); 12%, neuropathic pain (postherpetic neuralgia, diabetic neuropathy or phantom limb pain); 7%, fibromyalgia; and 1%, mixed pain. The methodological quality of 87% of the studies was high. The opioids studied were classified as weak (tramadol, propoxyphene, codeine) or strong (morphine, oxycodone). Average duration of treatment was 5 (range 1-16) weeks. Dropout rates averaged 33% in the opioid groups and 38% in the placebo groups. Opioids were more effective than placebo for both pain and functional outcomes in patients with nociceptive or neuropathic pain or fibromyalgia. Strong, but not weak, opioids were significantly superior to naproxen and nortriptyline, and only for pain relief. Among the side effects of opioids, only constipation and nausea were clinically and statistically significant. INTERPRETATION: Weak and strong opioids outperformed placebo for pain and function in all types of CNCP. Other drugs produced better functional outcomes than opioids, whereas for pain relief they were outperformed only by strong opioids. Despite the relative shortness of the trials, more than one-third of the participants abandoned treatment.