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ID PMID Title PublicationDate abstract
21214903 Salivary glands of primary Sjögren's syndrome patients express factors vital for plasma c 2011 Jan 7 INTRODUCTION: The presence of circulating Ro/SSA and La/SSB autoantibodies has become an important marker in the classification criteria for primary Sjögren's syndrome (pSS). Plasma cells producing these autoantibodies are mainly high affinity plasma cells originating from germinal centre reactions. When exposed to the right microenvironment these autoimmune plasma cells become long-lived and resistant to immunosuppressive treatment. Since autoimmune plasma cells have been detected in the salivary glands of SS patients, we wanted to investigate if the glandular microenvironment is suitable for plasma cell survival and if glandular residing plasma cells are the long-lived plasma cell subset. METHODS: Single, double and triple immunohistochemistry as well as immunofluorescence staining was performed on minor salivary gland tissue retrieved from pSS, chronically inflamed and normal subjects. RESULTS: We detected significant numbers of CD138+, non-proliferating, Bcl-2 expressing plasma cells in the salivary glands of pSS patients with high focus score (FS). Furthermore, we demonstrated that CXCL12 and interleukin (IL)-6 survival factors were highly expressed in pSS salivary gland epithelium and by focal mononuclear infiltrating cells. Notably, adipocytes when present in the salivary gland tissue were an important source of CXCL12. We clearly demonstrate that plasma cells are localised in close proximity to CXCL12 and IL-6 expressing cells and thus that the environment of salivary glands with high FS provide factors vital for plasma cell survival. CONCLUSIONS: Plasma cells residing in the salivary glands of pSS patients with high FS showed phenotypic characteristics of the long-lived plasma cell subtype. Furthermore, the pSS salivary gland microenvironment provided niches rich in factors vital for plasma cell survival.
23153748 Parotid space: anatomic imaging. 2012 Dec The authors present imaging anatomy of the parotid space and discuss non-neoplastic lesions, autoimmune disorders, cysts, neoplastic lesions, epithelial tumors, and nonepithelial lesions. They describe the diseases and their appearance on imaging, describing how the differential diagnoses appear, along with presenting examples of the images, primarily computed tomography and magnetic resonance imaging.
22740247 Successful treatment of osteomalacia caused by renal tubular acidosis associated with Sjö 2013 Mar A 62-year-old woman was diagnosed with severe osteomalacia caused by renal tubular acidosis associated with Sjögren's syndrome. She was treated with sodium bicarbonate, risedronate, alfacalcidol, and prednisolone (1 mg/kg). By 24 months, renal tubular acidosis was improved and the bone density had normalized. Here we report the successful amelioration of bone lesions through a multidisciplinary approach that improved renal tubular acidosis, with a special focus on treatment of the underlying inflammatory disorder with glucocorticoids.
21889967 Autoimmune and inflammatory mechanisms of CNS damage. 2011 Nov Brain morphology and function are susceptible to various psysiological influences, including changes in the immune system. Inflammation and autoimmunity are two principal immunological responses that can compromise the function of multiple organs and tissues, including the central nervous system. The present article reviews clinical and experimental evidence pointing to structural brain damage induced by chronic autoimmune and/or inflammatory processes. Largely due to the vast complexity of neuroendocrine and immune systems, most of the principal pathogenic circuits are far from elucidated. In addition to summarizing the current knowledge, this article aims to highlight the importance of interdisciplinary research and combined efforts of physicians and scientists in revealing the intricate links between immunity and mental health.
21986780 The "MESACA" study: methylsulfonylmethane and boswellic acids in the treatment of gonarthr 2011 Oct INTRODUCTION: Osteoarthritis is a chronic rheumatoid disease mediated by metalloproteinases and inflammatory cytokines. Methylsulfonylmethane (MSM) and boswellic acids (BA) each show promise in the treatment of inflammatory processes, but the efficacy of combined treatment with these substances in the treatment of arthritis has not yet been studied. METHODS: In this prospective randomized clinical trial, MESACA (for "methylsulfonylmethane and boswellic acids in the treatment of knee arthritis"), 60 subjects affected by arthritis of the knee were randomly assigned to an experimental group treated for 60 days with 5 g of MSM and 7.2 mg of BA daily, or a control group which was administered a placebo. At 2 and 6 months follow-up (FU), the efficacy of combined treatment with these two dietary supplements was assessed using the visual analog pain scale (VAS) and the Lequesne index (LI) for joint function, as well as monitoring the use of anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs and anti-cyclooxygenase-2). RESULTS: Pain, assessed with the VAS scale, was worse in the group treated with MSM and BA as compared with the placebo group at 2 months FU (3.8 vs. 2.7; P=0.04), whereas no difference between the two groups was observed at 6 months FU (2.7 vs. 3.6; P=0.2). No statistically significant differences were found in the LI between the two groups at either FU (2 months: 4.8 vs. 4.2; P=0.51; 6 months: 4.4 vs. 4.5; P=0.91). By contrast, a statistically significant difference in patients need for anti-inflammatory drugs was seen in the experimental as compared to the placebo group, even by 2 months FU (0.2 vs. 0.6 tablets/day; P<0.0001), that persisted up to the end of the study (0.1 vs. 0.6 tablets/day; P<0.0001). CONCLUSIONS: Although the combined administration of MSM and BA in the treatment of gonarthrosis was not shown to be more efficacious than placebo in the management of the clinical and functional picture, it significantly reduced patients need for anti-inflammatory drugs.
21989653 Selective up-regulation of the soluble pattern-recognition receptor pentraxin 3 and of vas 2012 Mar OBJECTIVE: To assess local expression and plasma levels of pentraxin 3 (PTX3) in patients with giant cell arteritis (GCA). METHODS: Plasma and serum samples were obtained from 75 patients with GCA (20 of whom had experienced optic nerve ischemia in the previous 3 weeks and 24 of whom had experienced symptom onset in the previous 6 months and had no history of optic nerve ischemia) and 63 controls (35 age-matched healthy subjects, 15 patients with rheumatoid arthritis, and 13 patients with chronic stable angina). In 9 patients in whom GCA was recently diagnosed, circulating levels of interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12p70, CCL2/monocyte chemotactic protein 1, CCL3/macrophage inflammatory protein 1α (MIP-1α), CCL4/MIP-1β, CCL11/eotaxin, CXCL9/monokine induced by interferon-γ, CXCL10/interferon-γ-inducible 10-kd protein, tumor necrosis factor α (TNFα), interferon-γ, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor, and FasL were measured via a multiplexed cytometric assay. PTX3 and VEGF concentrations were assessed by enzyme-linked immunosorbent assay. PTX3 and CD68 expression were determined by immunohistochemistry and immunofluorescence on temporal artery samples. RESULTS: GCA patients with very recent optic nerve ischemia had significantly higher PTX3 and VEGF levels compared to other GCA patients and controls. GCA patients with a disease duration of <6 months had significantly higher PTX3 levels compared to other GCA patients and controls. Immunohistochemistry revealed selective PTX3 expression in the wall of inflamed arteries. CONCLUSION: Our findings indicate that local expression of PTX3 is a feature of vascular inflammation in GCA; elevated circulating levels of PTX3 identify patients with very recent optic nerve ischemia or a recent diagnosis. Optic nerve ischemia is also associated with increased circulating VEGF levels.
23253850 Implant location and radiotherapy are the only factors linked to 2-year implant failure. 2012 Sep SUBJECTS: The subjects in this retrospective case series were derived from a review of 700 patient files within the implant practice of the Department of Periodontology, University Hospital, Catholic University of Leuven. Inclusion criteria were met by 412 patients (240 females, 172 males) receiving a total of 1514 Nobel Biocare dental implants. These patients were included based on data availability for the time period 2 years after abutment surgery (considered to represent late implant failure). KEY EXPOSURE/STUDY FACTOR: Given the concern of the authors to assess the probability of late implant failure among clinic patients with certain local and systemic factors, the potential factors were multiple. The local factors included the following: implant length and diameter, bone quality and quantity, insertion site, type of edentulism, antibiotic use perioperatively, dehiscence and/or perforation of the site during surgery, and stability at insertion (measured by Periotest values). The related health and behavioral factors included the following: medications, smoking (<10 cigarettes/day, 10-20 cigarettes/day, >20 cigarettes/day), hypertension, ischemic cardiac problems, coagulation anomalies, gastric ulcers, thyroid disorders, hypercholesterolemia, rheumatoid arthritis, asthma, diabetes (types 1 and 2), Crohn's disease, and chemotherapy. MAIN OUTCOME MEASURE: The primary outcome was described as "late implant failure." The current study, which follows a similar study on early implant failure,(1) aims to identify negative influences on maintenance of integration. The authors used the clinical experience related to the 412 patients with 1514 implants to identify whether the observed failure rates were influenced by local and systemic factors. Failure was defined as "late" when occurring between abutment connection surgery and 2 years after this date. Patients/implants that were not available for this interval of time were not included. However, even when records were available, not all patient records provided all data sought. MAIN RESULTS: Regarding local factors, the authors reported that implant diameter and location were relevant to late implant loss, whereas implant length was not (P value = .01, = .34, respectively; univariate generalized estimating equation [GEE] logistic regression). Regarding implant diameter, significantly more loss was noted for 5.00-mm implants when compared with the 4.00-mm or 4.75-mm implants. Failure related to location revealed that the maxilla compared with the mandible, posterior jaws compared with anterior jaws, and the posterior maxilla compared with all other oral locations were associated with more late failures (Table 1). Assessment of systemic factors revealed radiotherapy to be related to more late implant loss (P = .003). Neither systemic disease nor smoking exposure was associated with late failure. CONCLUSIONS: The authors concluded that late implant failure was influenced by the local factor "implant location" and the systemic factor "radiotherapy." Neither smoking nor systemic health factors were found to adversely influence implant integration from abutment connection through 2 years' performance.
23219581 Evaluation of the new anti-inflammatory compound ethyl salicylate 2-O-β-D-glucoside and i 2013 Feb Ethyl salicylate 2-O-β-d-glucoside (ESG) is a derivative of natural salicylate isolated from Gaultheria yunnanensis (Franch.) Rehder, it has been used for the treatments of rheumatoid arthritis, swelling and pain. The aim of this study was to evaluate the anti-inflammatory effects of ESG and explore the anti-inflammatory mechanisms. We found that ESG had potent anti-inflammatory effects on the lipopolysaccharide (LPS)-activated murine macrophages RAW264.7. ESG exerted a dose-dependent inhibition of the LPS-stimulated release of the pro-inflammatory cytokines TNF-α and IL-1β. Moreover, it significantly inhibited LPS-stimulated the production of NO and PGE2 by repressing the expression of iNOS and COX protein respectively. Western blot analysis showed that ESG prominently inhibited LPS-induced activation of NF-κB in RAW264.7 cells by blocking phosphorylation of inhibitor IκBα and p65. Consistent with these results, we found that ESG prevented the nuclear translocation of NF-κB induced by LPS. Our study suggests that ESG may be effective in the treatment of inflammatory diseases by inhibiting the pro-inflammatory cytokine production and regulating the NF-κB signal pathway.
23216412 Comparison of gastroduodenal ulcer incidence in healthy Japanese subjects taking celecoxib 2013 Feb BACKGROUND: Although nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed globally, their chronic use increases the risk of upper gastrointestinal (GI) damage. Cyclooxygenase-2-selective NSAIDs are considered to reduce this risk. Current guidelines in Japan recommend loxoprofen sodium (loxoprofen), a pro-drug in the propionic acid class of nonselective NSAIDs, as first-line therapy in rheumatoid arthritis. AIM: To confirm the superiority of celecoxib, a cyclooxygenase-2-selective NSAID, to loxoprofen in the incidence of gastroduodenal (GD) endoscopic ulcers. METHODS: A randomised, multicentre, placebo-controlled, double-blind, phase IV clinical trial in healthy Japanese volunteers [mean age 57.5 (range: 40-74) years; >70% female], stratified by Helicobacter pylori status at screening (~40% positive) and randomised 2:2:1 to receive celecoxib 100 mg b.d., loxoprofen 60 mg t.d.s. or placebo. Primary end point was incidence of any GD endoscopic ulcers after 2 weeks of treatment. RESULTS: Of 190 randomised subjects, 189 received at least one dose of celecoxib (n = 76), loxoprofen (n = 76), or placebo (n = 37). Incidence of GD ulcers was 1.4%, 27.6% and 2.7% in the celecoxib, loxoprofen and placebo groups respectively (P < 0.0001 in favour of the celecoxib group); incidence of adverse events (AEs) was 34.2%, 51.3% and 21.6% in the celecoxib, loxoprofen and placebo groups respectively. No serious or severe AEs were reported. CONCLUSIONS: Celecoxib 100 mg b.d. was superior to loxoprofen 60 mg t.d.s. regarding the incidence of gastro-duodenal endoscopic ulcers over 2 weeks. Celecoxib was well tolerated and no major safety concerns were observed.
23078396 Ligand activation of peroxisome proliferator-activated receptor delta suppresses cathepsin 2012 Oct Peroxisome proliferator-activated receptor (PPAR) delta agonists are known to have distinct anti-inflammatory and antitumor effects; though, the knowledge regarding their mode of action has thus far been limited. Different cathepsins have been shown to be upregulated in a broad range of pathological events, such as rheumatoid arthritis, psoriasis, atherosclerosis and diverse tumor entities, for example melanoma. Recent work demonstrated that cathepsin B in particular is an important pro-angiogenic protease in various pathological conditions. We therefore analysed whether cathepsins are a valid target for PPARδ agonists. This study reveals an inhibitory effect of two commonly used PPARδ agonists, GW501516 and L-165,041, on the protein expression and enzyme activity of cathepsin B in human endothelial cells. In contrast, no inhibitory effects were observed on cathepsin L and cathepsin D protein expression after treatment with PPARδ agonists. Furthermore, the results substantiate that PPARδ activators mediate their inhibitory action in a PPARδ-dependent manner and that the underlying regulatory mechanism is not based on a transcriptional but rather on a posttranslational mode of action, via the reduction in the cathepsin B protein half-life. Mechanisms conveying the suppressive effect by 5'-alternative splicing, a 3'-UTR-dependent way or by miRNA could be excluded. The data of this study explore cathepsin B as a new valid target for PPARδ agonists in endothelial cells. The results bolster other studies demonstrating PPARδ agonists as anti-inflammatory and anticarcinogenic agents and thus might have the potential to help to develop new pharmaceutical drugs.
22834815 Immunomodulatory and anti-inflammatory properties of artesunate in experimental colitis. 2012 BACKGROUND: Inflammatory bowel disease is a chronic and idiopathic gastrointestinal inflammation mediated by disregulated immune responses. Artemisinin (a chemical from a traditional Chinese herbal medicine Artemisia annua L.) and its derivatives have been proven to exhibit anti-inflammatory and immunomodulatory effects in the treatment of systemic lupus erythematosus and rheumatoid arthritis with low side-effects. This study is aimed to evaluate the potential therapeutic value of artesunate for inflammatory bowel disease. METHODS: Murine colitis was induced by either oral administration of dextran sulfate sodium salt (DSS) or intrarectal delivery of 2,4,6- trinitrobenzene sulfonic acid (TNBS) or oxazolone. Mice were treated with artesunate (150mg/kg/day). Peritoneal macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of artesunate. Changes in cytokines or proteins of interests were analyzed by enzyme-linked immunosorbent assay (ELISA) or SDS-PAGE/Western blot. RESULTS: Artesunate significantly ameliorated DSS colitis and TNBS colitis (but not oxazolone colitis), including reduced weight loss and disease activity, as well as macroscopic and microscopic colonic injury. The expression of NF-κBp65 and p-IκB-α were reduced in artesunate treated TNBS colitis compared with untreated. The levels of IFN-γ, IL-17, and TNF-α were significantly decreased in artesunate treated TNBS colitis or DSS colitis. Furthermore, in vitro artesunate treatment significantly inhibited TNF-α production by LPS-activated macrophages. CONCLUSIONS: Artesunate suppresses TNF-α expression in vitro and in vivo as well as T-helper (Th)1/Th17 responses in TNBS colitis model. Our data suggest a novel clinical application of artesunate as a potential therapy for Crohn's disease.
22769242 Identification of a selective RORγ ligand that suppresses T(H)17 cells and stimulates T r 2012 Sep 21 Nuclear receptors (NRs) are ligand-regulated transcription factors, many of which are validated targets for clinical purposes. The retinoic acid receptor-related orphan nuclear receptors alpha and gamma t (RORα and RORγt) are considered to be the master regulators of development of T(H)17 cells, a subset of T cells that have been implicated in the pathology of several autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis (RA). We report here the identification of a novel RORγ-specific synthetic ligand, SR1555, that not only inhibits T(H)17 cell development and function but also increases the frequency of T regulatory cells. Our data suggests synthetic RORγ ligands can be developed that target both suppression of T(H)17 and stimulation of T regulatory cells, offering key advantages in development of therapeutics targeting autoimmune diseases.
22765957 Fluoroenzymeimmunoassay to detect systemic sclerosis-associated antibodies: diagnostic per 2012 Sep OBJECTIVES: Detection of systemic sclerosis-associated antibodies (SSc-Ab) in routine clinical practice is mostly restricted to anti-centromere and anti-Scl-70 antibodies. However, also other antinuclear antibodies have been shown to be valuable diagnostic and prognostic markers for the disease. The aim of this study was to evaluate the diagnostic performance of measuring the most prevalent SSc-Ab with fluoroenzymeimmunoassay (FEIA) as an alternative for the combined conventional techniques (CCT). METHODS: Sera from 144 consecutive systemic sclerosis (SSc) patients previously tested by CCT (indirect immunofluorescence on HEp-2000, western blotting, protein radio immunoprecipitation and a well-documented line immunoassay) and an additional group of 266 disease controls (80 rheumatoid arthritis, 58 systemic lupus erythematosus, 50 spondyloarthropathy, 48 osteoarthritis, 18 polymyalgia rheumatica and 12 ANCA-associated vasculitis) were retrospectively evaluated. Anti-centromere-B, anti-Scl-70, anti-RNA polymerase III and anti-PM/Scl antibodies were measured using FEIA. RESULTS: Using cut-off values corresponding with likelihood ratios larger than 10 FEIA obtained the following sensitivities: 45.1% for anti-centromere-B, 15.3% for anti-Scl-70, 5.6% for anti-RNA polymerase III and 2.1% for anti-PM/Scl. The overall agreement between combined conventional techniques and FEIA was good for all individual reactivities (kappa>0.800). The overall diagnostic sensitivity of 68.1% and diagnostic specificity of 98.1% were comparable to those obtained by CCT. CONCLUSIONS: FEIA testing for anti-centromere-B, anti-Scl-70, anti-RNA polymerase III and anti-PM/Scl-100 shows good performance and represents an accurate alternative for the time-consuming combined conventional techniques.
22678060 The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and prot 2012 Sep 1 The gene B lymphocyte kinase (BLK) is associated with rheumatoid arthritis, systemic lupus erythematosus and several other autoimmune disorders. The disease risk haplotype is known to be associated with reduced expression of BLK mRNA transcript in human B cell lines; however, little is known about cis-regulation of BLK message or protein levels in native cell types. Here, we show that in primary human B lymphocytes, cis-regulatory effects of disease-associated single nucleotide polymorphisms in BLK are restricted to naïve and transitional B cells. Cis-regulatory effects are not observed in adult B cells in later stages of differentiation. Allelic expression bias was also identified in primary human T cells from adult peripheral and umbilical cord blood (UCB), thymus and tonsil, although mRNA levels were reduced compared with B cells. Allelic regulation of Blk expression at the protein level was confirmed in UCB B cell subsets by intracellular staining and flow cytometry. Blk protein expression in CD4(+) and CD8(+) T cells was documented by western blot analysis; however, differences in protein expression levels by BLK genotype were not observed in any T cell subset. Blk allele expression differences at the protein level are thus restricted to early B cells, indicating that the involvement of Blk in the risk for autoimmune disease likely acts during the very early stages of B cell development.
22615845 VIP deficient mice exhibit resistance to lipopolysaccharide induced endotoxemia with an in 2012 Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide with immunomodulatory properties. The administration of this peptide has been shown to have beneficial effects in murine models of inflammatory diseases including septic shock, rheumatoid arthritis, multiple sclerosis (MS) and Crohn's disease. However, the role of the endogenous peptide in inflammatory disease remains obscure because VIP-deficient mice were recently found to exhibit profound resistance in a model of MS. In the present study, we analyzed the response of female VIP deficient (KO) mice to intraperitoneal lipopolysaccharide (LPS) administration. We observed significant resistance to LPS in VIP KO mice, as evidenced by lower mortality and reduced tissue damage. The increased survival was associated with decreased levels of proinflammatory cytokines (TNFα, IL-6 and IL-12) in sera and peritoneal suspensions of these mice. Moreover, the expression of TNFα and IL-6 mRNA was reduced in peritoneal cells, spleens and lungs from LPS-treated VIP KO vs. WT mice, suggesting that the resistance might be mediated by an intrinsic defect in the responsiveness of immune cells to endotoxin. In agreement with this hypothesis, peritoneal cells isolated from VIP KO naive mice produced lower levels of proinflammatory cytokines in response to LPS in vitro. Finally, decreased NF-κB pathway activity in peritoneal cells was observed both in vivo and in vitro, as determined by assay of phosphorylated I-κB. The results demonstrate that female VIP KO mice exhibit resistance to LPS-induced shock, explainable in part by the presence of an intrinsic defect in the responsiveness of inflammatory cells to endotoxin.
22541000 Anti-inflammatory active gold(I) complexes involving 6-substituted-purine derivatives. 2012 May 24 The gold(I) complexes of the general formula [Au(L(n))(PPh(3))]·xH(2)O (1-8; n = 1-8 and x = 0-1.5), where L(n) stands for a deprotonated form of the benzyl-substituted derivatives of 6-benzylaminopurine, were prepared, thoroughly characterized (elemental analyses, FT-IR, Raman and multinuclear NMR spectroscopy, ESI+ mass spectrometry, conductivity, DFT calculations), and studied for their in vitro cytotoxicity and in vitro and in vivo anti-inflammatory effects on LPS-activated macrophages (derived from THP-1 cell line) and using the carrageenan-induced hind paw edema model on rats. The obtained results indicate that the representative complexes (1, 3, 6) exhibit a strong ability to reduce the production of pro-inflammatory cytokines TNF-α, IL-1β and HMGB1 without influence on the secretion of anti-inflammatory cytokine IL-1RA in the LPS-activated macrophages. The complexes also significantly influence the formation of edema, caused by the intraplantar application of polysaccharide λ-carrageenan to rats in vivo. All the tested complexes showed similar or better biological effects as compared with Auranofin, but contrary to Auranofin they were found to be less cytotoxic in vitro. The obtained results clearly indicate that the gold(I) complexes behave as very effective anti-inflammatory agents and could prove to be useful for the treatment of difficult to treat inflammatory diseases such as rheumatoid arthritis.
22403660 Decreased neutrophil apoptosis in quiescent ANCA-associated systemic vasculitis. 2012 BACKGROUND: ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues. Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV. METHODS: Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS. Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA. Expression of pro/anti-apoptotic factors, transcription factors C/EBP-α, C/EBP-β and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR. RESULTS: AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50 ± 14% vs. HBD 64 ± 11%, p<0.0001). In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1. AASV patients had normal levels of G-CSF, GM-CSF and IL-3. Both C/EBP-α, C/EBP-β were significantly higher in neutrophils from AASV patients than HBD. Levels of sFAS were significantly higher in AASV compared to HBD. CONCLUSION: Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ. Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV. Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.
22403115 [Osteoporosis - whom to treat? The importance of FRAX® in Switzerland]. 2012 Mar The WHO fracture risk assessment tool FRAX® is a computer based algorithm that provides models for the assessment of fracture probability in men and women. The approach uses easily obtained clinical risk factors (CRFs) to estimate 10-year probability of a major osteoporotic fracture (hip, clinical spine, humerus or wrist fracture) and the 10-year probability of a hip fracture. The estimate can be used alone or with femoral neck bone mineral density (BMD) to enhance fracture risk prediction. FRAX® is the only risk engine which takes into account the hazard of death as well as that of fracture. Probability of fracture is calculated in men and women from age, body mass index, and dichotomized variables that comprise a prior fragility fracture, parental history of hip fracture, current tobacco smoking, ever long-term use of oral glucocorticoids, rheumatoid arthritis, other causes of secondary osteoporosis, daily alcohol consumption of 3 or more units daily. The relationship between risk factors and fracture probability was constructed using information of nine population-based cohorts from around the world. CRFs for fracture had been identified that provided independent information on fracture risk based on a series of meta-analyses. The FRAX® algorithm was validated in 11 independent cohorts with in excess of 1 million patient-years, including the Swiss SEMOF cohort. Since fracture risk varies markedly in different regions of the world, FRAX® models need to be calibrated to those countries where the epidemiology of fracture and death is known. Models are currently available for 31 countries across the world. The Swiss-specific FRAX® model was developed very soon after the first release of FRAX® in 2008 and was published in 2009, using Swiss epidemiological data, integrating fracture risk and death hazard of our country. Two FRAX®-based approaches may be used to explore intervention thresholds. They have recently been investigated in the Swiss setting. In the first approach the guideline that individuals with a fracture probability equal to or exceeding that of women with a prior fragility fracture should be considered for treatment is translated into thresholds using 10-year fracture probabilities. In that case the threshold is age-dependent and increases from 16 % at the age of 60 ys to 40 % at the age of 80 ys. The second approach is a cost-effectiveness approach. Using a FRAX®-based intervention threshold of 15 % for both, women and men 50 years and older, should permit cost-effective access to therapy to patients at high fracture probability in our country and thereby contribute to further reduce the growing burden of osteoporotic fractures.
22325804 Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory a 2012 Apr Sinomenine (1) is clinically available for the treatment of rheumatoid arthritis (RA), however, its efficacy is quite weak. In the present study, a library of novel sinomenine-based homodimers and monomers through variable-length linkers were designed and synthesized, and their bioactivities were evaluated using RAW264.7 cells and mice. Among the compounds, 2f and 3b possessed much more potent inhibitory effects on the production of nitric oxide (NO), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) than 1. Preliminary mechanism investigation revealed that 3b inhibited nuclear factor-κB (NF-κB) signaling pathway specifically, 2f suppressed both NF-κB and mitogen-activated protein kinase (MAPK) cascades. Moreover, 3b and 2f significantly alleviated the lipopolysaccharide (LPS)-induced mortality. These two compounds might serve as valuable candidates for anti-inflammatory drug discovery.
22258491 Combination of IL-17 and TNFα induces a pro-inflammatory, pro-coagulant and pro-thromboti 2012 May OBJECTIVE: Cardiovascular events remain the leading cause of death in rheumatoid arthritis (RA). To study the role of cytokines in these observations, the effects of tumour necrosis factor α (TNFα) and interleukin (IL)-17, a classical and a new key player in RA, were assessed in endothelial cell (EC) dysfunction. METHODS: Primary human EC were treated with IL-17 alone or combined with TNFα. mRNA expression was quantified by qRT PCR and Affymetrix microarrays. The role of IL-17 was studied using functional assays of platelet aggregation, EC migration and invasion. RESULTS: IL-17 alone induced 248 pro-inflammatory genes and 9803, when combined with TNFα. IL-17 plus TNFα induced synergistically chemokine genes such as CCL5, IL-8 and cytokine genes such as IL-6. In contrast, IL-17 decreased genes involved in the regulation of inflammation such as IL-33. IL-17 induced EC migration and invasion in synergy with TNFα. Such invasion was inhibited with an antiCXCR4 antibody, indicating the contribution of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 axis. Supernatants of IL-17-treated EC induced strong platelet aggregation. IL-17 inhibited endothelial CD39/ATPDase expression, an inhibitor of platelet activation. Finally, IL-17 enhanced genes critical for coagulation such as tissue factor and decreased thrombomodulin, leading to a pro-thrombotic state. CONCLUSION: These results indicate that IL-17 specifically when combined with TNFα has major pro-coagulant and pro-thrombotic effects on vessels.