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Deoxyribonuclease1 (DNase1) is involved in chromatin degradation of apoptotic cells. Its deficiency results in accumulation of self-DNA, which in turn may induce inflammation and autoimmunity. We assessed for the first time serum DNase1-activity in a large consecutive cohort of treatment-naïve patients with autoimmune liver diseases (ALD). DNase1-activity was determined by single radial enzyme-diffusion (SRED) at diagnosis of 224 patients with autoimmune hepatitis (AIH), 249 with primary biliary cirrhosis (PBC) and 36 with primary sclerosing cholangitis (PSC). Sera from 146 patients with chronic hepatitis B or C, 140 with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) and 114 healthy individuals served as disease and healthy controls. Available serum samples during remission from 50 AIH and 39 PBC patients were also investigated by paired analyzes. DNase1-activity was significantly lower in AIH, PBC and PSC compared to viral hepatitis (p < 0.02, p < 0.001, p = 0.03), NAFLD/NASH (p < 0.001) and healthy (p < 0.001). No significant difference was found in between each specific ALD. In AIH, DNAse1-activity was positively correlated with aspartate aminotransferase (AST) (p < 0.02), bilirubin (p < 0.01) and increased IgG (>1400 mg/dl; p < 0.05); in PBC, with AST (p < 0.01), alanine aminotransferase (ALT) (p < 0.03) and anti-mitochondrial antibodies (AMA) (p = 0.008). In PSC, DNase1-activity was inversely associated with alkaline phosphatase (ALP) (p < 0.05). In AIH, complete responders were characterized by increased baseline DNase1-activity compared to partial responders, relapsers and non-responders (p < 0.02), whereas it was significantly increased after achievement of remission (p < 0.001). Serum DNase1-activity is significantly decreased in ALD patients, indicating its potential implication in their pathogenesis. Furthermore, DNase1-activity could be used as a new surrogate biomarker for predicting response to AIH treatment. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

A database containing sub-seasonal to seasonal forecasts from 11 operational centres is available to the research community and will help advance our understanding of the sub-seasonal to seasonal time range.\ud \ud Demands are growing rapidly in the operational prediction and applications communities for forecasts that fill the gap between medium-range weather and long-range or seasonal forecasts. Based on the potential for improved forecast skill at the sub-seasonal to seasonal time range, a sub-seasonal prediction (S2S) research project has been established by the World Weather Research Program/World Climate Research Program. A main deliverable of this project is the establishment of an extensive database, containing sub-seasonal (up to 60 days) forecasts, 3-weeks behind real-time, and reforecasts from 11 operational centers, modelled in part on the THORPEX Interactive Grand Global Ensemble (TIGGE) database for medium range forecasts (up to 15 days).\ud \ud The S2S database, available to the research community since May 2015, represents an important tool to advance our understanding of the sub-seasonal to seasonal time range that has been considered for a long time as a “desert of predictability”. In particular, this database will help identify common successes and shortcomings in the model simulation and prediction of sources of sub-seasonal to seasonal predictability. For instance, a preliminary study suggests that the S2S models underestimate significantly the amplitude of the Madden Julian Oscillation (MJO) teleconnections over the Euro-Atlantic sector. The S2S database represents also an important tool for case studies of extreme events. For instance, a multi-model combination of S2S models displays higher probability of a landfall over Vanuatu islands 2 to 3 weeks before tropical cyclone Pam devastated the islands in March 2015.

Objective. To assess and compare the sensitivity to change of the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI) with that of other primary Sjogren's syndrome (SS) disease activity indexes.Methods. We abstracted 96 patient profiles, including data on 3 successive visits (visits 1-3), from the medical charts of patients with primary SS. Patient profiles were scored with the ESSDAI, SS Disease Activity Index (SSDAI), and Sjogren's Systemic Clinical Activity Index (SCAI). Thirty-nine experts assessed 5 profiles for whether disease activity had improved, worsened, or remained stable at visits 2 and 3.Results. For improved patients, the standardized response means (SRMs) for all scores did not differ, and ranged from -1.08 to -1.38 between visits 1 and 2 and from -0.50 to -0.76 between visits 2 and 3. For patients with worsened activity, the SRMs between visits 1 and 2 and between visits 2 and 3 were +0.46 and +1.10 for the ESSDAI, -0.03 and +0.79 for the SSDAI, and +0.17 and +1.02 for the SCAI, respectively. For patients with stable activity, the SRMs between visits 1 and 2 and between visits 2 and 3 were 0.00 and -0.13 for the ESSDAI, -0.44 and -0.11 for the SSDAI, and -0.36 and +0.34 for the SCAI, respectively.Conclusion. For patients with improved activity, the 3 disease activity indexes showed similar, large sensitivity to change. However, the ESSDAI seemed to detect changes in activity more accurately than other disease activity indexes. Notably, for patients with stable activity, the ESSDAI did not show erroneous improvement.

We have previously demonstrated that Greek thyme honey inhibits significantly the cell viability of human prostate cancer cells. Herein, 15 thyme honey samples from several regions of Greece were submitted to phytochemical analysis for the isolation, identification and determination (through modern spectral means) of the unique thyme honey monoterpene, the compound trihydroxy ketone E-4-(1,2,4-trihydroxy-2,6,6-trimethylcyclohexyl)-but- 3-en-2-one. We investigated the anti-growth and apoptotic effects of the trihydroxy ketone on PC-3 human androgen independent prostate cancer cells using MTT assay and Annexin V-FITC respectively. The molecular pathways involved to such effects were further examined by evaluating its ability to inhibit (a) the NF-κB phosphorylation (S536), (b) JNK and Akt phosphorylation (Thr183/Tyr185 and S473 respectively) and (c) IL-6 production, using ELISA method. The anti-microbial effects of the trihydroxy ketone against a panel of nine pathogenic bacteria and three fungi were also assessed. The trihydroxy ketone exerted significant apoptotic activity in PC-3 prostate cancer cells at 100 μM, while it inhibited NF-κB phosphorylation and IL-6 secretion at a concentration range 10-6-10-4 M. Akt and JNK signaling were not found to participate in this process. The trihydroxy ketone exerted significant anti-microbial profile against many human pathogenic bacteria and fungi (MIC values ranged from 0.04 to 0.57 mg/ml). Conclusively, the Greek thyme honey-derived monoterpene exerted significant apoptotic activity in PC-3 cells, mediated, at least in part, through reduction of NF-κB activity and IL-6 secretion and may play a key role in the anti-growth effect of thyme honey on prostate cancer cells. © 2014 Elsevier GmbH. All rights reserved.

CREST syndrome represents a subset of systemic sclerosis (SSc). Five patients with CREST syndrome and 5 with SSc without cardiac symptoms and with normal routine cardiac examination were investigated by cardiovascular magnetic resonance. All CREST patients had ectatic coronary arteries, and in 1 of them, an inferior, transmural myocardial infarction was identified. Furthermore, patchy fibrosis was identified in all the patients with SSc, although their coronary arteries were normal. Cardiovascular magnetic resonance can be a useful, noninvasive diagnostic tool in the evaluation of asymptomatic CREST and SSc patients. © 2011 Canadian Cardiovascular Society.

ObjectiveTo develop a disease activity index for patients with primary Sjögren's syndrome (SS): the European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI).MethodsThirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific ‘domains’ contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0–10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain.ResultsAll 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, pConclusionsThe ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials.

The levels of soluble interleukin‐2 receptors (sIL‐2R) were determined in the serum of 53 patients with B‐cell lymphoproliferative malignancies, including 31 patients with non‐Hodgkin lymphomas (NHL), 16 with chronic lymphocytic leukemia (CLL), and 6 with multiple myeloma. In addition, serum samples from 40 patients with various solid tumors as well as from 53 healthy individuals were used as controls. It was found that the mean serum levels of sIL‐2R were significantly increased (P < 0.001) in NHL (mean ± standard error of the mean 2,327 ± 320 units/ml) and CLL patients (2517 ± 451 units/ml) as compared to normal controls (207 ± 17 units/ml). No such difference was observed when the serum sIL‐2R levels of patients with multiple myeloma or solid tumors were analyzed. Serum sIL‐2R levels were closely related to the clinical stage, the presence of B‐symptoms, and the disease activity of patients with NHL and CLL. In fact, response to chemotherapy was followed by marked decrease or normalization of sIL‐2R levels, while in a number of patients sIL‐2R values were even able to predict disease relapse. Finally, no association with histologic grade in NHL patients, could be demonstrated. We conclude that serum sIL‐2R (1) are increased only in B‐NHL and B‐CLL but not in myeloma patients, (2) are related to the tumor burden, and (3) can serve as a valuable tumor marker for the monitoring of patients treatment. Copyright © 1992 Wiley‐Liss, Inc., A Wiley Company 20 1 26 31

Journal URL: http://rheumatology.oxfordjournals.org/

Journal URL: http://www.sciencedirect.com/science/journal/08968411

Journal URL: http://www.sciencedirect.com/science/journal/15216616

PPARγ, a member of the peroxisome proliferator-activated receptor family, is overexpressed in prostate cancer. Natural and synthetic ligands of PPARγ via genomic and nongenomic actions promote cell cycle arrest and apoptosis of several prostate cancer cells, in vitro. Insulin-like growth factor 1 (IGF-1) inhibits the adriamycin-induced apoptosis of PC-3 human prostate cancer cells. Therefore, we have analyzed the ability of two PPARγ ligands,15dPGJ2 and rosiglitazone, a natural and a synthetic PPARγ ligand, respectively, to increase the adriamycin-induced cytotoxicity of PC-3 cells and to suppress the IGF-1 survival effect on adriamycin-induced apoptosis of PC-3 cells. Our data revealed that both the PPARγ ligands increased the adriamycin-induced cytostasis of PC-3 cells, however, only rosiglitazone added to the adriamycin-induced apoptosis of PC-3 cells. In addition, rosiglitazone attenuated the type I IGF receptor (IGF-1R) survival signaling on adriamycin-induced apoptosis of PC-3 cells via its nongenomic action on ERK1/2 and AKT phosphorylation. Because the IGF-1R signaling is probably the most important host tissue (bone) metastasis microenvironment-related survival signaling for prostate cancer cells, we conclude that rosiglitazone effects on IGF-1R-mediated activation of ERK1/2 and AKT could have clinical implications for the management of androgen ablation-refractory and chemotherapy-resistant advanced prostate cancer with bone metastasis.

The aim of our study was to analyze the action of zoledronic acid on MG-63 human osteosarcoma cells. The proliferation of MG-63 cells was inhibited by either continuous or pulsatile exposures of zoledronic acid in a dose-dependent manner (10-250 μM). Zoledronic acid did not produce evidence of MG-63 cell death when administered at 100 mM for 48 hours, but only after exposure of 96 hours. Zoledronic acid (100 μM) increased the distribution of MG-63 cells in G0/G1 phase, however, it did not increase the adriamycin-induced apoptosis. In addition, zoledronic acid action was partially neutralized by exogenous administration of geranylgeranyl pyrophosphate (GGPP), but not by farnesyl pyrophosphate (FPP). Furthermore, zoledronic acid resulted in the attenuation of the prenylated form of Ras. Zoledronic acid and EDTA increased fluorescence of Fluo-3 loaded MG-63 cells in a similar pattern. This increase was owing to the release of Ca2+ from intracellular stores since zoledronic acid failed to reveal such a change to intracellular Ca2+ when cells were previously treated with 1 mM caffeine. Moreover, zoledronic acid significantly decreased the expression of estrogen receptor α (ERα) whereas it did not change significantly the expression of estrogen receptor β (ERβ) in MG-63 cells. These data suggest that zoledronic acid can control the proliferation and the differentiation of osteosarcoma-like cells. © Georg Thieme Verlag KG Stuttgart.

The aim of the study was to assess the possible associations between allergies and type 1 diabetes mellitus (DM1), stratified by social class. We studied 127 children with DM1 with a median age of 10.8yr and 150 controls of comparable age and sex distribution. The parents completed questionnaires on their education and occupation and on their children's history of allergic symptoms, breast-feeding, viral infections, and measles-mumps-rubella (MMR) vaccination. Lower family's social class was more frequently encountered among the DM1 families than in the controls (OR=0.56, 95% CI: 0.35-0.92). The occurrence of any allergic symptoms among children with DM1 (35.45%) was not significantly different from the controls (38.78%), neither in the total group (OR=0.87, 95% CI: 0.52-1.45) nor in the stratified analysis by social class. Similar findings were observed regarding the different types of allergic symptoms. In the univariate analysis, breast-feeding, the experience of viral infections, and MMR vaccination were found to be protective of DM1 presentation in both upper and lower social classes. In the multiple logistic regression analysis, the experience of more than 2 infections/yr (OR=0.12, 95% CI: 0.04-0.34), the origin from middle and upper social classes (OR=0.42, 95% CI: 0.22-0.80) and breast-feeding (OR=0.58, 95% CI: 0.31-1.07) were protective of DM1 occurrence. In children with DM1, the presence of allergic symptoms was not associated with the development of DM1. Among the environmental factors, the origin from middle or upper social classes, breast-feeding, the experience of viral infections, and MMR vaccination were found to have a protective effect on DM1 presentation. © Journal compilation © 2008 Blackwell Munksgaard.

Purpose: Glucocorticoids are widely used as adjuvant therapy in hormonal refractory prostate cancer; their therapeutic role, however, remains unclear. Ursolic acid, a natural triterpene, structurally similar to dexamethasone, exhibits antitumor effects in various cell types. Our main objective was to investigate the effects of ursolic acid on cell viability, apoptosis and bcl-2 protein, in human hormone refractory and androgen-sensitive prostate cancer cells. Methods: The ursolic acid-induced changes in cell viability, apoptosis and bcl-2 protein were examined in human hormone refractory prostate cancer PC-3 cells and androgen-sensitive LNCaP cells, by MTT assay, flow cytometry and western blot analysis, respectively. Results: Ursolic acid inhibited significantly the cell viability and induced apoptosis in PC-3 cells at 55 μM and in LNCaP cells at 45 μM associated with a downregulation of bcl-2 protein. Conclusions: The antiproliferative and apoptotic effects of ursolic acid in PC-3 and LNCaP cells implicate its potential therapeutic use for the treatment of hormone refractory and androgen-sensitive prostate cancer. The downregulation of bcl-2 may be one of the molecular mechanisms via which it induces apoptosis in PC-3 and LNCaP cells. © 2007 Springer-Verlag.