Current concepts regarding pharmacologic treatment of rheumatoid and osteoarthritis.

PubMed

Wildy, K S; Wasko, M C

2001-05-01

Treating patients with osteoarthritis (OA) and rheumatoid arthritis (RA) remains challenging; however, new agents offer the chance for an improved quality of life. As an alternative to traditional nonsteroidal anti-inflammatories, cyclooxygenase-2 inhibitors provide pain relief for OA and RA patients with possible fewer side effects. Otherwise, OA patients may opt for topical agents, injections, or supplements. Rheumatoid arthritis research has led to an improved understanding of the inflammatory cascade and an appreciation of the early tissue destruction. A new treatment philosophy has thus emerged along with the development of new biologic agents; the latter, along with combination therapy and a new disease modifying antirheumatic drug, leflunomide, have greatly expanded the chances for disease control in RA patients.

Antagonism of cytotoxic chemotherapy in neuroblastoma cell lines by 13-cis-retinoic acid is mediated by the anti-apoptotic Bcl-2 family proteins

PubMed Central

Hadjidaniel, Michael Daniel; Reynolds, Charles Patrick

2010-01-01

13-cis-retinoic acid (13-cis-RA), is given at completion of cytotoxic therapy to control minimal residual disease in neuroblastoma. We investigated the effect of combining 13-cis-RA with cytotoxic agents employed in neuroblastoma therapy using a panel of 6 neuroblastoma cell lines. The effect of 13-cis-RA on the mitochondrial apoptotic pathway, was studied by flow cytometry, cytotoxicity by DIMSCAN, and protein expression by immuoblotting. Pre-treatment and direct combination of 13-cis-RA with etoposide, topotecan, cisplatin, melphalan, or doxorubicin markedly antagonized the cytotoxicity of those agents in 4 out of 6 tested neuroblastoma cell lines, increasing fractional cell survival by 1 to 3 logs. The inhibitory concentration of drugs (IC99) increased from clinically achievable levels to non-achievable levels: > 5-fold (cisplatin) to > 7-fold (etoposide). In SMS-KNCR neuroblastoma cells, 13-cis-RA upregulated expression of Bcl-2 and Bcl-xL RNA and protein, and this was associated with protection from etoposide-mediated apoptosis at the mitochondrial level. A small molecule inhibitor of the Bcl-2 family of proteins (ABT-737) restored mitochondrial membrane potential loss and apoptosis in response to cytotoxic agents in 13-cis-RA treated cells. Prior selection for resistance to RA did not diminish the response to cytotoxic treatment. Thus, combining 13-cis-RA with cytotoxic chemotherapy significantly reduced the cytotoxiciity for neuroblastoma in vitro, mediated at least in part via the anti-apoptotic Bcl-2 family of proteins. PMID:21159604

Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care.

PubMed

Gillooly, Kathleen M; Pulicicchio, Claudine; Pattoli, Mark A; Cheng, Lihong; Skala, Stacey; Heimrich, Elizabeth M; McIntyre, Kim W; Taylor, Tracy L; Kukral, Daniel W; Dudhgaonkar, Shailesh; Nagar, Jignesh; Banas, Dana; Watterson, Scott H; Tino, Joseph A; Fura, Aberra; Burke, James R

2017-01-01

Bruton's tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren's syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.

Distributed Planning in a Mixed-Initiative Environment

DTIC Science & Technology

2008-06-01

Knowledge Sources Control Remote Blackboard Remote Knowledge Sources Remot e Data Remot e Data Java Distributed Blackboard Figure 3 - Distributed...an interface agent or planning agent and the second type is a critic agent. Agents in the DEEP architecture extend and use the Java Agent...chosen because it is fully implemented in Java , and supports these requirements. 2.3.3 Interface Agents Interface agents are the interfaces through

Prognostic factors of methotrexate-associated lymphoproliferative disorders associated with rheumatoid arthritis and plausible application of biological agents.

PubMed

Katsuyama, Takayuki; Sada, Ken-Ei; Yan, Minglu; Zeggar, Sonia; Hiramatsu, Sumie; Miyawaki, Yoshia; Ohashi, Keiji; Morishita, Michiko; Watanabe, Haruki; Katsuyama, Eri; Takano-Narazaki, Mariko; Toyota-Tatebe, Noriko; Sunahori-Watanabe, Katsue; Kawabata, Tomoko; Miyake, Kohei; Kiguchi, Toru; Wada, Jun

2017-09-01

To determine prognostic factors of methotrexate-associated lymphoproliferative disorder (MTX-LPD) and evaluate the efficacy and safety of biological therapy in rheumatoid arthritis (RA) complicated with MTX-LPD. Thirty RA patients who developed MTX-LPD were investigated in this study. We compared the clinical and laboratory parameters of patients who achieved regression of LPD by MTX withdrawal with those who required chemotherapy and evaluated the clinical course of RA after LPD development. Twenty-three patients (76.7%) achieved regression of LPD by MTX withdrawal. Chemotherapy-free patients had a tendency of shorter RA duration (13.1 vs. 22.0 years, p = 0.108) and higher doses of MTX at LPD diagnosis (8.0 vs. 5.3 mg/w, p = 0.067) than patients who required chemotherapy. A significantly higher positive rate of peripheral blood Epstein-Barr virus (EBV)-DNA was observed in the chemotherapy-free group (9/9 vs. 0/3, p = 0.0002). Of 15 patients that received biological agents after LPD development, 14 patients (93.3%) demonstrated an improved disease activity of RA and persistent remission of LPD, whereas only one patient experienced relapse of LPD during tocilizumab therapy. Peripheral blood EBV-DNA positivity is a potential prognostic marker of better outcome in MTX-LPD. Biological agents could be an option for the treatment of RA patients with MTX-LPD.

Treatment of rheumatoid arthritis-associated interstitial lung disease: a perspective review

PubMed Central

Iqbal, Kundan; Kelly, Clive

2015-01-01

Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting 0.5–1% of the worldwide population. Whilst predominantly causing chronic pain and inflammation in synovial joints, it is also associated with significant extra-articular manifestations in a large proportion of patients. Among the various pulmonary manifestations, interstitial lung disease (ILD), a progressive fibrotic disease of the lung parenchyma, is the commonest and most important, contributing significantly to increased morbidity and mortality. The most frequent patterns of RA-associated ILD (RA-ILD) are usual interstitial pneumonia and nonspecific interstitial pneumonia. New insights during the past several years have highlighted the epidemiological impact of RA-ILD and have begun to identify factors contributing to its pathogenesis. Risk factors include smoking, male sex, human leukocyte antigen haplotype, rheumatoid factor and anticyclic citrullinated protein antibodies (ACPAs). Combined with clinical information, chest examination and pulmonary function testing, high-resolution computed tomography of the chest forms the basis of investigation and allows assessment of subtype and disease extent. The management of RA-ILD is a challenge. Several therapeutic agents have been suggested in the literature but as yet no large randomized controlled trials have been undertaken to guide clinical management. Therapy is further complicated by commonly prescribed drugs of proven articular benefit such as methotrexate, leflunomide (LEF) and anti-tumour necrosis factor α agents having been implicated in both ex novo occurrence and acceleration of existing ILD. Agents that offer promise include immunomodulators such as mycophenolate and rituximab as well as newly studied antifibrotic agents. In this review, we discuss the current literature to evaluate recommendations for the management of RA-ILD and discuss key gaps in our knowledge of this important disease. PMID:26622326

Remote Agent Demonstration

NASA Technical Reports Server (NTRS)

Dorais, Gregory A.; Kurien, James; Rajan, Kanna

1999-01-01

We describe the computer demonstration of the Remote Agent Experiment (RAX). The Remote Agent is a high-level, model-based, autonomous control agent being validated on the NASA Deep Space 1 spacecraft.

An update on pharmacogenomics in rheumatoid arthritis with a focus on TNF-blocking agents.

PubMed

Ranganathan, Prabha

2008-12-01

TNFalpha is a proinflammatory cytokine, which is crucial in the pathogenesis of rheumatoid arthritis (RA). In recent years, biological therapies which block the damaging effects of TNFalpha on synovium and cartilage have been developed. TNF antagonists, such as etanercept, infliximab and adalimumab, although highly effective in RA, are expensive, totaling several thousand US dollars in yearly costs. In addition, only approximately 60% of patients respond to these agents. This has led to the need to prospectively identify patients most likely to respond to these agents, which can be achieved by pharmacogenomics approaches. Polymorphisms in genes encoding for TNFalpha, the MHC region, and the Fcgamma receptor IIIA, as well as their ability to predict disease progression in RA and response to anti-TNF therapies, have been the focus of a number of studies, which are discussed in this review. There is no consensus at present as to whether pharmacogenomics will allow prediction of anti-TNF therapy efficacy in RA. Large, prospective, multicenter studies are needed to replicate and validate the results of the studies outlined in this review.

Homeostasis 6: nurses as external control agents in rheumatoid arthritis.

PubMed

Clancy, John; McVicar, Andrew; Mooney, Janice

All disorders involve a disturbance of cellular and hence chemical function in the body. Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease that usually attacks synovial joints and surrounding ligaments, muscles and their tendons and blood vessels. This article applies the concept of health professionals operating as external agents of homeostatic control (Clancy and McVicar, 20011a; 2011b) to RA and to the care of affected patients, using a case scenario to illustrate attempts to minimize homeostatic imbalances. After reading the article, nurses should be able to understand: how the principles of homeostatic theory apply to skeletomuscular function, in particular to synovial joint function; the skeletomuscular homeostatic role in movement; and that homeostatic failure of reduced mobility, as in RA, is a result of nature-nurture interaction; that illness arises from a cellular, hence chemical, homeostatic imbalance(s) (Clancy and McVicar, 2011a; 2011b; 2011c; 2011d; 2011e). RA is considered a cellular (B-lymphocyte) hence chemical (autoantibody) imbalance that causes the homeostatic imbalances (inflammatory pain, reduced mobility, reduced activities of daily living) associated with the condition. Health professionals are able at act as external agents of homeostatic control to only a limited extent when caring for people with RA because, as with any progressive disorder, they will only be managing signs and symptoms to improve patients' quality of life.

Biological agents and respiratory infections: Causative mechanisms and practice management.

PubMed

Takayanagi, Noboru

2015-09-01

Biological agents are increasingly being used to treat patients with immune-mediated inflammatory disease. In Japan, currently approved biological agents for patients with rheumatoid arthritis (RA) include tumor necrosis factor inhibitors, interleukin-6 receptor-blocking monoclonal antibody, and T-cell costimulation inhibitor. Rheumatologists have recognized that safety issues are critical aspects of treatment decisions in RA. Therefore, a wealth of safety data has been gathered from a number of sources, including randomized clinical trials and postmarketing data from large national registries. These data revealed that the most serious adverse events from these drugs are respiratory infections, especially pneumonia, tuberculosis, nontuberculous mycobacteriosis, and Pneumocystis jirovecii pneumonia, and that the most common risk factors associated with these respiratory infections are older age, concomitant corticosteroid use, and underlying respiratory comorbidities. Because of this background, in 2014, the Japanese Respiratory Society published their consensus statement of biological agents and respiratory disorders. This review summarizes this statement and adds recent evidence, especially concerning respiratory infections in RA patients, biological agents and respiratory infections, and practice management of respiratory infections in patients treated with biological agents. To decrease the incidence of infections and reduce mortality, we should know the epidemiology, risk factors, management, and methods of prevention of respiratory infections in patients receiving biological agents. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Incretin-based therapy in type 2 diabetes: An evidence based systematic review and meta-analysis.

PubMed

Waldrop, Greer; Zhong, Jixin; Peters, Matthew; Goud, Aditya; Chen, Yin-Hsiu; Davis, Stephen N; Mukherjee, Bhramar; Rajagopalan, Sanjay

2018-01-01

Incretin based therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) are increasingly used for the treatment of Type 2 diabetes mellitus. In clinical practice and in previously performed clinical trials, these agents are often used in combination with other oral anti-diabetic agents (OADs) and Insulin. Prior meta-analytic reviews however do not adequately address the impact of background therapy and active comparator arms. Accordingly, we aimed to further investigate the efficacy of incretin based therapies by updating existing reviews by including clinical trial evidence after 2008; estimating the pooled effect of incretin therapies on glycemic efficacy and weight-loss, stratified by comparator therapy (placebo, mono-therapy, etc.), estimating the impact of background OADs and within class (GLP-1Ra or DPP-4i) comparative efficacy, on glycemia control. 82 randomized controlled trials after 2008 with glycemic control and weight loss as primary end-points were included. Both DPP-4i and GLP-1Ra reduced HbA1c, but only GLP-1Ra caused weight loss when compared to either active comparator drugs or placebo. GLP-1Ra were more effective than DPP-4i in glycemia lowering. Long acting GLP-1Ra were more effective in HbA1c lowering than short-acting agents but with similar weight loss effect. The effect of DPP-4i incretin glycemic efficacy was not modified by background therapy used in the study. Copyright © 2016. Published by Elsevier Inc.

Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control Analysis.

PubMed

Chou, Richard C; Kane, Michael; Ghimire, Sanjay; Gautam, Shiva; Gui, Jiang

2016-11-01

It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown. To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients. We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease. AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08-0.89; p = 0.02) was associated with a decreased risk of AD in RA patients. There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD.

Current and future pharmaceutical therapy for rheumatoid arthritis.

PubMed

Ruderman, Eric M

2005-01-01

Rheumatoid arthritis (RA) is a chronic, inflammatory arthritis with a population prevalence of approximately 1%. Pharmaceutical treatment includes both anti-inflammatory medications and disease modifying drugs (DMARDs) that impact the course of the damage associated with this disease. Traditional DMARD therapy includes immunomodulatory agents such as methotrexate, used both alone and in combination. Recently available biologic response modifiers are very effective at reducing both the clinical symptoms of disease and the radiographic damage that accompanies them. This manuscript describes the clinical assessments used to measure response to therapy in RA and reviews the results seen with the various treatment strategies in this disease. In addition, the clinical and structural outcomes seen in trials of newly available and pending biologic therapies are reviewed, along with the specific toxicity issues associated with these agents. Clinical trial data is reviewed for the TNF antagonists, which have become the standard of care in RA patients with an inadequate response to methotrexate. RA has been clearly shown to be a destructive and disabling disease. The widespread use of newer agents, however, along with more aggressive use of existing therapies, appears to limit disease progression very effectively, and should lead to better long-term outcomes for these patients.

RARα-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia

PubMed Central

Guidez, Fabien; Parks, Sarah; Wong, Henna; Jovanovic, Jelena V.; Mays, Ashley; Gilkes, Amanda F.; Mills, Kenneth I.; Guillemin, Marie-Claude; Hobbs, Robin M.; Pandolfi, Pier Paolo; de Thé, Hugues; Solomon, Ellen; Grimwade, David

2007-01-01

Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARα by the t(11;17)(q23;q21) translocation associated with retinoic acid (RA)-resistant acute promyelocytic leukemia (APL). PLZF represses the CRABPI locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RARα oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARα-PLZF binds to this remote binding site, recruiting p300, inducing promoter hypomethylation and CRABPI gene up-regulation. In line with these observations, RA-resistant murine PLZF/RARα+RARα/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARα APL. RARα-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-dependent fashion. This study supports an active role for PLZF and RARα-PLZF in leukemogenesis, identifies up-regulation of CRABPI as a mechanism contributing to retinoid resistance, and reveals the ability of the reciprocal fusion gene products to mediate distinct epigenetic effects contributing to the leukemic phenotype. PMID:18000064

Cardiovascular safety of biologic therapies for the treatment of RA.

PubMed

Greenberg, Jeffrey D; Furer, Victoria; Farkouh, Michael E

2011-11-15

Cardiovascular disease represents a major source of extra-articular comorbidity in patients with rheumatoid arthritis (RA). A combination of traditional cardiovascular risk factors and RA-related factors accounts for the excess risk in RA. Among RA-related factors, chronic systemic inflammation has been implicated in the pathogenesis and progression of atherosclerosis. A growing body of evidence--mainly derived from observational databases and registries--suggests that specific RA therapies, including methotrexate and anti-TNF biologic agents, can reduce the risk of future cardiovascular events in patients with RA. The cardiovascular profile of other biologic therapies for the treatment of RA has not been adequately studied, including of investigational drugs that improve systemic inflammation but alter traditional cardiovascular risk factors. In the absence of large clinical trials adequately powered to detect differences in cardiovascular events between biologic drugs in RA, deriving firm conclusions on cardiovascular safety is challenging. Nevertheless, observational research using large registries has emerged as a promising approach to study the cardiovascular risk of emerging RA biologic therapies.

Redox-active compounds with a history of human use: antistaphylococcal action and potential for repurposing as topical antibiofilm agents.

PubMed

Ooi, N; Eady, E A; Cove, J H; O'Neill, A J

2015-02-01

To investigate the antistaphylococcal/antibiofilm activity and mode of action (MOA) of a panel of redox-active (RA) compounds with a history of human use and to provide a preliminary preclinical assessment of their potential for topical treatment of staphylococcal infections, including those involving a biofilm component. Antistaphylococcal activity was evaluated by broth microdilution and by time-kill studies with growing and slow- or non-growing cells. The antibiofilm activity of RA compounds, alone and in combination with established antibacterial agents, was assessed using the Calgary Biofilm Device. Established assays were used to examine the membrane-perturbing effects of RA compounds, to measure penetration into biofilms and physical disruption of biofilms and to assess resistance potential. A living skin equivalent model was used to assess the effects of RA compounds on human skin. All 15 RA compounds tested displayed antistaphylococcal activity against planktonic cultures (MIC 0.25-128 mg/L) and 7 eradicated staphylococcal biofilms (minimum biofilm eradication concentration 4-256 mg/L). The MOA of all compounds involved perturbation of the bacterial membrane, whilst selected compounds with antibiofilm activity caused destructuring of the biofilm matrix. The two most promising agents [celastrol and nordihydroguaiaretic acid (NDGA)] in respect of antibacterial potency and selective toxicity against bacterial membranes acted synergistically with gentamicin against biofilms, did not damage artificial skin following topical application and exhibited low resistance potential. In contrast to established antibacterial drugs, some RA compounds are capable of eradicating staphylococcal biofilms. Of these, celastrol and NDGA represent particularly attractive candidates for development as topical antistaphylococcal biofilm treatments. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

The Impact of DMARD and Anti-TNF Therapy on Functional Characterization of Short-Term T-Cell Activation in Patients with Rheumatoid Arthritis – A Follow-Up Study

PubMed Central

Szalay, Balázs; Cseh, Áron; Mészáros, Gergő; Kovács, László; Balog, Attila; Vásárhelyi, Barna

2014-01-01

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a systemic dysfunction of T-cells. In this study we tested the impact of DMARD and anti-TNF agents on short-term activation characteristics of T-cells. We enrolled 12 patients with newly diagnosed RA (naïve RA) who were treated with methothrexate (MTX) and glucocorticsteroid (GCS) and 22 patients with established RA non responding to conventional DMARD therapy who were treated with different anti-TNF agents. Nine healthy volunteers served as controls. Blood samples were taken at baseline, then at 4th and 8th week of therapy. The characteristics of several intracellular activation processes during short-term activation of T-cells including cytoplasmic Ca2+ level, mitochondrial Ca2+ level, reactive oxygen species (ROS) and nitric oxide (NO) generation were determined by a novel flow-cytometry technique. At baseline, the tested processes were comparable to controls in naïve RA. During GCS therapy, cytoplasmic Ca2+ level and ROS generation decreased. After the addition of MTX to GCS cytoplasmic Ca2+ level became comparable to controls, while ROS generation decreased further. In DMARD non responders, cytoplasmic Ca2+ level was higher than controls at baseline. The cytoplasmic Ca2+ level became comparable to controls and ROS generation decreased during each of the three anti-TNF-α agent therapies. Mitochondrial Ca2+ level and NO generation were unaltered in all of the patient groups. These results indicate that intracellular machinery is affected in T-cells of RA patients. This may alter the behavior of T-cells during activation. Different therapeutic approaches may modulate the abnormal T-cell functions. PMID:25098248

Hierarchical Controlled Remote State Preparation by Using a Four-Qubit Cluster State

NASA Astrophysics Data System (ADS)

Ma, Peng-Cheng; Chen, Gui-Bin; Li, Xiao-Wei; Zhan, You-Bang

2018-06-01

We propose a scheme for hierarchical controlled remote preparation of an arbitrary single-qubit state via a four-qubit cluster state as the quantum channel. In this scheme, a sender wishes to help three agents to remotely prepare a quantum state, respectively. The three agents are divided into two grades, that is, an agent is in the upper grade and other two agents are in the lower grade. In this process of remote state preparation, the agent of the upper grade only needs the assistance of any one of the other two agents for recovering the sender's original state, while an agent of the lower grade needs the collaboration of all the other two agents. In other words, the agents of two grades have different authorities to reconstruct sender's original state.

Impact of anti-rheumatic treatment on cardiovascular risk in Asian patients with rheumatoid arthritis.

PubMed

Cho, Soo-Kyung; Kim, Dam; Won, Soyoung; Lee, Jiyoung; Park, ByeongJu; Jang, Eun Jin; Bae, Sang-Cheol; Sung, Yoon-Kyoung

2018-02-01

To estimate the incidence of cardiovascular disease (CVD) in Asian patients with rheumatoid arthritis (RA) and to evaluate the impact of anti-rheumatic treatment on the development of CVD. A retrospective cohort of Asian patients with RA was established to identify the incidence rate (IR) of CVD in RA patients. The cohort was generated using the Korean National Healthcare claims database, which contained claims from Jan 2009 to Dec 2013. A total of 137,512 RA patients were identified; individuals with a history of CVD for 6 months or more before the index date were excluded. Nested case-control samples were drawn from the full study population with a case:control ratio of 1:4 (n = 7102 cases; n = 27,018 controls without CVD). A conditional multivariate regression model was used to evaluate the impact of anti-rheumatic treatment on the development of CVD in RA patients after matching for age, sex, RA index date, comorbidities, and drug use (e.g., antiplatelet agents and cholesterol-lowering agents). The IR for development of overall CVD in RA patients was 182.1 (95% CI: 178.4-185.9) per 10,000 person-years. In models adjusted for other CVD risk factors, disease-modifying anti-rheumatic drugs (DMARDs) (OR = 0.79) were protective against CVD, and biologic DMARDs were not significantly associated with CVD risk (OR = 0.85). Corticosteroids (OR = 1.26) and NSAIDs (nonselective NSAIDs: OR = 1.32, Cox-2 inhibitors: OR = 1.31) were risk factors for CVD in RA patients. The use of DMARDs is protective against CVD, while corticosteroids and NSAIDs increased the risk of CVD in RA patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Satellite Ephemeris Correction via Remote Site Observation for Star Tracker Navigation Performance Improvement

DTIC Science & Technology

2016-03-01

squared RMS root mean squared GCRF Geocentric Celestial Reference Frame xi List of Figures Figure Page 1 Geometry of single observation...RA and DEC in the celestial sphere. The Geocentric Celestial Reference Frame (GCRF) is the standard geocentric frame that measures the RA east in the...Figure 2. Right ascension (α) and declination (δ) in the celestial sphere[6] 7 made between geocentric and topocentric angles. Geocentric is referred to

Current drug therapy for rheumatoid arthritis.

PubMed

Kawai, Shinichi

2003-01-01

The etiology of rheumatoid arthritis (RA) remains unclear at present, but advances have been made in the drug therapy for RA. Recent attention has been focused on selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit a subtype of cyclooxygenase. Various clinical studies have confirmed that the selective COX-2 inhibitors cause fewer severe gastrointestinal complications, although an increased incidence of myocardial infarction was suggested. Terminal enzymes of the arachidonic acid cascade, such as membrane-associated prostaglandin E synthase, might be a target for new NSAIDs in the near future. Low-dose glucocorticoid treatment for RA has been reconsidered possibly to prevent articular destruction of RA. Special attention for glucocorticoid-induced osteoporosis by concomitant administration of bisphosphonates might be necessary. Disease-modifying antirheumatic drugs should be effective in delaying the progression of joint destruction and physical disability. Methotrexate, sulfasalazine, and leflunomide have shown such an effect. Inhibition of articular destruction was also proven by administration of the biologic agents etanercept and infliximab plus methotrexate. Tuberculosis complicated with infliximab therapy is one of the most important concerns in Japan. Agents that improve the quality of life of patients with RA are still needed.

A Radium-223 Microgenerator from Cyclotron-Produced Trace Actinium-227

PubMed Central

Abou, Diane S.; Pickett, Juile; Mattson, John E.; Thorek, Daniel L. J.

2016-01-01

The alpha particle emitter Radium-223 dichloride (223RaCl2) has recently been approved for treatment of late-stage bone metastatic prostate cancer. There is considerable interest in studying this new agent outside of the clinical setting, however the supply of 223Ra is limited and expensive. We have engineered a 223Ra microgenerator using traces of 227Ac previously generated from cyclotron-produced 225Ac. Radiochemically pure 223RaCl2 was made, characterized, evaluated in vivo, and the source was recovered in high yield for regeneration of the microgenerator. PMID:27835737

Functionalized NaA nanozeolites labeled with 224,225Ra for targeted alpha therapy.

PubMed

Piotrowska, Agata; Leszczuk, Edyta; Bruchertseifer, Frank; Morgenstern, Alfred; Bilewicz, Aleksander

2013-01-01

The 223 Ra, 224 Ra, and 225 Ra radioisotopes exhibit very attractive nuclear properties for application in radionuclide therapy. Unfortunately the lack of appropriate bifunctional ligand for radium is the reason why these radionuclides have not found application in receptor-targeted therapy. In the present work, the potential usefulness of the NaA nanozeolite as a carrier for radium radionuclides has been studied. 224 Ra and 225 Ra, α-particle emitting radionuclides, have been absorbed in the nanometer-sized NaA zeolite (30-70 nm) through simple ion exchange. 224,225 Ra-nanozeolites exhibited very high stability in solutions containing physiological salt, EDTA, amino acids, and human serum. To make NaA nanozeolite particles dispersed in water their surface was modified with a silane coupling agent containing poly(ethylene glycol) molecules. This functionalization approach let us covalently attach a biomolecule to the NaA nanozeolite surface.

Could early rheumatoid arthritis resolve after periodontitis treatment only?: case report and review of the literature.

PubMed

Salemi, Simonetta; Biondo, Michela I; Fiorentino, Chiara; Argento, Giuseppe; Paolantonio, Michele; Di Murro, Carlo; Malagnino, Vito A; Canzoni, Marco; Diamanti, Andrea Picchianti; D'Amelio, Raffaele

2014-12-01

Rheumatoid arthritis (RA) is an immune-mediated polyarthritis; currently no pathogenic agent has been identified as a disease trigger. A patient with RA, presumably caused by periodontal infection, whose remission has been observed after periodontitis treatment in absence of specific RA therapy, is reported here for the first time, to our knowledge. A 61-year-old male patient presented migrant arthritis associated with antibodies against citrullinated protein antigens positivity. The clinical features allowed to make RA diagnosis according to the 2010 European League against Rheumatism/American College of Rheumatology RA classification criteria. X-ray of the second upper molar showed chronic apical periodontitis. After its treatment, arthritis remission has been observed in the absence of specific RA therapy. It has been suggested that periodontitis may have a trigger role in RA pathogenesis. This could be explained by the enzymatic action of Porphyromonas gingivalis, probably leading to break tolerance to collagen. The identification and subsequent treatment of periodontitis should therefore be considered pivotal in RA prophylaxis and management.

Inhibition of HIF-1{alpha} activity by BP-1 ameliorates adjuvant induced arthritis in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shankar, J.; Thippegowda, P.B., E-mail: btprabha@uic.edu; Kanum, S.A.

Rheumatoid arthritis (RA) is a chronic inflammatory, angiogenic disease. Inflamed synovitis is a hallmark of RA which is hypoxic in nature. Vascular endothelial growth factor (VEGF), one of the key regulators of angiogenesis, is overexpressed in the pathogenesis of RA. VEGF expression is regulated by hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), a master regulator of homeostasis which plays a pivotal role in hypoxia-induced angiogenesis. In this study we show that synthetic benzophenone analogue, 2-benzoyl-phenoxy acetamide (BP-1) can act as a novel anti-arthritic agent in an experimental adjuvant induced arthritis (AIA) rat model by targeting VEGF and HIF-1{alpha}. BP-1 administered hypoxic endothelial cells andmore » arthritic animals clearly showed down regulation of VEGF expression. Further, BP-1 inhibits nuclear translocation of HIF-1{alpha}, which in turn suppresses transcription of the VEGF gene. These results suggest a further possible clinical application of the BP-1 derivative as an anti-arthritic agent in association with conventional chemotherapeutic agents.« less

Combinational treatment with retinoic acid derivatives in non-small cell lung carcinoma in vitro.

PubMed

Choi, Eun Jung; Whang, Young Mi; Kim, Seok Jin; Kim, Hyun Jin; Kim, Yeul Hong

2007-09-01

The growth inhibitory effects of four retinoic acid (RA) derivatives, 9-cis RA, 13-cis RA, N-(4-hydroxyphenyl) retinamide (4-HPR), and all-trans retinoic acid (ATRA) were compared. In addition, the effects of various combinations of these four agents were examined on non-small cell lung carcinoma (NSCLC) cell-lines, and on the expressions of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) on these cells. At the clinically achievable concentration of 1 microM, only 4-HPR inhibited the growths of H1299 and H460 cells-lines. However, retinoic acid receptor beta(RAR beta) expression was up-regulated on H460 and H1299 cells treated with 1 microM of ATRA, 13-cis RA, or 9-cis RA. All NSCLC cell lines showed growth inhibition when exposed sequentially to 1 microM ATRA and 0.1 microM 4-HPR. In particular, sequential treatment with 1 microM ATRA or 13-cis RA and 4-HPR markedly inhibited H1703 cell growth; these cells exhibited no basal RAR beta expression and were refractory to 4-HPR. However, in NSCLC cell lines that expressed RAR beta, the expressional levels of RAR beta were up-regulated by ATRA alone and by sequential treatment with ATRA and 4-HPR. 4-HPR was found to be the most active of the four agents in terms of NSCLC growth-inhibition. Moreover, sequential treatments with ATRA or 13-cis RA followed by 4-HPR were found to have synergistic growth-inhibitory effects and to regulate RAR expression.

Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions

PubMed Central

Smolen, Josef S; Schoels, Monika M; Nishimoto, Norihiro; Breedveld, Ferdinand C; Burmester, Gerd R; Dougados, Maxime; Emery, Paul; Ferraccioli, Gianfranco; Gabay, Cem; Gibofsky, Allan; Gomez-Reino, Juan Jesus; Jones, Graeme; Kvien, Tore K; Murakami, Miho; Betteridge, Neil; Bingham, Clifton O; Bykerk, Vivian; Choy, Ernest H; Combe, Bernard; Cutolo, Maurizio; Graninger, Winfried; Lanas, Angel; Martin-Mola, Emilio; Montecucco, Carlomaurizio; Ostergaard, Mikkel; Pavelka, Karel; Rubbert-Roth, Andrea; Sattar, Naveed; Scholte-Voshaar, Marieke; Tanaka, Yoshiya; Trauner, Michael; Valentini, Gabriele; Winthrop, Kevin L; de Wit, Maarten; van der Heijde, Désirée

2013-01-01

Background Since approval of tocilizumab (TCZ) for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), interleukin 6 (IL-6) pathway inhibition was evaluated in trials of TCZ and other agents targeting the IL-6 receptor and ligand in various RA populations and other inflammatory diseases. This consensus document informs on interference with the IL-6 pathway based on evidence and expert opinion. Methods Preparation of this document involved international experts in RA treatment and RA patients. A systematic literature search was performed that focused on TCZ and other IL6-pathway inhibitors in RA and other diseases. Subsequently, incorporating available published evidence and expert opinion, the steering committee and a broader expert committee (both including RA patients) formulated the current consensus statement. Results The consensus statement covers use of TCZ as combination- or monotherapy in various RA populations and includes clinical, functional and structural aspects. The statement also addresses the second approved indication in Europe JIA and non-approved indications. Also early phase trials involving additional agents that target the IL-6 receptor or IL-6 were evaluated. Safety concerns, including haematological, hepatic and metabolic issues as well as infections, are addressed likewise. Conclusions The consensus statement identifies points to consider when using TCZ, regarding indications, contraindications, screening, dose, comedication, response evaluation and safety. The document is aimed at supporting clinicians and informing patients, administrators and payers on opportunities and limitations of IL-6 pathway inhibition. PMID:23172750

Bone effects of biologic drugs in rheumatoid arthritis.

PubMed

Corrado, Addolorata; Neve, Anna; Maruotti, Nicola; Cantatore, Francesco Paolo

2013-01-01

Biologic agents used in the treatment of rheumatoid arthritis (RA) are able to reduce both disease activity and radiographic progression of joint disease. These drugs are directed against several proinflammatory cytokines (TNF α , IL-6, and IL-1) which are involved both in the pathogenesis of chronic inflammation and progression of joint structural damage and in systemic and local bone loss typically observed in RA. However, the role of biologic drugs in preventing bone loss in clinical practice has not yet clearly assessed. Many clinical studies showed a trend to a positive effect of biologic agents in preventing systemic bone loss observed in RA. Although the suppression of inflammation is the main goal in the treatment of RA and the anti-inflammatory effects of biologic drugs exert a positive effect on bone metabolism, the exact relationship between the prevention of bone loss and control of inflammation has not been clearly established, and if the available biologic drugs against TNF α , IL-1, and IL-6 can exert their effect on systemic and local bone loss also through a direct mechanism on bone cell metabolism is still to be clearly defined.

Pharmacological interventions for stress ulcer prophylaxis in critically ill patients: a mixed treatment comparison network meta-analysis and a recursive cumulative meta-analysis.

PubMed

Sridharan, Kannan; Sivaramakrishnan, Gowri; Gnanaraj, Jerome

2018-02-01

Proton pump inhibitors (PPI), histamine-2 receptor antagonists (H2RA), sucralfate and antacids are the commonly administered agents for stress ulcer prophylaxis (SUP) in critically ill patients. The authors of this paper have conducted a network meta-analysis to compare the efficacy of these agents in SUP. Electronic databases were searched for randomized controlled trials, cohort studies and conference abstracts for studies comparing a SUP agent in critically ill patients to another active SUP agent or placebo. Overt, occult and clinically significant upper gastro-intestinal (UGI) bleeding, all-cause mortality, pneumonia, gastric colonization and ICU length of stay were considered as the outcome measures. A random effects model was used to generate pooled estimates. A total of 53 studies (4258 participants) were included. The pooled estimates were in favor of PPI and sucralfate for the overt UGI bleeding. PPI and H2RA bolus were associated with increased risk of gastric colonization and pneumonia. SUP in critically ill patients was not associated with any benefit with regard to clinically significant bleeding episodes. However, PPI and sucralfate significantly reduces overt UGI bleeding. On the contrary, PPI and H2RA bolus are associated with an increased risk of gastric colonization and pneumonia.

Potent Antiarthritic Properties of Phloretin in Murine Collagen-Induced Arthritis.

PubMed

Wang, Shun-Ping; Lin, Shih-Chao; Li, Shiming; Chao, Ya-Hsuan; Hwang, Guang-Yuh; Lin, Chi-Chen

2016-01-01

In the exploration of potential therapeutic agents for rheumatoid arthritis (RA), DBA/1J mice are used as the RA model of collagen-induced arthritis (CIA). Phloretin, a flavonoid compound extracted from Prunus mandshurica , has been found to exhibit anti-inflammatory activity, making it a potential candidate for treatment of RA. The objective of this study was to evaluate the therapeutic effects of phloretin on CIA mice. CIA mice were dosed daily with phloretin at either 50 or 100 mg/kg among two treatment groups. CIA treated mice showed mitigation of clinical symptoms of RA in addition to reduced inflammation of hind-limbs compared to mice who did not receive phloretin. Histological analysis showed that phloretin suppressed the severity of RA and effectively mitigated joint inflammation and cartilage- and bone-destruction via reducing proinflammatory cytokine productions (TNF- α , IL-6, IL-1 β , and IL-17). This was at least partially mediated by causing inadequate splenocyte activation and proliferation. Moreover, phloretin-treated CIA mice showed decreased oxidative stress and diminished levels of malondialdehyde (MDA) and hydrogen peroxide (H 2 O 2 ) in paw tissues as well as reduced productivity of anti-collagen antibodies in serum. We have concluded that phloretin could be a potent and effective antiarthritis agent, demonstrating anti-inflammatory, antioxidative, and immunomodulatory effects in CIA mice.

Remote memory in a patient with amnesia due to hypoxia.

PubMed

Beatty, W W; Salmon, D P; Bernstein, N; Butters, N

1987-08-01

It has been suggested that amnesic patients suffer a selective loss of episodic memory while semantic memory remains well preserved. To assess the validity of this idea we studied remote memory in an amnesic patient, (M.R.L.), using several different measures that differ in the extent to which they engage episodic or semantic memory. On two different versions of the Albert et al. (1979) remote memory battery M.R.L. displayed severe retrograde amnesia (RA) extending backwards in time for about 15 years with excellent preservation of older memories. With standard recall instructions his overall performance on the Crovitz test of autobiographical memory was impaired and all of M.R.L.'s specific, temporally dated memories were given from the first half of his life. When asked to reconstruct his past residential history in detail, M.R.L. provide specific and generally accurate information for residences occupied from his boyhood until 1970, but thereafter his memory became quite unreliable. On a test of knowledge of terms commonly employed in the surveying profession, in which he worked for the past 20 years, M.R.L.'s performance was also impaired. The consistent pattern of RA displayed by this patient on all of the tests of remote memory indicates that both episodic and semantic memory are impaired in amnesia.

Metabolism of oral 9-cis-retinoic acid in the human. Identification of 9-cis-retinoyl-beta-glucuronide and 9-cis-4-oxo-retinoyl-beta-glucuronide as urinary metabolites.

PubMed

Sass, J O; Masgrau, E; Saurat, J H; Nau, H

1995-09-01

Data from a number of investigators suggest that the 9-cis-isomer of RA1 (9-cis-RA) may be a promising agent in chemoprevention and treatment of certain types of cancer. Therefore, clinical studies on this retinoid have been initiated. However, up to now, no information has been published on the metabolism of 9-cis-RA in the human. Herein, we report the first data on retinoid metabolism after multiple administration of 9-cis-RA (20 mg/day po) to human volunteers. After 2 and 12-13 hr, plasma concentrations of 9-cis-RA and its metabolites 9,13-dicis-RA, 13-cis-RA, and all-trans-RA were low. In contrast, dosing with 13-cis-RA yielded much higher plasma retinoid levels. Effects on plasma retinol concentrations did not become obvious after any drug treatment. Several retinoid metabolites were found in the urine of 9-cis-RA-treated individuals, and 9-cis-RAG, as well as 9-cis-4-oxo-RAG, could be identified. After treatment with 9-cis-RA, high concentrations of the administered drug were found in the feces, along with comparably low concentrations of 13-cis-RA, 9,13-dicis-RA, and all-trans-RA. Our report indicates that 9-cis-RA is either eliminated much more rapidly than 13-cis-RA, or it is poorly absorbed, and presents the characterization of two urinary glucuronides.

Functional retrograde amnesia: a multiple case study.

PubMed

Fujiwara, Esther; Brand, Matthias; Kracht, Lutz; Kessler, Josef; Diebel, Andrea; Netz, Johannes; Markowitsch, Hans J

2008-01-01

Functional retrograde amnesia (RA) is a rare pathology and has been rarely studied in detail across different patients. We extensively examined five functional RA patients and compared their neuropsychological profile including anterograde and retrograde memory performance, executive functions, emotional processing, and formally assessed psychiatric symptoms. Across patients, neuropsychological deficits beyond RA were most consistently seen in executive functions and attention suggesting that these dysfunctions contribute to the remote memory deficit. In a majority of the patients, problems in social cognition and emotional behaviour were reflected in Theory of Mind deficits and accompanying psychiatric symptoms. Aberrances in a measure of social desirability were detected, pointing to repressive tendencies in three out of the five patients. Future studies of functional RA patients may investigate more specifically which frontal-lobe associated (dys-) functions contribute to the memory retrieval deficit. Moreover, studying more closely the interaction between social cognition, repressive personality style and memory inhibition in this disease seems worthwhile pursuing.

Treatment with Biologicals in Rheumatoid Arthritis: An Overview.

PubMed

Rein, Philipp; Mueller, Ruediger B

2017-12-01

Management and therapy of rheumatoid arthritis (RA) has been revolutionized by the development and approval of the first biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumor necrosis factor (TNF) α at the end of the last century. Today, numerous efficacious agents with different modes of action are available and achievement of clinical remission or, at least, low disease activity is the target of therapy. Early therapeutic interventions aiming at a defined goal of therapy (treat to target) are supposed to halt inflammation, improving symptoms and signs, and preserving structural integrity of the joints in RA. Up to now, bDMARDs approved for therapy in RA include agents with five different modes of action: TNF inhibition, T cell co-stimulation blockade, IL-6 receptor inhibition, B cell depletion, and interleukin 1 inhibition. Furthermore, targeted synthetic DMARDs (tsDMARDs) inhibiting Janus kinase (JAK) and biosimilars also are approved for RA. The present review focuses on bDMARDs and tsDMARDS regarding similarities and possible drug-specific advantages in the treatment of RA. Furthermore, compounds not yet approved in RA and biosimilars are discussed. Following the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) recommendations, specific treatment of the disease will be discussed with respect to safety and efficacy. In particular, we discuss the question of favoring specific bDMARDs or tsDMARDs in the two settings of insufficient response to methotrexate and to the first bDMARD, respectively.

Ex vivo model exhibits protective effects of sesamin against destruction of cartilage induced with a combination of tumor necrosis factor-alpha and oncostatin M.

PubMed

Khansai, Manatsanan; Boonmaleerat, Kanchanit; Pothacharoen, Peraphan; Phitak, Thanyaluck; Kongtawelert, Prachya

2016-07-11

Rheumatoid arthritis (RA) is an autoimmune disease associated with chronic inflammatory arthritis. TNF-α and OSM are pro-inflammatory cytokines that play a key role in RA progression. Thus, reducing the effects of both cytokines is practical in order to relieve the progression of the disease. This current study is interested in sesamin, an active compound in sesame seeds. Sesamin has been shown to be a chondroprotective agent in osteoarthritis models. Here, we have evaluated a porcine cartilage explant as a cartilage degradation model related to RA induced by TNF-α and/or OSM in order to investigate the effects of sesamin on TNF-α and OSM in the cartilage degradation model. A porcine cartilage explant was induced with a combination of TNF-α and OSM (test group) or IL-1β and OSM (control group) followed by a co-treatment of sesamin over a long-term period (35 days). After which, the tested explants were analyzed for indications of both the remaining and the degradation aspects using glycosaminoglycan and collagen as an indicator. The combination of TNF-α and OSM promoted cartilage degradation more than either TNF-α or OSM alone and was comparable with the combination of IL-1β and OSM. Sesamin could be offering protection against cartilage degradation by reducing GAGs and collagen turnover in the generated model. Sesamin might be a promising agent as an alternative treatment for RA patients. Furthermore, the generated model revealed itself to be an impressive test model for the analysis of phytochemical substances against the cartilage degradation model for RA. The model could be used to test for the prevention of cartilage degradation in other biological agents induced with TNF-α and OSM as well.

The effect of home bleaching agents on the surface roughness of five different composite resins: A SEM evaluation.

PubMed

Cengiz, Esra; Kurtulmus-Yilmaz, Sevcan; Ulusoy, Nuran; Deniz, Sule Tugba; Yuksel-Devrim, Ece

2016-05-01

The aim of this study was to investigate the effect of hydrogen peroxide (HP) and carbamide peroxide (CP) on the surface roughness of five different composite resins using profilometer and scanning electron microscope (SEM). Thirty-six specimens (1 mm thick, 10 mm in diameter) of five composite resins were fabricated. Each composite group was equally divided into three subgroups as control, CP and HP. In control group, specimens were stored in daily refreshed distilled water during the 14-day testing period. In other groups, 10% HP (Opalescence Treswhite) and 10% CP (Opalescence PF) were applied and surface roughness values (Ra) of each specimen were measured with a profilometer at the end of 14 days. Additionally, SEM analysis was performed to evaluate the surface deformations of composite resins. Data were analyzed with Kruskal-Wallis and Mann-Whitney U tests. Ra values of composite groups exposed to bleaching agents were statistically higher than control group (p < 0.05). There was no significant difference between Ra values after HP and CP application within each composite group while SEM micrographs showed higher surface alterations at HP group compared to CP. Among the composite resins tested, Ceram-X Mono revealed the lowest Ra values after CP and HP applications as seen at SEM images. Home bleaching agents increased the surface roughness of all composites. Except CP applied Ceram-X mono specimens, Ra values of all composite resins evaluated in this study exceeded the critical limit of 0.2 μm. Ceram-X mono was the least affected composite material after bleaching application. SCANNING 38:277-283, 2016. © 2016 Wiley Periodicals, Inc. © Wiley Periodicals, Inc.

Aggressive treatment of early rheumatoid arthritis: recognizing the window of opportunity and treating to target goals.

PubMed

Resman-Targoff, Beth H; Cicero, Marco P

2010-11-01

Evidence supports the use of aggressive therapy for patients with early rheumatoid arthritis (RA). Clinical outcomes in patients with early RA can improve with a treat-to-target approach that sets the goal at disease remission. The current selection of antirheumatic therapies, including conventional and biologic disease-modifying antirheumatic drugs (DMARDs), has made disease remission a realistic target for patients with early RA. The challenge is selecting the optimal antirheumatic drug or combination of drugs for initial and subsequent therapy to balance the clinical benefits, risks, and economic considerations. In some cases, the use of biologic agents as part of the treatment regimen has shown superior results compared with conventional DMARDs alone in halting the progression of disease, especially in reducing radiographic damage. However, the use of biologic agents as initial therapy is challenged by cost-effectiveness analyses, which favor the use of conventional DMARDs. The use of biologic agents may be justified in certain patients with poor prognostic factors or those who experience an inadequate response to conventional DMARDs as a means to slow or halt disease progression and its associated disability. In these cases, the higher cost of treatment with biologic agents may be offset by decreased societal costs, such as lost work productivity, and increased health-related quality of life. Further research is needed to understand optimal strategies for balancing costs, benefits, and risks of antirheumatic drugs. Some key questions are (1) when biologic agents are appropriate for initial therapy, and (2) when to conclude that response to conventional DMARDs is inadequate and biologic agents should be initiated.

Next Generation Remote Agent Planner

NASA Technical Reports Server (NTRS)

Jonsson, Ari K.; Muscettola, Nicola; Morris, Paul H.; Rajan, Kanna

1999-01-01

In May 1999, as part of a unique technology validation experiment onboard the Deep Space One spacecraft, the Remote Agent became the first complete autonomous spacecraft control architecture to run as flight software onboard an active spacecraft. As one of the three components of the architecture, the Remote Agent Planner had the task of laying out the course of action to be taken, which included activities such as turning, thrusting, data gathering, and communicating. Building on the successful approach developed for the Remote Agent Planner, the Next Generation Remote Agent Planner is a completely redesigned and reimplemented version of the planner. The new system provides all the key capabilities of the original planner, while adding functionality, improving performance and providing a modular and extendible implementation. The goal of this ongoing project is to develop a system that provides both a basis for future applications and a framework for further research in the area of autonomous planning for spacecraft. In this article, we present an introductory overview of the Next Generation Remote Agent Planner. We present a new and simplified definition of the planning problem, describe the basics of the planning process, lay out the new system design and examine the functionality of the core reasoning module.

Methotrexate: the emerging drug of choice for serious rheumatoid arthritis.

PubMed

Salach, R H; Cash, J M

1994-01-01

The recently recognized high morbidity and unexpected mortality associated with rheumatoid arthritis (RA) has spurred new interest in more aggressive, early treatment of this disease. Methotrexate (MTX) has rapidly become the rheumatologist's drug of choice for serious RA because of its favorable efficacy to toxicity ratio and rapid onset of action compared with other second-line agents. The initial concerns about hepatic fibrosis and cirrhosis in psoriatic patients has subsided somewhat as long-term liver toxicity data are accumulating in patients with RA. Routine liver biopsy with incremental doses of MTX is no longer recommended. Potential for severe lung, hematologic, and infectious complications exists, mandating careful monitoring of RA patients taking MTX.

Introduction to economic modeling for clinical rheumatologists: application to biologic agents in rheumatoid arthritis.

PubMed

Marra, Carlo A; Bansback, Nick; Anis, Aslam H; Shojania, Kamran

2011-03-01

Rheumatoid arthritis (RA) is a chronic, debilitating inflammatory, progressive musculoskeletal disease that affects 0.5-1.0% of the adult population in Western countries. The joint destruction and progressive functional disability associated with uncontrolled RA result in tremendous impacts on health-related quality of life, ability to work, and mortality. In addition, the treatment of the disease and associated complications exact a substantial economic burden to the patients, their families, and society. In the last decade, several biological agents (biologics) have been approved for use in RA, revolutionizing treatment. These biologics, which target cytokines such as tumor necrosis factor or lymphocytes such as B or T cells, reduce functional disability and substantially slow the progression of joint damage. However, because these agents typically cost ten to 100 times more than existing available older drug therapies, there has been worldwide concern regarding their impact on healthcare budgets. As such, there has been increased attention towards economic evaluation as a means to determine whether, and in which subgroup of patients, these newer, more expensive agents confer appropriate value for their additional cost. Indeed, evaluations have guided coverage decisions for both private and public health insurance agencies such as the National Institute for Health and Clinical Excellence in the UK. The use of economic evaluations to determine value for money for these agents has attracted both debate and controversy. Some of the controversy is related to the appropriateness of the structure of, and assumptions underlying, the decision models employed to estimate the long-term costs and benefits of these agents over existing therapies. To fully appreciate the debate, one must first understand the basic principles of economic evaluation and the necessity for using decision models to evaluate cost effectiveness. To understand the basic principles of economic evaluation, we refer the reader to an introductory article aimed at clinical rheumatologists. This paper attempts to explain the rationale for the use of economic modeling approaches to assess the value of biologics for RA using specific examples from the literature.

Biological agents: investigation into leprosy and other infectious diseases before indication*

PubMed Central

Antônio, João Roberto; Soubhia, Rosa Maria Cordeiro; Paschoal, Vania Del Arco; Amarante, Carolina Forte; Travolo, Ana Regina Franchi

2013-01-01

Biological agents are widely used for various immune-mediated diseases, with remarkable effectiveness in the treatment of rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. However, attention needs to be drawn to the adverse effects of these therapies and the risk of reactivating underlying granulomatous infectious diseases such as tuberculosis, leprosy, syphilis, leishmaniasis, among others. The objective of this paper is to describe a case of leprosy in a patient with RA using anti-TNF alfa, demonstrating the need for systematic investigation of skin lesions suggestive of leprosy in patients who require rheumatoid arthritis therapeutic treatment, especially in endemic regions like Brazil. PMID:24346871

Advances in the treatment of rheumatoid arthritis: old versus new therapies.

PubMed

Saravanan, Vadivelu; Hamilton, Jennifer

2002-07-01

Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.

"Design characteristics of the CORRONA CERTAIN study: a comparative effectiveness study of biologic agents for rheumatoid arthritis patients".

PubMed

Pappas, Dimitrios A; Kremer, Joel M; Reed, George; Greenberg, Jeffrey D; Curtis, Jeffrey R

2014-04-01

Comparative effectiveness research has recently attracted considerable attention. The Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) is an ongoing prospective cohort study of adult patients with Rheumatoid Arthritis (RA). CERTAIN uses the existing Consortium of Rheumatology Researchers of North America (CORRONA) network of participating private and academic sites in order to recruit patients fulfilling the 1987 ACR criteria that have at least moderate disease activity. Patients starting or switching biologic agents either anti-TNF therapy or a non anti-TNF biologic are eligible for enrollment, depending on the treatment selected by their physician. Enrollment is expected to be completed by March of 2014, and 2711 patients will participate in the study. As of October 7th 2013, 2234 patients have been enrolled. Patient visits and laboratory blood work are mandated every three months for one year. Safety data is collected through one year and beyond. The primary comparative effectiveness endpoint is attainment of low RA disease activity at one year among patients who have been exposed to at least one prior TNF-α inhibitor agent prior to enrollment. Multiple secondary effectiveness and safety endpoints will be addressed by investigating the entire population enrolled (naïve and biologic experienced). The unique design features of CERTAIN will inform comparative effectiveness and safety questions for choosing biologic agents for the management of RA.

Hierarchically controlled remote preparation of an arbitrary single-qubit state by using a four-qubit |χ > entangled state

NASA Astrophysics Data System (ADS)

Ma, Peng-Cheng; Chen, Gui-Bin; Li, Xiao-Wei; Zhan, You-Bang

2018-05-01

In this paper, we present a scheme for Hierarchically controlled remote preparation of an arbitrary single-qubit state via a four-qubit |χ > state as the quantum channel. In this scheme, a sender wishes to help three agents to remotely prepare a quantum state, respectively. The three agents are divided into two grades, that is, an agent is in the upper grade and other two agents are in the lower grade. It is shown that the agent of the upper grade only needs the assistance of any one of the other two agents for recovering the sender's original state, while an agent of the lower grade needs the collaboration of all the other two agents. In other words, the agents of two grades have different authorities to recover sender's original state.

Achievement of sustained deep remission with adalimumab in a patient with both refractory ulcerative colitis and seronegative erosive rheumatoid arthritis.

PubMed

Andrisani, G; Gremese, E; Guidi, L; Papa, A; Marzo, M; Felice, C; Pugliese, D; Armuzzi, A

2013-05-27

Inflammatory bowel disease (IBD) is commonly associated with peripheral inflammatory arthritis, and it has been estimated that as many as 12% of IBD patients report these manifestations. However, rheumatoid arthritis (RA) is rarely associated with ulcerative colitis (UC). Among all the biological agents available, nine have been currently approved for the treatment of RA. Conversely, only Infliximab and recently Adalimumab have been approved for UC. In particular, the efficacy of Adalimumab in UC has been demonstrated by both recent randomized controlled trials and real-life studies. Moreover, Adalimumab is a well-established treatment for RA. Herein, we describe a patient with RA and UC treated successfully with ADA.

Rheumatoid Arthritis-Associated Interstitial Lung Disease: Current Concepts.

PubMed

Brito, Yoel; Glassberg, Marilyn K; Ascherman, Dana P

2017-11-09

Among the many extra-articular complications of rheumatoid arthritis (RA), interstitial lung disease (ILD) contributes significantly to morbidity and mortality. Prevalence estimates for RA-ILD vary widely depending on the specific clinical, radiographic, and functional criteria used to establish the diagnosis. A key unresolved issue is whether early, subclinical forms of RA-ILD represent a precursor to end stage, fibrotic lung disease. Based on uncertainties surrounding the natural history of RA-ILD, incomplete understanding of underlying disease pathogenesis, and lack of controlled clinical trials, evidence-based therapeutic strategies remain largely undefined. Correlative clinico-epidemiological studies have identified key risk factors for disease progression. Complementing these findings, the identification of specific molecular and serological markers of RA-ILD has improved our understanding of disease pathogenesis and established the foundation for predictive biomarker profiling. Experience from case series and cohort studies suggests that newer biological agents such as rituximab may be viable treatment options. RA-ILD continues to have a major impact on "disease intrinsic" morbidity and mortality. Increased understanding of disease pathogenesis and the natural history of subclinical RA-ILD will promote the development of more refined therapeutic strategies.

Incorporating the treat-to-target concept in rheumatoid arthritis.

PubMed

Ruderman, Eric M; Nola, Kamala M; Ferrell, Stanley; Sapir, Tamar; Cameron, Davecia R

2012-01-01

Recent publications have proposed revisions to disease classification criteria, new definitions of remission, and guidelines for implementing treat-to-target strategies for the management of patients with rheumatoid arthritis (RA). Despite developments leading to this practice-changing approach, the concept of treat to target has not yet been widely accepted or implemented in managed care. At the 24th Annual Meeting Expo of the Academy of Managed Care Pharmacy (AMCP), held in San Francisco on April 18, 2012, a 4-hour activity titled Incorporating New Treat-to-Target Guidance and Strategies in RA: What Managed Care Needs to Know was conducted in association with AMCP's Continuing Professional Education Partner Program. The practicum featured didactic presentations, a roundtable session, and an expert panel discussion detailing research evidence, ideas, and discussion topics central to the treat-to target concept in RA and its applications to managed care. To (a) discuss recent advances in RA management, (b) evaluate strategies to optimize the use of disease-modifying antirheumatic drugs(DMARDs), and (c) explain how to incorporate the treat-to-target paradigm in contemporary clinical practice and clinical care models in order to improve outcomes for patients. The past decade has seen a tremendous amount of change in the field of rheumatology. The early and aggressive treatment of RA, including the use of novel biologic agents, has been shown to have favorable patient outcomes in reducing synovial inflammation, delaying joint damage,and maintaining functional status, leading to the recently published revisions in classification criteria and updated recommendations for the utilization of conventional DMARDs and biologic agents in the treatment of RA. The revised classification criteria can be used to diagnose RA patients at an earlier point in the disease course by placing greater emphasis on clinical features that manifest early in the disease process. The concept of achieving tight control of RA and treating to target has been well established and utilizes early diagnosis, aggressive treatment, and regular monitoring,leading to positive outcomes in a significant number of patients with RA who achieve current treatment goals of low levels of disease activity or clinical remission.

A randomized phase II chemoprevention trial of 13-CIS retinoic acid with or without alpha tocopherol or observation in subjects at high risk for lung cancer.

PubMed

Kelly, Karen; Kittelson, John; Franklin, Wilbur A; Kennedy, Timothy C; Klein, Catherine E; Keith, Robert L; Dempsey, Edward C; Lewis, Marina; Jackson, Mary K; Hirsch, Fred R; Bunn, Paul A; Miller, York E

2009-05-01

No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without alpha tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus alpha tocopherol (13-cis RA/alpha toco) or observation for 12 months. Outcome measures are derived from histologic evaluation of bronchial biopsy specimens obtained by bronchoscopy at baseline and follow-up. The primary outcome measure is treatment "failure" defined as histologic progression (any increase in the maximum histologic score) or failure to return for follow-up bronchoscopy. Seventy-five subjects were randomized (27/22/26 to observations/13-cis RA/13-cis RA/alpha toco); 59 completed the trial; 55 had both baseline and follow-up bronchoscopy. The risk of treatment failure was 55.6% (15 of 27) and 50% (24 of 48) in the observation and combined (13 cis RA plus 13 cis RA/alpha toco) treatment arms, respectively (odds ratio adjusted for baseline histology, 0.97; 95% confidence interval, 0.36-2.66; P = 0.95). Among subjects with complete histology data, maximum histology score in the observation arm increased by 0.37 units and by 0.03 units in the treated arms (difference adjusted for baseline, -0.18; 95% confidence interval, -1.16 to 0.81; P = 0.72). Similar (nonsignificant) results were observed for treatment effects on endobronchial proliferation as assessed by Ki-67 immunolabeling. Twelve-month treatment with 13-cis RA produced nonsignificant changes in bronchial histology, consistent with results in other trials. Agents advancing to phase III randomized trials should produce greater histologic changes. The addition of alpha tocopherol did not affect toxicity.

A Randomized Phase II Chemoprevention Trial of 13-CIS Retinoic Acid with Or without α Tocopherol or Observation in Subjects at High Risk for Lung Cancer

PubMed Central

Kelly, Karen; Kittelson, John; Franklin, Wilbur A.; Kennedy, Timothy C.; Klein, Catherine E.; Keith, Robert L.; Dempsey, Edward C.; Lewis, Marina; Jackson, Mary K.; Hirsch, Fred R.; Bunn, Paul A.; Miller, York E.

2011-01-01

No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without α tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus α tocopherol (13-cis RA/α toco) or observation for 12 months. Outcome measures are derived from histologic evaluation of bronchial biopsy specimens obtained by bronchoscopy at baseline and follow-up. The primary outcome measure is treatment “failure” defined as histologic progression (any increase in the maximum histologic score) or failure to return for follow-up bronchoscopy. Seventy-five subjects were randomized (27/22/26 to obervations/13-cis RA/13-cis RA/α toco); 59 completed the trial; 55 had both baseline and follow-up bronchoscopy. The risk of treatment failure was 55.6% (15 of 27) and 50% (24 of 48) in the observation and combined (13 cis RA plus 13 cis RA/α toco) treatment arms, respectively (odds ratio adjusted for baseline histology, 0.97; 95% confidence interval, 0.36–2.66; P = 0.95). Among subjects with complete histology data, maximum histology score in the observation arm increased by 0.37 units and by 0.03 units in the treated arms (difference adjusted for baseline, −0.18; 95% confidence interval, −1.16 to 0.81; P = 0.72). Similar (nonsignificant) results were observed for treatment effects on endobronchial proliferation as assessed by Ki-67 immunolabeling. Twelve-month treatment with 13-cis RA produced nonsignificant changes in bronchial histology, consistent with results in other trials. Agents advancing to phase III randomized trials should produce greater histologic changes. The addition of α tocopherol did not affect toxicity. PMID:19401528

Preparation and properties of calcium-silicate filled resins for dental restoration. Part II: Micro-mechanical behaviour to primed mineral-depleted dentine.

PubMed

Profeta, Andrea Corrado

2014-11-01

Evaluating microtensile bond strength (μTBS) and Knoop micro-hardness (KHN) of resin bonded-dentine interfaces created with two methacrylate-based systems either incorporating Bioglass 45S5 (3-E&RA/BG) or MTA (3-E&RA/WMTA). Solvated resins (50% ethanol/50% co-monomers) were used as primers while their neat counterparts were filled with the two calcium-silicate compounds. Application of neat resin adhesive with no filler served as control (3-E&RA). μTBS, KHN analysis and confocal tandem scanning microscopy (TSM) micropermeability were carried out after 24 h and 10 months of storage in phosphate buffer solution (DPBS). Scanning electron microscopy (SEM) was also performed after debonding. High μTBS values were achieved in all groups after 24 h of DPBS storage. On the contrary, solely the specimens created using 3-E&RA/BG and 3-E&RA/WMTA agents showed no significant reduction in terms of μTBS even after 10 months in DPBS; similarly, they did not restore the average superficial micro-hardness to the level of sound dentine, but maintained unchanged KHN values, and no statistical decrease was found following 10 months of DPBS storage. The only statistically significant changes occurred in the resin-dentine interfaces bonded with 3-E&RA that were subjected to a reduction of both μTBS and KHN values with ageing. In terms of micropermeability, adverse results were obtained with 3-E&RA while 3-E&RA/BG and 3-E&RA/WMTA demonstrated a beneficial effect after prolonged DPBS storage. Calcium-silicate filled composite resins performed better than a current etch-and-rinse adhesive and had a therapeutic/protective effect on the micro-mechanical properties of mineral-depleted resin-dentine interfaces. The incorporation of calcium-silicates into dental restorative and bonding agents can create more biomimetic (life-like) restorations. This will not only enable these materials to mimic the physical characteristics of the tooth structure, but will also stabilize and protect the remaining dental hard tissues.

Radium-223: From Radiochemical Development to Clinical Applications in Targeted Cancer Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruland, Oyvind S.; Jonasdottir, Thora J.; Fisher, Darrell R.

2008-09-15

The radiochemical properties of radium-223 (223Ra, T1/2 = 11.4 d) render this alpha-emitting radionuclide promising for targeted cancer therapy. Together with its short-lived daughters, each 223Ra decay produces four alpha-particle emissions—which enhance therapy effectiveness at the cellular level. In this paper, we review the recently published data reported for pre-clinical and clinical use of 223Ra in cancer treatment. We have evaluated two distinct chemical forms of 223Ra in vivo: 1) cationic 223Ra as dissolved RaCl2, and 2) liposome-encapsulated 223Ra. Cationic 223Ra seeks metabolically active osteoblastic bone and tumor lesions with high uptake and strong binding affinity based on its similaritiesmore » to calcium. Based on these properties, we have advanced the clinical use of 223Ra for treating bone metastases from late-stage breast and prostate cancer. The results show impressive anti-tumor activity and improved overall survival in hormone-refractory prostate cancer patients with bone metastases. In other studies, we have evaluated the biodistribution and tumor uptake of liposomally encapsulated 223Ra in mice with human osteosarcoma xenografts, and in dogs with spontaneous osteosarcoma and associated soft tissue metastases. Results indicate excellent biodistributions in both species. In dogs, we found considerable uptake of liposomal 223Ra in cancer metastases in multiple organs, resulting in favorable tumor-to-normal soft tissue ratios. Collectively, these findings show an outstanding potential for 223Ra as a therapeutic agent.« less

Raddeanin A, a triterpenoid saponin isolated from Anemone raddeana, suppresses the angiogenesis and growth of human colorectal tumor by inhibiting VEGFR2 signaling.

PubMed

Guan, Ying-Yun; Liu, Hai-Jun; Luan, Xin; Xu, Jian-Rong; Lu, Qin; Liu, Ya-Rong; Gao, Yun-Ge; Zhao, Mei; Chen, Hong-Zhuan; Fang, Chao

2015-01-15

Raddeanin A (RA) is an active triterpenoid saponin from a traditional Chinese medicinal herb, Anemone raddeana Regel. It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells. However, whether RA can inhibit angiogenesis, an essential step in cancer development, remains unknown. In this study, we found that RA could significantly inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration, and tube formation. RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane (CAM), restrained the trunk angiogenesis in zebrafish, and suppressed angiogenesis and growth of human HCT-15 colorectal cancer xenograft in mice. Western blot assay showed that RA suppressed VEGF-induced phosphorylation of VEGFR2 and its downstream protein kinases including PLCγ1, JAK2, FAK, Src, and Akt. Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis, demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy. Copyright © 2014 Elsevier GmbH. All rights reserved.

3-O-galloylated procyanidins from Rumex acetosa L. inhibit the attachment of influenza A virus.

PubMed

Derksen, Andrea; Hensel, Andreas; Hafezi, Wali; Herrmann, Fabian; Schmidt, Thomas J; Ehrhardt, Christina; Ludwig, Stephan; Kühn, Joachim

2014-01-01

Infections by influenza A viruses (IAV) are a major health burden to mankind. The current antiviral arsenal against IAV is limited and novel drugs are urgently required. Medicinal plants are known as an abundant source for bioactive compounds, including antiviral agents. The aim of the present study was to characterize the anti-IAV potential of a proanthocyanidin-enriched extract derived from the aerial parts of Rumex acetosa (RA), and to identify active compounds of RA, their mode of action, and structural features conferring anti-IAV activity. In a modified MTT (MTTIAV) assay, RA was shown to inhibit growth of the IAV strain PR8 (H1N1) and a clinical isolate of IAV(H1N1)pdm09 with a half-maximal inhibitory concentration (IC50) of 2.5 µg/mL and 2.2 µg/mL, and a selectivity index (SI) (half-maximal cytotoxic concentration (CC50)/IC50)) of 32 and 36, respectively. At RA concentrations>1 µg/mL plaque formation of IAV(H1N1)pdm09 was abrogated. RA was also active against an oseltamivir-resistant isolate of IAV(H1N1)pdm09. TNF-α and EGF-induced signal transduction in A549 cells was not affected by RA. The dimeric proanthocyanidin epicatechin-3-O-gallate-(4β→8)-epicatechin-3'-O-gallate (procyanidin B2-di-gallate) was identified as the main active principle of RA (IC50 approx. 15 µM, SI≥13). RA and procyanidin B2-di-gallate blocked attachment of IAV and interfered with viral penetration at higher concentrations. Galloylation of the procyanidin core structure was shown to be a prerequisite for anti-IAV activity; o-trihydroxylation in the B-ring increased the anti-IAV activity. In silico docking studies indicated that procyanidin B2-di-gallate is able to interact with the receptor binding site of IAV(H1N1)pdm09 hemagglutinin (HA). In conclusion, the proanthocyanidin-enriched extract RA and its main active constituent procyanidin B2-di-gallate protect cells from IAV infection by inhibiting viral entry into the host cell. RA and procyanidin B2-di-gallate appear to be a promising expansion of the currently available anti-influenza agents.

Profile of sarilumab and its potential in the treatment of rheumatoid arthritis.

PubMed

Raimondo, Maria Gabriella; Biggioggero, Martina; Crotti, Chiara; Becciolini, Andrea; Favalli, Ennio Giulio

2017-01-01

In recent years the use of biotechnological agents has drastically revolutionized the therapeutic approach and the progression of rheumatoid arthritis (RA). In particular, interleukin-6 (IL-6) has been demonstrated as a pivotal cytokine in the pathogenesis of the disease by contributing to both the innate and the adaptive immune system perturbation, and to the production of acute-phase proteins involved in the systemic expression of the disorder. The first marketed IL-6 blocker was tocilizumab, a humanized anti-IL-6 receptor (anti-IL-6R) monoclonal antibody. The successful use of tocilizumab in RA has encouraged the development of other biologic agents specifically targeting the IL-6 pathway, either directed against IL-6 cytokine (sirukumab, olokizumab, and clazakizumab) or IL-6 receptor (sarilumab). One Phase II and six Phase III randomized controlled trials demonstrated a broad efficacy of sarilumab across all RA patient subtypes, ranging from methotrexate (MTX) to tumor necrosis factor inhibitor insufficient responders. In particular, sarilumab as monotherapy demonstrated a clear head-to-head superiority over adalimumab in MTX-intolerant subjects. In addition, compared with tocilizumab, sarilumab showed a similar safety profile with significantly higher affinity and longer half-life, responsible for a reduction of the frequency of administration (every other week instead weekly). All these aspects may be important in defining the strategy for positioning sarilumab in the treatment algorithm of RA. Indeed, observational data coming from post-marketing real-life studies may provide crucial additional information for better understanding the role of sarilumab in the management of the disease. This review summarizes both the biological role of IL-6 in RA and the clinical data available on sarilumab as an alternative therapeutic option in RA patients.

“Design characteristics of the CORRONA CERTAIN study: a comparative effectiveness study of biologic agents for rheumatoid arthritis patients”

PubMed Central

2014-01-01

Background Comparative effectiveness research has recently attracted considerable attention. The Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) is an ongoing prospective cohort study of adult patients with Rheumatoid Arthritis (RA). Methods/Design CERTAIN uses the existing Consortium of Rheumatology Researchers of North America (CORRONA) network of participating private and academic sites in order to recruit patients fulfilling the 1987 ACR criteria that have at least moderate disease activity. Patients starting or switching biologic agents either anti-TNF therapy or a non anti-TNF biologic are eligible for enrollment, depending on the treatment selected by their physician. Enrollment is expected to be completed by March of 2014, and 2711 patients will participate in the study. As of October 7th 2013, 2234 patients have been enrolled. Patient visits and laboratory blood work are mandated every three months for one year. Safety data is collected through one year and beyond. The primary comparative effectiveness endpoint is attainment of low RA disease activity at one year among patients who have been exposed to at least one prior TNF-α inhibitor agent prior to enrollment. Multiple secondary effectiveness and safety endpoints will be addressed by investigating the entire population enrolled (naïve and biologic experienced). Discussion The unique design features of CERTAIN will inform comparative effectiveness and safety questions for choosing biologic agents for the management of RA. PMID:24690143

Trojan horses and guided missiles: targeted therapies in the war on arthritis.

PubMed

Ferrari, Mathieu; Onuoha, Shimobi C; Pitzalis, Costantino

2015-06-01

Despite major advances in the treatment of rheumatoid arthritis (RA) led by the success of biologic therapies, the lack of response to therapy in a proportion of patients, as well as therapy discontinuation owing to systemic toxicity, are still unsolved issues. Unchecked RA might develop into progressive structural joint damage, loss of function and long-term disability, disorders which are associated with a considerable health-economic burden. Therefore, new strategies are required to actively target and deliver therapeutic agents to disease sites in order to promote in situ activity and decrease systemic toxicity. Polymer-drug conjugates can improve the pharmacokinetics of therapeutic agents, conferring desirable properties such as increased solubility and tissue penetration at sites of active disease. Additionally, nanotechnology is an exciting modality in which drugs are encapsulated to protect them from degradation or early activation in the circulation, as well as to reduce systemic toxicity. Together with the targeting capacity of antibodies and site-specific peptides, these approaches will facilitate selective accumulation of therapeutic agents in the inflamed synovium, potentially improving drug efficacy at disease sites without affecting healthy tissues. This Review aims to summarize key developments in the past 5 years in polymer conjugation, nanoparticulate drug delivery and antibody or peptide-based targeting--strategies that might constitute the platform for the next generation of RA therapeutics.

Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat.

PubMed

McCormick, D L; Rao, K V

1999-01-01

The high incidence and long latent period of prostate cancer make it an ideal target for chemoprevention. We have evaluated a series of agents for chemopreventive efficacy using a model in which hormone-dependent prostate cancers are induced in the Wistar-Unilever (WU) rat by sequential treatment with antiandrogen (cyproterone acetate), androgen (testosterone propionate), and direct-acting chemical carcinogen (N-methyl-N-nitrosourea), followed by chronic androgen stimulation (testosterone). This regimen reproducibly induces prostate cancers in high incidence, with no gross toxicity and a low incidence of neoplasia in the seminal vesicle and other non-target tissues. Dehydroepiandrosterone (DHEA) and 9-cis-retinoic acid (9-cis-RA) are the most active agents identified to date. DHEA inhibits prostate cancer induction both when chronic administration is begun prior to carcinogen exposure, and when administration is delayed until preneoplastic prostate lesions are present. 9-cis-RA is the most potent inhibitor of prostate carcinogenesis identified; a study to determine the efficacy of delayed administration of 9-cis-RA is in progress. Liarozole fumarate confers modest protection against prostate carcinogenesis, while N-(4-hydroxyphenyl)retinamide (fenretinide), alpha-difluoromethylornithine, oltipraz, DL-alpha-tocopherol acetate (vitamin E), and L-selenomethionine are inactive. Chemoprevention efficacy evaluations in the WU rat will support the identification of agents that merit study for prostate cancer chemoprevention in humans.

AMPEROMETRIC THICK-FILM STRIP ELECTRODES FOR MONITORING ORGANOPHOSPHATE NERVE AGENTS BASED ON IMMOBILIZED ORGANOPHOSPHORUS HYDROLASE. (R823663)

EPA Science Inventory

An amperometric biosensor based on the immobilization of organophosphorus hydrolase
(OPH) onto screen-printed carbon electrodes is shown useful for the rapid, sensitive, and low-cost
detection of organophosphate (OP) nerve agents. The sensor relies upon the sensitive and ra...

Use of health insurance claim patterns to identify patients using nonsteroidal anti-inflammatory drugs for rheumatoid arthritis.

PubMed

Bernard, Marie-Agnès; Bénichou, Jacques; Blin, Patrick; Weill, Alain; Bégaud, Bernard; Abouelfath, Abdelilah; Moore, Nicholas; Fourrier-Réglat, Annie

2012-06-01

To determine healthcare claim patterns associated using nonsteroidal anti-inflammatory drugs (NSAIDs) for rheumatoid arthritis (RA). The CADEUS study randomly identified NSAID users within the French health insurance database. One-year claims data were extracted, and NSAID indication was obtained from prescribers. Logistic regression was used in a development sample to identify claim patterns predictive of RA and models applied to a validation sample. Analyses were stratified on the dispensation of immunosuppressive agents or specific antirheumatism treatment, and the area under the receiver operating characteristic curve was used to estimate discriminant power. NSAID indication was provided for 26,259 of the 45,217 patients included in the CADEUS cohort; it was RA for 956 patients. Two models were constructed using the development sample (n = 13,143), stratifying on the dispensation of an immunosuppressive agent or specific antirheumatism treatment. Discriminant power was high for both models (AUC > 0.80) and was not statistically different from that found when applied to the validation sample (n = 13,116). The models derived from this study may help to identify patients prescribed NSAIDs who are likely to have RA in claims databases without medical data such as treatment indication. Copyright © 2012 John Wiley & Sons, Ltd.

Chrysin alleviates testicular dysfunction in adjuvant arthritic rats via suppression of inflammation and apoptosis: Comparison with celecoxib

DOE Office of Scientific and Technical Information (OSTI.GOV)

Darwish, Hebatallah A.; Arab, Hany H., E-mail: hany.arab@pharma.cu.edu.eg; Abdelsalam, Rania M.

Long standing rheumatoid arthritis (RA) is associated with testicular dysfunction and subfertility. Few studies have addressed the pathogenesis of testicular injury in RA and its modulation by effective agents. Thus, the current study aimed at evaluating the effects of two testosterone boosting agents; chrysin, a natural flavone and celecoxib, a selective COX-2 inhibitor, in testicular impairment in rats with adjuvant arthritis, an experimental model of RA. Chrysin (25 and 50 mg/kg) and celecoxib (5 mg/kg) were orally administered to Wistar rats once daily for 21 days starting 1 h before arthritis induction. Chrysin suppressed paw edema with comparable efficacy tomore » celecoxib. More important, chrysin, dose-dependently and celecoxib attenuated the testicular injury via reversing lowered gonadosomatic index and histopathologic alterations with preservation of spermatogenesis. Both agents upregulated steroidogenic acute regulatory (StAR) mRNA expression and serum testosterone with concomitant restoration of LH and FSH. Furthermore, they suppressed inflammation via abrogation of myeloperoxidase, TNF-α and protein expression of COX-2 and iNOS besides elevation of IL-10. Alleviation of the testicular impairment was accompanied with suppression of oxidative stress via lowering testicular lipid peroxides and nitric oxide. With respect to apoptosis, both agents downregulated FasL mRNA expression and caspase-3 activity in favor of cell survival. For the first time, these findings highlight the protective effects of chrysin and celecoxib against testicular dysfunction in experimental RA which were mediated via boosting testosterone in addition to attenuation of testicular inflammation, oxidative stress and apoptosis. Generally, the 50 mg/kg dose of chrysin exerted comparable protective actions to celecoxib. - Highlights: • Chrysin and celecoxib alleviated testicular suppression in adjuvant arthritis. • They attenuated histopathological damage and preserved spermatogenesis. • They upregulated StAR expression and testosterone with restoration of LH and FSH. • They abrogated myeloperoxidase, TNF-α and COX-2 and iNOS expression. • They suppressed oxidative stress and FasL-associated apoptosis.« less

Remote sensing of chemical warfare agent by CO2 -lidar

NASA Astrophysics Data System (ADS)

Geiko, Pavel P.; Smirnov, Sergey S.

2014-11-01

The possibilities of remote sensing of chemical warfare agent by differential absorption method were analyzed. The CO2 - laser emission lines suitable for sounding of chemical warfare agent with provision for disturbing absorptions by water vapor were choose. The detection range of chemical warfare agents was estimated for a lidar based on CO2 - laser The other factors influencing upon echolocation range were analyzed.

Sensitivity analysis

MedlinePlus

... Katsikas A, Beavis KG. In vitro testing of antimicrobial agents. In: McPherson RA, Pincus MR, eds. ... Department of Family Medicine, UW Medicine, School of Medicine, University of Washington, ...

Postinflammatory hyperpigmentation: evolving combination treatment strategies.

PubMed

Taylor, Susan C; Burgess, Cheryl M; Callender, Valerie D; Fu, Jan; Rendon, Marta I; Roberts, Wendy E; Shalita, Alan R

2006-08-01

Postinflammatory hyperpigmentation (PIH) is a common acquired excess of pigment in the epidermal and/or dermal layers of the skin. Lesions persist for extended periods if untreated, thus therapy is warranted. Topical monotherapies include the standard bleaching agent hydroquinone (HQ) as well as retinoids. Recently, several fixed-dose combination products were introduced to the armamentarium: HQ 4%-retinol 0.15% in a microsponge formulation; HQ 4%-retinol 0.3%; mequinol 2%-tretinoin (RA) 0.01%; and fluocinolone acetonide (FA) 0.01%, HQ 4%, and RA 0.05%. Recent findings have suggested that mequinol 2%-RA 0.01% solution is a promising alternative for the treatment of PIH.

In situ-generated metal oxide catalyst during CO oxidation reaction transformed from redox-active metal-organic framework-supported palladium nanoparticles

PubMed Central

2012-01-01

The preparation of redox-active metal-organic framework (ra-MOF)-supported Pd nanoparticles (NPs) via the redox couple-driven method is reported, which can yield unprotected metallic NPs at room temperature within 10 min without the use of reducing agents. The Pd@ra-MOF has been exploited as a precursor of an active catalyst for CO oxidation. Under the CO oxidation reaction condition, Pd@ra-MOF is transformed into a PdOx-NiOy/C nanocomposite to generate catalytically active species in situ, and the resultant nanocatalyst shows sustainable activity through synergistic stabilization. PMID:22898143

Recent advances in the pathogenesis, prediction, and management of rheumatoid arthritis-associated interstitial lung disease.

PubMed

Johnson, Cheilonda

2017-05-01

To provide an overview of recently published articles covering interstitial lung disease associated with rheumatoid arthritis (RA-ILD). Over the past year, many studies replicated previous findings in more diverse and occasionally larger populations internationally. Specifically, the association among cigarette smoking, high rheumatoid factor titer, elevated anticitrullinated protein antibody (ACPA) levels, and RA-ILD was strengthened. Clinical characteristics, autoantibodies, and biomarkers to aid in RA-ILD development, progression, and mortality prediction were explored. Finally, direct and indirect treatment effects were highlighted. The ability to identify risk factors for preclinical RA-ILD has been enhanced, but the proper management strategy for these patients is yet to be defined. ACPAs and cigarette smoking are highly associated with RA-ILD, but the mechanistic relationship between lung injury and autoantibody generation remains unknown. There is conflicting evidence regarding the significance of a usual interstitial pneumonia (UIP) versus non-UIP pattern on high-resolution computed tomography. The use of biologic agents in patients with rheumatoid arthritis does not appear to increase the risk of incident ILD or RA-ILD exacerbation. Randomized prospective studies of specific therapy for RA-ILD are still lacking.

The efficacy of 9-cis retinoic acid in experimental models of cancer.

PubMed

Gottardis, M M; Lamph, W W; Shalinsky, D R; Wellstein, A; Heyman, R A

1996-01-01

9-cis retinoic acid (9-cis RA) is a retinoid receptor pan-agonist that binds with high affinity to both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Using a variety of in vivo and in vitro cancer models, we present experimental data that 9-cis RA has activity as a potential chemotherapeutic agent. Treatment of the human promyelocytic leukemia cell line HL-60 with 9-cis RA decreases cell proliferation, increases cell differentiation, and increases apoptosis. Induction of apoptosis correlates with an increase in tissue transglutaminase (type II) activity. In vivo, 9-cis RA induces complete tumor regression of an early passage human lip squamous cell carcinoma xenograft. Finally, 9-cis RA inhibits the anchorage-independent growth of the human breast cancer cell lines MCF-7 and LY2 (an antiestrogen-resistant MCF-7 variant). Transient co-transfection assays indicate that 9-cis RA inhibits estrogen receptor transcription of an ERE-tk-LUC reporter through RAR or RXR receptors. These data suggest that retinoid receptors can antagonize estrogen-dependent transcription and provides one possible mechanism for the inhibition of cell growth by 9-cis RA in breast cancer cell lines. In summary, these findings present evidence that 9-cis RA has a wide range of activities in human cancer models.

Coexistence of bronchiectasis and rheumatoid arthritis: revisited.

PubMed

Wilczynska, Maria M; Condliffe, Alison M; McKeon, Damian J

2013-04-01

The presence of bronchiectasis (BR) in patients with rheumatoid arthritis (RA) has been recognized for many decades; nevertheless, little research has been undertaken in this area. It is important to recognize that BR coexistent with RA differs from the other types of BR. The purpose of this descriptive review was to delineate the epidemiology, etiology, risk factors, pulmonary function testing, imaging, prognosis and management of concomitant BR and RA. To inform our study we searched the PubMed, EMBASE, CINAHL, and MEDLINE databases, using combinations of the following key words: computed tomography, lung function tests, rheumatoid arthritis, bronchiectasis, biological agents, and interstitial lung disease. The number of published papers covering this topic is limited, but several relevant conclusions can be drawn. Patients with concomitant RA and BR have worse obstructive airways disease, increased susceptibility to recurrent pulmonary infections, faster lung function decline, and higher mortality, compared with subjects with either RA or BR alone. The use of disease-modifying anti-rheumatic drugs (both biological and non-biological) for RA in RA-BR patients imparts a further challenge in managing these patients. Although there are not any published guidelines on the management of coexisting RA-BR, we have attempted to provide such recommendations, based on the literature review and our experience.

Incidence and time trends of Herpes zoster in rheumatoid arthritis: a population-based cohort study

PubMed Central

Veetil, Bharath Manu Akkara; Myasoedova, Elena; Matteson, Eric L.; Gabriel, Sherine E.; Green, Abigail B.; Crowson, Cynthia S.

2012-01-01

Objective To determine the incidence, time trends, risk factors and severity of herpes zoster (HZ) in a population-based incidence cohort of patients with rheumatoid arthritis (RA) compared to a group of individuals without RA from the same population. Methods All residents of Olmsted County, MN who first fulfilled 1987 American College of Rheumatology criteria for RA between 1/1/1980 and 12/31/2007 and a cohort of similar residents without RA were assembled and followed by retrospective chart review until death, migration, or 12/31/2008. Results There was no difference in the presence of HZ prior to RA incidence/index date between the cohorts (p=0.85). During follow-up 84 patients with RA (rate: 12.1 per 1000 person-years) and 44 subjects without RA (rate: 5.4 per 1000 person-years) developed HZ. Patients with RA were more likely to develop HZ than those without RA (hazard ratio: 2.4; 95% confidence interval: 1.7, 3.5). Patients diagnosed with RA in 1995–2007 had a higher likelihood of developing HZ than those diagnosed in 1980–1994. Erosive disease, previous joint surgery, use of hydroxychloroquine and corticosteroids were significantly associated with the development of HZ in RA, while the use of methotrexate or biologic agents was not. Complications of HZ occurred at a similar rate in both cohorts. Conclusion The incidence of HZ is increased in RA and has risen in recent years. The increasing incidence of HZ in more recent years is also noted in the general population. RA disease severity is associated with development of HZ. PMID:23281295

Retrospective cohort study of anti-tumor necrosis factor agent use in a veteran population

PubMed Central

Madkour, Nermeen; Kazerooni, Rashid

2014-01-01

Introduction. Anti-tumor necrosis factor (TNF) agents are effective for several immunologic conditions (rheumatoid arthritis (RA), Crohn’s disease (CD), and psoriasis). The purpose of this study was to evaluate the efficacy and safety of anti-TNF agents via chart review. Methods. Single-site, retrospective cohort study that evaluated the efficacy and safety of anti-TNF agents in veterans initiated between 2010 and 2011. Primary aim evaluated response at 12 months post-index date. Secondary aims evaluated initial response prior to 12 months post-index date and infection events. Results. A majority of patients were prescribed anti-TNF agents for CD (27%) and RA (24%). Patients were initiated on etanercept (41%), adalimumab (40%), and infliximab (18%) between 2010 and 2011. No differences in patient demographics were reported. Response rates were high overall. Sixty-five percent of etanercept patients, 82% of adalimumab patients, and 59% of infliximab patients were either partial or full responders, respectively. Approximately 16%, 11%, and 12% of etanercept, adalimumab, and infliximab were non-responders, respectively. Infections between the groups were non-significant. Etanercept and adalimumab patients had higher but non-significant odds of being a responder relative to infliximab. Conclusions. Most patients initiated with anti-TNF agent were responders at 12 months follow-up for all indications in a veteran population. PMID:24883246

Costs of Providing Infusion Therapy for Rheumatoid Arthritis in a Hospital-based Infusion Center Setting.

PubMed

Schmier, Jordana; Ogden, Kristine; Nickman, Nancy; Halpern, Michael T; Cifaldi, Mary; Ganguli, Arijit; Bao, Yanjun; Garg, Vishvas

2017-08-01

Many hospital-based infusion centers treat patients with rheumatoid arthritis (RA) with intravenous biologic agents, yet may have a limited understanding of the overall costs of infusion in this setting. The purposes of this study were to conduct a microcosting analysis from a hospital perspective and to develop a model using an activity-based costing approach for estimating costs associated with the provision of hospital-based infusion services (preparation, administration, and follow-up) in the United States for maintenance treatment of moderate to severe RA. A spreadsheet-based model was developed. Inputs included hourly wages, time spent providing care, supply/overhead costs, laboratory testing, infusion center size, and practice pattern information. Base-case values were derived from data from surveys, published studies, standard cost sources, and expert opinion. Costs are presented in year-2017 US dollars. The base case modeled a hospital infusion center serving patients with RA treated with abatacept, tocilizumab, infliximab, or rituximab. Estimated overall costs of infusions per patient per year were $36,663 (rituximab), $36,821 (tocilizumab), $44,973 (infliximab), and $46,532 (abatacept). Of all therapies, the biologic agents represented the greatest share of overall costs, ranging from 87% to $91% of overall costs per year. Excluding infusion drug costs, labor accounted for 53% to 57% of infusion costs. Biologic agents represented the highest single cost associated with RA infusion care; however, personnel, supplies, and overhead costs also contributed substantially to overall costs (8%-16%). This model may provide a helpful and adaptable framework for use by hospitals in informing decision making about services offered and their associated financial implications. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Contact angle and surface free energy of experimental resin-based dental restorative materials after chewing simulation.

PubMed

Rüttermann, Stefan; Beikler, Thomas; Janda, Ralf

2014-06-01

To investigate contact angle and surface free energy of experimental dental resin composites containing novel delivery systems of polymeric hollow beads and low-surface tension agents after chewing simulation test. A delivery system of novel polymeric hollow beads differently loaded with two low-surface tension agents was used in different amounts to modify commonly formulated experimental dental resin composites. The non-modified resin was used as standard. Surface roughness Ra, contact angle Θ, total surface free energy γS, its apolar γS(LW), polar γS(AB), Lewis acid γS(+) and base γS(-) terms were determined and the results prior to and after chewing simulation test were compared. Significance was p<0.05. After chewing simulation Ra increased, Θ decreased, Ra increased for two test materials and γS decreased or remained constant for the standard or the test materials after chewing simulation. Ra of one test material was higher than of the standard, Θ and γS of the test materials remained lower than of the standard and, indicating their highly hydrophobic character (Θ≈60-75°, γS≈30mJm(-2)). γS(LW), and γS(-) of the test materials were lower than of the standard. Some of the test materials had lower γS(AB) and γS(+) than of the standard. Delivery systems based on novel polymeric hollow beads highly loaded with low-surface tension agents were found to significantly increase contact angle and thus to reduce surface free energy of experimental dental resin composites prior to and after chewing simulation test. Copyright © 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Rheumatoid Arthritis in Sickle-Cell Population: Pathophysiologic Insights, Clinical Evaluation and Management

PubMed Central

McFarlane, Isabel M; Ozeri, David J; Saperstein, Yair; Alvarez, Milena Rodriguez; Leon, Su Zhaz; Koci, Kristaq; Francis, Sophia; Singh, Soberjot; Salifu, Moro

2018-01-01

The advent of hydroxyurea and advanced medical care, including immunizations has led to improved survival among patients with Sickle Cell Disease (SCD). This prolonged survival however, introduces a chronic inflammatory disorder, Rheumatoid Arthritis (RA), which presents at a relatively older age and is rarely reported among SCD patients. In this review, we highlight the epidemiological association of SCD-RA and discuss the underlying common pathogenetic mechanisms, such as endothelial dysfunction, the role of inflammatory cytokines and oxidative stress. We also point to the difficulties in ascertaining the clinical diagnosis of RA in SCD patients. Finally, we provide rationale for therapeutic options available for RA and the challenges in the management of these patients with agents that are known to increase the risk of infection and immunosuppression such as steroids, disease modifying anti-rheumatic drugs and biologics. PMID:29375934

Applications of 211At and 223Ra in Targeted Alpha-Particle Radiotherapy

PubMed Central

Vaidyanathan, Ganesan; Zalutsky, Michael R.

2012-01-01

Targeted radiotherapy using agents tagged with α-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used α-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted α-particle radiotherapy. PMID:22202151

Pneumocystis jirovecii infection: an emerging threat to patients with rheumatoid arthritis

PubMed Central

Sugimoto, Mineharu

2012-01-01

Accompanying the increased use of biologic and non-biologic antirheumatic agents, patients with RA have been exposed to an increased risk of Pneumocystis jirovecii infection, which causes acute fulminant P. jirovecii pneumonia (PCP). Mortality in this population is higher than in HIV-infected individuals. Several guidelines and recommendations for HIV-infected individuals are available; however, such guidelines for RA patients remain less clear. Between 2006 and 2008 we encountered a clustering event of P. jirovecii infection among RA outpatients. Through our experience with this outbreak and a review of the recent medical literature regarding asymptomatic colonization and its clinical significance, transmission modes of infection and prophylaxis of PCP, we have learned the following lessons: PCP outbreaks among RA patients can occur through person-to-person transmission in outpatient facilities; asymptomatic carriers serve as reservoirs and sources of infection; and short-term prophylaxis for eradication of P. jirovecii is effective in controlling PCP outbreaks among RA outpatients. PMID:23001613

Retinoic acid induces nuclear accumulation of Raf1 during differentiation of HL-60 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, James; Bunaciu, Rodica P.; Reiterer, Gudrun

All trans-retinoic acid (RA) is a standard therapeutic agent used in differentiation induction therapy treatment of acute promyelocytic leukemia (APL). RA and its metabolites use a diverse set of signal transduction pathways during the differentiation program. In addition to the direct transcriptional targets of the nuclear RAR and RXR receptors, signals derived from membrane receptors and the Raf-MEK-ERK pathway are required. Raf1 phosphorylation and the prolonged activation of Raf1 persisting during the entire differentiation process are required for RA-dependent differentiation of HL-60 cells. Here we identify a nuclear redistribution of Raf1 during the RA-induced differentiation of HL-60 cells. In addition,more » the nuclear accumulation of Raf1 correlates with an increase in Raf1 phosphorylated at serine 621. The serine 621 phosphorylated Raf1 is predominantly localized in the nucleus. The RA-dependent nuclear accumulation of Raf1 suggests a novel nuclear role for Raf1 during the differentiation process.« less

Physical-chemical characteristics of whitening toothpaste and evaluation of its effects on enamel roughness.

PubMed

Hilgenberg, Sérgio Paulo; Pinto, Shelon Cristina Souza; Farago, Paulo Vitor; Santos, Fábio André; Wambier, Denise Stadler

2011-01-01

This in vitro study evaluated the physical-chemical characteristics of whitening toothpastes and their effect on bovine enamel after application of a bleaching agent (16% carbamide peroxide). Physical-chemical analysis was made considering mass loss by desiccation, ash content and pH of the toothpastes. Thirty bovine dental enamel fragments were prepared for roughness measurements. The samples were subjected to bleaching treatments and simulated brushing: G1. Sorriso Dentes Brancos (Conventional toothpaste), G2. Close-UP Whitening (Whitening toothpaste), and G3. Sensodyne Branqueador (Whitening toothpaste). The average roughness (Ra) was evaluated prior to the bleaching treatment and after brushing. The results revealed differences in the physical-chemical characteristics of the toothpastes (p < 0.0001). The final Ra had higher values (p < 0.05) following the procedures. The mean of the Ra did not show significant differences, considering toothpaste groups and bleaching treatment. Interaction (toothpaste and bleaching treatment) showed significant difference (p < 0.0001). The whitening toothpastes showed differences in their physical-chemical properties. All toothpastes promoted changes to the enamel surface, probably by the use of a bleaching agent.

Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti‑TNF therapy: results from the British Society for Rheumatology Biologics Register

PubMed Central

Davies, Rebecca; Galloway, James B; Watson, Kath D; Lunt, Mark; Symmons, Deborah P M; Hyrich, Kimme L

2011-01-01

Objectives Past studies have reported conflicting rates of venous thrombotic events (VTEs) in rheumatoid arthritis (RA). The current study aimed to compare (1) the rates of VTEs in patients with RA treated with anti-tumour necrosis factor (anti-TNF) therapy versus those treated with non-biological disease-modifying antirheumatic drugs (nbDMARDs) alone and (2) the rates between each individual anti-TNF agent and nbDMARDs. Methods Using data from the British Society for Rheumatology Biologics Register, a national prospective observational cohort study of biological safety in patients with RA, the authors compared the incidence of VTEs between 11 881 anti-TNF- and 3673 nbDMARD-treated patients. Analysis was limited to the first VTE per person. HRs were calculated using Cox modelling. Adjustment was made for potential confounders including surgery performed during follow-up. Results A total of 196 first VTEs were reported (151 anti-TNF, 45 nbDMARD). Overall there was no difference in the rates of VTEs between anti-TNF- and nbDMARD-treated patients (adjusted HR 0.8 (95% CI 0.5 to 1.5)). The risk was similar across all anti-TNF agents. Rates of postoperative VTEs did not significantly differ between groups. Conclusions These data suggest that anti-TNF therapy is not associated with an increased risk of VTEs in RA patients. PMID:21784722

Changing patterns of tumor necrosis factor inhibitor use in 9074 patients with rheumatoid arthritis.

PubMed

Yazici, Yusuf; Krasnokutsky, Svetlana; Barnes, Jaime P; Hines, Patricia L; Wang, Jason; Rosenblatt, Lisa

2009-05-01

Patients with rheumatoid arthritis (RA) commonly switch between tumor necrosis factor (TNF) inhibitors after failing to control disease activity. Much of the clinical data that support switching to a second TNF agent when one agent fails to work has come from small, short-term studies. We utilized a US insurance claims database to determine patterns of use such as dose escalation, time to discontinuation, and switching between TNF inhibitors in patients with RA. A retrospective analysis was performed using an insurance claims database in the US from 2000 to 2005. TNF inhibitor use, time to switch, dose escalation, and continuation times were analyzed in patients with RA. Nine thousand seventy-four patients with RA started TNF inhibitors during the period 2000 to 2005. Etanercept was the most commonly used TNF inhibitor; infliximab had the highest duration of continuation, about 50% at 2 years. In addition, infliximab showed higher rates of dose escalation compared to etanercept and adalimumab. For all TNF inhibitors, time to switching decreased from 2000 to 2005. TNF inhibitor use patterns changed from 2000 to 2005, with more frequent changes among the different TNF inhibitors and a shorter duration of treatment before the change. Only about 50% of TNF inhibitors are still continued at 2 years, reflecting the difference between randomized clinical trials and real-world experience.

Releasing biocontrol agents: Risk assessment and overdue reform

Treesearch

Bob Peterson; Sharlene Sing

2007-01-01

Although the need for universally instituting formal risk assessment (RA) in the screening and approval process for non-native biological control (BC) agent releases has been widely acknowledged for the past several years, little seems to have been accomplished in terms of codifying this practice within a regulatory framework. Given the low success rate of classical BC...

Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van Wauwe, J.P.; Coene, M.C.; Goossens, J.

1988-05-01

Ketoconazole, an antifungal agent and inhibitor of certain mammalian cytochrome P-450-dependent enzymes, was studied for its effects on the in vitro and in vivo metabolism of all-trans-retinoic acid (RA). In vitro, ketoconazole (Ki = 0.75 microM) inhibited, in an apparently competitive manner, the cytochrome P-450-mediated metabolism to 4-hydroxy- and 4-keto-retinoic acids by hamster liver microsomes. In vivo, ketoconazole suppressed the formation of polar RA metabolites by normal rats dosed intrajugularly with 200 ng of (/sup 3/H)RA. After p.o. treatment with ketoconazole (2.5-40 mg/kg) given 1 hr before the (/sup 3/H)RA injection, the radioactivity extracted from the liver consisted of 25more » to 50% polar metabolites (control 66 +/- 1%) and 50 to 75% undegraded RA (control 34 +/- 1%) as evidenced by reverse-phase high-performance liquid chromatography. Time course experiments showed that ketoconazole's inhibitory effects lasted for 3 hr. Our data indicate the quantitative importance of the cytochrome P-450 enzymatic pathway in the biotransformation of RA. They also suggest that ketoconazole is capable of prolonging the biological half-life of RA and of improving the tissue levels of this compound.« less

[Development of Biliary Contrast Agents Remote Pushing Device].

PubMed

Zhu, Haoyang; Dong, Dinghui; Luo, Yu; Ren, Fenggang; Zhang, Jing; Tan, Wenjun; Shi, Aihua; Hu, Liangshuo; Wu, Rongqian; Lyu, Yi

2018-01-30

A biliary contrast agents pushing device, including a syringe pushing system and a remote controller is introduced. The syringe pushing system comprises an injector card slot, a support platform and an injection bolus fader. A 20 mL syringe can be fitted on the syringe pushing system and kept with the ground about 30 degree. This system can perform air bubble pumping back and contrast agents bolus injection as well as speed adjustment. Remote controller is an infrared remote control which can start and stop the syringe pushing system. With this device, the remote controlled cholangiography technology can be achieved, which can not only protect doctors from X-ray radiation but also improve the traditional T-tube cholangiography and the contrast effect, reduce postoperative complications in patients as well. The application of this device will improve the current diagnosis and treatment system, the device will benefit the majority of doctors and patients.

Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia

NASA Astrophysics Data System (ADS)

Ferreira, R.; Fonseca, M. C.; Santos, T.; Sargento-Freitas, J.; Tjeng, R.; Paiva, F.; Castelo-Branco, M.; Ferreira, L. S.; Bernardino, L.

2016-04-01

Stroke is one of the leading causes of death and disability worldwide. However, current therapies only reach a small percentage of patients and may cause serious side effects. We propose the therapeutic use of retinoic acid-loaded nanoparticles (RA-NP) to safely and efficiently repair the ischaemic brain by creating a favourable pro-angiogenic environment that enhances neurogenesis and neuronal restitution. Our data showed that RA-NP enhanced endothelial cell proliferation and tubule network formation and protected against ischaemia-induced death. To evaluate the effect of RA-NP on vascular regulation of neural stem cell (NSC) survival and differentiation, endothelial cell-conditioned media (EC-CM) were collected. EC-CM from healthy RA-NP-treated cells reduced NSC death and promoted proliferation while EC-CM from ischaemic RA-NP-treated cells decreased cell death, increased proliferation and neuronal differentiation. In parallel, human endothelial progenitor cells (hEPC), which are part of the endogenous repair response to vascular injury, were collected from ischaemic stroke patients. hEPC treated with RA-NP had significantly higher proliferation, which further highlights the therapeutic potential of this formulation. To conclude, RA-NP protected endothelial cells from ischaemic death and stimulated the release of pro-survival, proliferation-stimulating factors and differentiation cues for NSC. RA-NP were shown to be up to 83-fold more efficient than free RA and to enhance hEPC proliferation. These data serve as a stepping stone to use RA-NP as vasculotrophic and neurogenic agents for vascular disorders and neurodegenerative diseases with compromised vasculature.

Antibacterial activity, surface roughness, flexural strength, and solubility of conventional luting cements containing chlorhexidine diacetate/cetrimide mixtures.

PubMed

Korkmaz, Fatih Mehmet; Tüzüner, Tamer; Baygin, Ozgul; Buruk, Celal Kurtulus; Durkan, Rukiye; Bagis, Bora

2013-08-01

The failure of fixed dental restorations is commonly associated with caries. The use of conventional luting cements containing antibacterial agents may overcome this problem. The purpose of this study was to evaluate the antibacterial activity (ABA), surface roughness (Ra), flexural strength (FS), and solubility (SL) patterns of the conventional dental luting cements zinc phosphate (ZP), zinc polycarboxylate (PC), and glass ionomer (GIC) after the addition of 5% chlorhexidine diacetate/cetrimide (CHX+CT). Antibacterial agents with a total concentration of 5% (2.5% CHX+2.5% CT) were added to antibacterial agent-free conventional luting cement powders (ZPC, PCC, and GICC) and designated as experimental groups (ZPE, PCE, and GICE). ABA against Streptococcus mutans (SM) and Lactobacillus casei (LB) was examined by using the agar diffusion test method. Ra, FS, and SL values were obtained after storage in distilled water at 37°C for 24 hours. The Kruskal-Wallis and Mann Whitney U with Bonferroni correction tests were used to test for agar diffusion (α=.05) and 2-way ANOVA and Fisher Least Significant Difference (LSD) test were used to measure Ra, FS, and SL (α=.05). The control groups exhibited limited ABA. With the exception of PCE>PCC on day 1 for SM, all experimental groups showed significantly greater and longer-lasting protection against SM and LB bacteria for up to 180 days than their controls (P<.05). Ra values decreased (ZPC>ZPE; P>.05, PCC>PCE; P<.05) except that GICE>GICC (P>.05) when compared with their individual controls. Control groups exhibited higher FS values than did the experimental groups (ZPC>ZPE; P<.05, PCC>PCE; P<.05, GICC>GICE; P>.05). The experimental groups exhibited higher solubilities than did their controls in the ZPC (P>.05) and GICC groups (P<.05) but were lower in PCC group (P<.05). Incorporating a 5% CHX+CT mixture into conventional dental luting cements and altering their Ra, FS, and SL values may provide greater antibacterial protection against SM and LB. Copyright © 2013 The Editorial Council of the Journal of Prosthetic Dentistry. Published by Mosby, Inc. All rights reserved.

Retinoic Acid and Arsenic Synergize to Eradicate Leukemic Cells in a Mouse Model of Acute Promyelocytic Leukemia

PubMed Central

Lallemand-Breitenbach, Valérie; Guillemin, Marie-Claude; Janin, Anne; Daniel, Marie-Thérèse; Degos, Laurent; Kogan, Scott C.; Michael Bishop, J.; de Thé, Hugues

1999-01-01

In acute promyelocytic leukemia (APL) patients, retinoic acid (RA) triggers differentiation while arsenic trioxide (arsenic) induces both a partial differentiation and apoptosis. Although their mechanisms of action are believed to be distinct, these two drugs both induce the catabolism of the oncogenic promyelocytic leukemia (PML)/RARα fusion protein. While APL cell lines resistant to one agent are sensitive to the other, the benefit of combining RA and arsenic in cell culture is controversial, and thus far, no data are available in patients. Using syngenic grafts of leukemic blasts from PML/RARα transgenic mice as a model for APL, we demonstrate that arsenic induces apoptosis and modest differentiation, and prolongs mouse survival. Furthermore, combining arsenic with RA accelerates tumor regression through enhanced differentiation and apoptosis. Although RA or arsenic alone only prolongs survival two- to threefold, associating the two drugs leads to tumor clearance after a 9-mo relapse-free period. These studies establishing RA/arsenic synergy in vivo prompt the use of combined arsenic/RA treatments in APL patients and exemplify how mouse models of human leukemia can be used to design or optimize therapies. PMID:10190895

Powerful Oxidizing Agents for the Oxidative Deintercalation of Lithium from Transition Metal Oxides

DTIC Science & Technology

1989-08-16

22217 11 TITLE dnrcluae Sec’.r/ 2 ’als.rit,catC Powerful Oxidizing Agents for the Oxidative Deintercalation of Lithium from Transition Metal Oxides...0 d dlentity by block number) FIELD GROUP SUB GROUP Oxidizing Agents, Lithium Oxides I - Deintercalation 19 AbS*RA?, trne on-tsxes~e it necessary...anid enit’y oy 010ck .1Uf~oer. N02+ andMoF6 are shown to be powerful oxidizing agents for the deintercalation of lithium from Li~oO2 an 62Ct . The

REMOTE BIOSENSOR FOR IN SITU MONITORING OF ORGANOPHOSPHATE NERVE AGENTS. (R823663)

EPA Science Inventory

A remote electrochemical biosensor for field monitoring of organophosphate nerve agents is described. The new sensor relies on the coupling of the effective biocatalytic action of organophosphorus hydrolase (OPH) with a submersible amperometric probe design. This combination resu...

Retinoic Acid Therapy Resistance Progresses from Unilineage to Bilineage in HL-60 Leukemic Blasts

PubMed Central

Jensen, Holly A.; Bunaciu, Rodica P.; Ibabao, Christopher N.; Myers, Rebecca; Varner, Jeffrey D.; Yen, Andrew

2014-01-01

Emergent resistance can be progressive and driven by global signaling aberrations. All-trans retinoic acid (RA) is the standard therapeutic agent for acute promyelocytic leukemia, but 10–20% of patients are not responsive, and initially responsive patients relapse and develop retinoic acid resistance. The patient-derived, lineage-bipotent acute myeloblastic leukemia (FAB M2) HL-60 cell line is a potent tool for characterizing differentiation-induction therapy responsiveness and resistance in t(15;17)-negative cells. Wild-type (WT) HL-60 cells undergo RA-induced granulocytic differentiation, or monocytic differentiation in response to 1,25-dihydroxyvitamin D3 (D3). Two sequentially emergent RA-resistant HL-60 cell lines, R38+ and R38-, distinguishable by RA-inducible CD38 expression, do not arrest in G1/G0 and fail to upregulate CD11b and the myeloid-associated signaling factors Vav1, c-Cbl, Lyn, Fgr, and c-Raf after RA treatment. Here, we show that the R38+ and R38- HL-60 cell lines display a progressive reduced response to D3-induced differentiation therapy. Exploiting the biphasic dynamic of induced HL-60 differentiation, we examined if resistance-related defects occurred during the first 24 h (the early or “precommitment” phase) or subsequently (the late or “lineage-commitment” phase). HL-60 were treated with RA or D3 for 24 h, washed and retreated with either the same, different, or no differentiation agent. Using flow cytometry, D3 was able to induce CD38, CD11b and CD14 expression, and G1/G0 arrest when present during the lineage-commitment stage in R38+ cells, and to a lesser degree in R38- cells. Clustering analysis of cytometry and quantified Western blot data indicated that WT, R38+ and R38- HL-60 cells exhibited decreasing correlation between phenotypic markers and signaling factor expression. Thus differentiation induction therapy resistance can develop in stages, with initial partial RA resistance and moderate vitamin D3 responsiveness (unilineage maturation block), followed by bilineage maturation block and progressive signaling defects, notably the reduced expression of Vav1, Fgr, and c-Raf. PMID:24922062

Critical analysis of economic tools and economic measurement applied to rheumatoid arthritis.

PubMed

Her, Minyoung; Kavanaugh, Arthur

2012-01-01

Rheumatoid arthritis (RA) is chronic, progressive systemic inflammatory disease that if uncontrolled may lead to significant joint damage, dysfunction, work disability and other sequelae that result in large economic losses. A rich literature estimating the economic burden of RA, has been intensified recently, driven by costly biologic agents that have had a notable effect improving the outcomes of patients with RA. In order to optimally assess the value of therapies, it is best to take a comprehensive approach, considering all related costs of illness. This includes direct costs (e.g. the costs of the medications themselves and the monitoring required), indirect costs (e.g. loss of productivity, such as employment due to uncontrolled disease) and intangible cost (e.g. effects on pain and quality of life). Indirect costs constitute a substantial part of total cost in the patient with RA. In order to help assess the impact of RA on productivity, various tools for measuring productive loss like absenteeism and presenteeism have been introduced. No single tool reflects the entire spectrum of the productive loss clearly, as other factors such as use of a human capital approach or friction cost approach affect the valuation of productive loss monetarily. Although favourable outcomes are achieved with the use of biologic agents, their higher acquisition costs, as compared to traditional disease-modifying anti-rheumatic drugs (DMARDs) remain a barrier to their use. Assessments of the cost effectiveness of novel therapies are critically important, but published results have been contradictory, in some measure due to the heterogeneity of instruments utilised. While the various instruments appear to be valid and reliable, correlations between instruments has been modest, driven by factors such as differences in recall times, attribution and other confounders.

Net primary productivity of China's terrestrial ecosystems from a process model driven by remote sensing.

PubMed

Feng, X; Liu, G; Chen, J M; Chen, M; Liu, J; Ju, W M; Sun, R; Zhou, W

2007-11-01

The terrestrial carbon cycle is one of the foci in global climate change research. Simulating net primary productivity (NPP) of terrestrial ecosystems is important for carbon cycle research. In this study, China's terrestrial NPP was simulated using the Boreal Ecosystem Productivity Simulator (BEPS), a carbon-water coupled process model based on remote sensing inputs. For these purposes, a national-wide database (including leaf area index, land cover, meteorology, vegetation and soil) at a 1 km resolution and a validation database were established. Using these databases and BEPS, daily maps of NPP for the entire China's landmass in 2001 were produced, and gross primary productivity (GPP) and autotrophic respiration (RA) were estimated. Using the simulated results, we explore temporal-spatial patterns of China's terrestrial NPP and the mechanisms of its responses to various environmental factors. The total NPP and mean NPP of China's landmass were 2.235 GtC and 235.2 gCm(-2)yr(-1), respectively; the total GPP and mean GPP were 4.418 GtC and 465 gCm(-2)yr(-1); and the total RA and mean RA were 2.227 GtC and 234 gCm(-2)yr(-1), respectively. On average, NPP was 50.6% of GPP. In addition, statistical analysis of NPP of different land cover types was conducted, and spatiotemporal patterns of NPP were investigated. The response of NPP to changes in some key factors such as LAI, precipitation, temperature, solar radiation, VPD and AWC are evaluated and discussed.

Influence of bleaching agents on surface roughness of sound or eroded dental enamel specimens.

PubMed

Azrak, Birgül; Callaway, Angelika; Kurth, Petra; Willershausen, Brita

2010-12-01

The aim of the present in vitro study was to assess the effect of bleaching agents on eroded and sound enamel specimens. Enamel specimens prepared from human permanent anterior teeth were incubated with different bleaching agents containing active ingredients as 7.5 or 13.5% hydrogen peroxide or 35% carbamide peroxide, ranging in pH from 4.9 to 10.8. The effect of the tooth whitening agents on surface roughness was tested for sound enamel surfaces as well as for eroded enamel specimens. To provoke erosive damage, the enamel specimens were incubated for 10 hours with apple juice (pH = 3.4). Afterwards, pretreated and untreated dental slices were incubated with one of the bleaching agents for 10 hours. The surface roughness (R(a)) of all enamel specimens (N = 80) was measured using an optical profilometric device. A descriptive statistical analysis of the R(a) values was performed. The study demonstrated that exposure to an acidic bleaching agent (pH = 4.9) resulted in a higher surface roughness (p = 0.043) than treatment with a high peroxide concentration (pH = 6.15). If the enamel surface was previously exposed to erosive beverages, subsequent bleaching may enhance damage to the dental hard tissue. Bleaching agents with a high concentration of peroxide or an acidic pH can influence the surface roughness of sound or eroded enamel. © 2010, COPYRIGHT THE AUTHORS. JOURNAL COMPILATION © 2010, WILEY PERIODICALS, INC.

Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure.

PubMed

Nasr, Rihab; Lallemand-Breitenbach, Valérie; Zhu, Jun; Guillemin, Marie-Claude; de Thé, Hugues

2009-10-15

Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosomal translocation that yields the PML/RARA fusion gene. Clinically, besides chemotherapy, two drugs induce clinical remissions: retinoic acid (RA) and arsenic trioxide (As). Both agents directly target PML/RARA-mediated transcriptional repression and protein stability, inducing to various extent promyelocyte differentiation and clinical remission of APL patients. RA targets the RARA moiety of the fusion, whereas arsenic targets its PML part. PML/RARA expression in the mouse is sufficient to initiate APL. The RA-As association, which synergizes for PML/RARA degradation but not for differentiation, rapidly clears leukemia initiating cells (LIC), resulting in APL eradication in murine APL models, but also in several APL clinical trials. Cyclic AMP triggered PML/RARA phosphorylation also enhances RA-induced APL regression, PML/RARA degradation, and LIC clearance, raising new options for therapy-resistant patients. Although differentiation has a major role in debulking of the tumor, PML/RARA degradation seems to be the primary basis for APL eradication by the RA-As association. Oncoprotein degradation could be a general therapeutic strategy that may be extended beyond APL.

Update on the use of steroids in rheumatoid arthritis.

PubMed

García-Magallón, Blanca; Silva-Fernández, Lucía; Andreu-Sánchez, José Luis

2013-01-01

Corticosteroids are a mainstay in the therapy of rheumatoid arthritis (RA). In recent years, a number of high-quality controlled clinical trials have shown their effect as a disease-modifying anti-rheumatic drug (DMARD) and a favourable safety profile in recent-onset RA. Despite this, they are more frequently used as bridge therapy while other DMARDs initiate their action than as true disease-modifying agents. Low-dose corticosteroid use during the first two years of disease slows radiologic damage and reduces the need of biologic therapy aimed at reaching a state of clinical remission in recent-onset RA. Thus, their systematic use in this clinical scenario should be considered. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Faithful teleportation of multi-particle states involving multi spatially remote agents via probabilistic channels

NASA Astrophysics Data System (ADS)

Jiang, Min; Li, Hui; Zhang, Zeng-ke; Zeng, Jia

2011-02-01

We present an approach to faithfully teleport an unknown quantum state of entangled particles in a multi-particle system involving multi spatially remote agents via probabilistic channels. In our scheme, the integrity of an entangled multi-particle state can be maintained even when the construction of a faithful channel fails. Furthermore, in a quantum teleportation network, there are generally multi spatially remote agents which play the role of relay nodes between a sender and a distant receiver. Hence, we propose two schemes for directly and indirectly constructing a faithful channel between the sender and the distant receiver with the assistance of relay agents, respectively. Our results show that the required auxiliary particle resources, local operations and classical communications are considerably reduced for the present purpose.

Modulation of Mycoplasma arthritidis-derived superantigen-induced cytokine gene expression by dexamethasone and interleukin-4.

PubMed

Mehindate, K; al-Daccak, R; Rink, L; Mecheri, S; Hébert, J; Mourad, W

1994-11-01

Activation of human monocytes or monocytic cell lines with all known stimuli coordinately induces the gene expression of various cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and the IL-1 receptor antagonist (IL-1Ra). In contrast, superantigens induce TNF-alpha and IL-1 beta but fail to affect IL-1Ra gene expression, suggesting that activation of monocytes via major histocompatibility complex class II is distinct from other signal transduction pathways. In the present study, we analyzed the regulation of the Mycoplasma arthritidis-derived superantigen (MAM)-induced IL-1 beta and TNF-alpha gene expression by studying the effects of two different anti-inflammatory agents: dexamethasone (DEX) and the T-cell-derived cytokine IL-4. Both agents contributed to the downregulation of MAM-induced IL-1 beta and TNF-alpha gene expression. They accelerated the normal decline of the gene expression of both MAM-induced cytokines by decreasing the stability of mRNAs via the induction or enhanced synthesis of one or more regulatory proteins. In addition, IL-4, but not DEX, induced a strong and rapid expression of IL-1Ra mRNA in MAM-stimulated and unstimulated THP-1 cells in a de novo protein synthesis-independent manner. The capacity of IL-4 to induce IL-1Ra gene expression reinforces its anti-inflammatory activity. This study illustrates some of the mechanisms by which MAM-induced proinflammatory monokine gene expression can be downregulated by IL-4 and DEX.

REST, regulated by RA through miR-29a and the proteasome pathway, plays a crucial role in RPC proliferation and differentiation.

PubMed

Wang, Yuyao; Zhang, Dandan; Tang, Zhimin; Zhang, Yi; Gao, Huiqin; Ni, Ni; Shen, Bingqiao; Sun, Hao; Gu, Ping

2018-04-18

One of the primary obstacles in the application of retinal progenitor cells (RPCs) to the treatment of retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), is their limited ability to proliferate and differentiate into specific retinal neurons. In this study, we revealed that repressor element-1-silencing transcription factor (REST), whose expression could be transcriptionally and post-transcriptionally mediated by retinoic acid (RA, one isomeride of a vitamin A derivative used as a differentiation-inducing agent in many disease treatments), plays a pivotal role in the regulation of proliferation and differentiation of RPCs. Our results show that direct knockdown of endogenous REST reduced RPC proliferation but accelerated RPC differentiation toward retinal neurons, which phenocopied the observed effects of RA on RPCs. Further studies disclosed that the expression level of REST could be downregulated by RA not only through upregulating microRNA (miR)-29a, which directly interacted with the 3'-untranslated region (3'-UTR) of the REST mRNA, but also through promoting REST proteasomal degradation. These results show us a novel functional protein, REST, which regulates RPC proliferation and differentiation, can be mediated by RA. Understanding the mechanisms of REST and RA in RPC fate determination enlightens a promising future for the application of REST and RA in the treatment of retinal degeneration diseases.

Use and Spending for Biologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis Among US Medicare Beneficiaries.

PubMed

Yazdany, Jinoos; Tonner, Chris; Schmajuk, Gabriela

2015-09-01

Biologic therapies have assumed an important role in treating rheumatoid arthritis (RA). We sought to investigate use, spending, and patient cost-sharing for Medicare beneficiaries using biologic drugs for RA, comparing patients exposed to minimal cost-sharing because of a Part D low-income subsidy (LIS) to those facing substantial out-of-pocket costs (OOP). We performed a retrospective, nationwide study using 2009 Medicare claims for a 5% random sample of beneficiaries with RA who had at least 1 RA drug dispensed. We analyzed biologic drug utilization and costs across the Part B (medical benefit) and Part D (pharmacy benefit) programs by LIS status using multinomial regression. We also projected OOP costs as the Affordable Care Act (ACA) mandates closure of the Part D coverage gap by 2020. Among 6,932 beneficiaries, 1,812 (26.1%) received a biologic drug. LIS beneficiaries were significantly more likely to obtain Part D home-administered biologics (relative risk ratio [RRR] 2.98, 95% confidence interval [95% CI] 2.50-3.56), while non-LIS beneficiaries were less likely to receive Part D biologic agents (RRR 0.58, 95% CI 0.48-0.69). OOP costs in Part D were lower, as expected, for LIS beneficiaries ($72 versus $3,751 per year for non-LIS). Non-LIS beneficiaries had lower costs for Part B facility-administered biologic agents (range $0-$2,584) than for Part D home-administered biologic agents. ACA reforms will narrow OOP differences between Part D and B for non-LIS beneficiaries. In contrast to LIS beneficiaries who receive mostly Part D home-administered biologic DMARDs, nonsubsidized beneficiaries have significant cost-based incentives to obtain facility-administered biologic DMARDs through Part B. The ACA will result in only slightly lower costs for Part D biologic drugs for these beneficiaries. © 2015, American College of Rheumatology.

Gap Between Official Guidelines and Clinical Practice for the Treatment of Rheumatoid Arthritis in São Paulo, Brazil.

PubMed

de Camargo, Iara Alves; Almeida Barros, Bruna Cipriano; do Nascimento Silveira, Miriam Sanches; Osorio-de-Castro, Claudia Garcia Serpa; Guyatt, Gordon; Lopes, Luciane Cruz

2016-05-01

Biological agents used for the treatment of rheumatoid arthritis (RA) are associated with serious adverse events. Guidelines provide standards for the prescribing and monitoring of these drugs. In São Paulo, health litigation for access to medicines has fueled the demand for biological therapy. The extent to which biological agents are being appropriately prescribed and patients are being appropriately monitored is uncertain. Our goal was to determine whether RA clinical guidelines are being translated into clinical practice for patients receiving treatment as a result of lawsuits against the government. We identified patients through records of the State Secretary of Health of São Paulo from 2003 to 2011. We consulted guidelines from 5 countries and chose those recommendations endorsed by all of the guidelines reviewed as standards. Pharmacy records provided data regarding biologic use. The guidelines recommended the use of biological agents only when patients had been receiving treatment with at least 1 disease-modifying antirheumatic drug (DMARD) and recommended annual monitoring of laboratory blood tests. Of the 238 patients identified in the database, 216 patients were interviewed, and 124 (57.4%) patients were still using biological agents at the time of the survey. Of the patients interviewed, 167 patients (77.3%) started biological treatment when using ≥2 DMARDs before, 22 patients (10.2%) were using 1 DMARD before, and 27 patients (12.5%) had never taken a DMARD. Of the 124 patients still taking biological drugs, 117 patients (94.3%) had visited a doctor at least once per year, but 28 patients (22.6%) did not undergo the recommended laboratory blood testing. Only 43 of the 124 patients (34.7%) still taking biological agents met the guideline criteria for both the use of previous agents and the appropriate monitoring. An important gap between clinical practice and the national guidelines exists among treatments prescribed for plaintiffs obtaining medicines for RA in São Paulo. The results suggest the need for intervention by health authorities. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

A review of the new GLP-1 receptor agonist/basal insulin fixed-ratio combination products.

PubMed

Nuffer, Wesley; Guesnier, Ashley; Trujillo, Jennifer M

2018-03-01

There have been several new treatment approaches established for the management of hyperglycemia in type 2 diabetes (T2D), with treatment guidelines listing both glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and basal insulin therapies as considerations for patients who have failed to control their blood glucose with oral antidiabetic agents. New studies have highlighted the importance of initiating combination therapy earlier in the T2D disease process to avoid clinical inertia and prevent the long-term complications arising from uncontrolled diabetes. Until recently, both GLP-1 RAs and basal insulin therapies were only available as single agents, but there are now two combination pen devices that deliver both a GLP-1 RA and basal insulin simultaneously. This article reviews the current clinical evidence evaluating the use of these combination GLP-1 RA/basal insulin preparations to treat T2D, presents both potential benefits as well as possible downsides with the use of these agents, and discusses the current place in therapy these products represent in the management of T2D.

Clinical impact of concomitant immunomodulators on biologic therapy: Pharmacokinetics, immunogenicity, efficacy and safety.

PubMed

Xu, Zhenhua; Davis, Hugh M; Zhou, Honghui

2015-03-01

Immune-mediated inflammatory diseases encompass a variety of different clinical syndromes, manifesting as either common diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis, or rare diseases such as cryopyrin-associated periodic syndromes. The therapy for these diseases often involves the use of a wide range of drugs including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, immunomodulators, and biologic therapies. Due to the abundance of relevant clinical data, this article provides a general overview on the clinical impact of the concomitant use of immunomodulators and biologic therapies, with a focus on anti-tumor necrosis factor-α agents (anti-TNFα), for the treatment of RA and Crohn's disease (CD). Compared to biologic monotherapy, concomitant use of immunomodulators (methotrexate, azathioprine, and 6-mercaptopurine) often increases the systemic exposure of the anti-TNFα agent and decreases the formation of antibodies to the anti-TNFα agent, consequently enhancing clinical efficacy. Nevertheless, long-term combination therapy with immunomodulators and anti-TNFα agents may be associated with increased risks of serious infections and malignancies. Therefore, the determination whether combination therapy is suitable for a patient should always be based on an individualized benefit-risk evaluation. More research should be undertaken to identify and validate prognostic markers for predicting patients who would benefit the most and those who are at greater risk from combination therapy with immunomodulators and anti-TNFα agents. © 2015, The American College of Clinical Pharmacology.

Lipid-Based Nanoparticles as a Potential Delivery Approach in the Treatment of Rheumatoid Arthritis

PubMed Central

Chuang, Shih-Yi; Lin, Chih-Hung; Huang, Tse-Hung

2018-01-01

Rheumatoid arthritis (RA), a chronic and joint-related autoimmune disease, results in immune dysfunction and destruction of joints and cartilages. Small molecules and biological therapies have been applied in a wide variety of inflammatory disorders, but their utility as a therapeutic agent is limited by poor absorption, rapid metabolism, and serious side effects. To improve these limitations, nanoparticles, which are capable of encapsulating and protecting drugs from degradation before they reach the target site in vivo, may serve as drug delivery systems. The present research proposes a platform for different lipid nanoparticle approaches for RA therapy, taking advantage of the newly emerging field of lipid nanoparticles to develop a targeted theranostic system for application in the treatment of RA. This review aims to present the recent major application of lipid nanoparticles that provide a biocompatible and biodegradable delivery system to effectively improve RA targeting over free drugs via the presentation of tissue-specific targeting of ligand-controlled drug release by modulating nanoparticle composition. PMID:29342965

Impact of traditional therapies and biologics on cardiovascular diseases in rheumatoid arthritis.

PubMed

Boyer, Jean-Frédéric; Cantagrel, Alain; Constantin, Arnaud

2008-07-01

In chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic inflammation appears as an independent risk factor, contributing to increased cardiovascular mortality. This high cardiovascular mortality reveals the existence of accelerated atherosclerosis, the pathogenesis of which may be associated with traditional risk factors such as smoking, hypertension, dyslipidemia, deterioration of insulin sensitivity, and less traditional risk factors such as hyperhomocysteinemia, inflammatory conditions and endothelial dysfunction. Control of systemic inflammation theoretically provides a means of preventing this higher cardiovascular mortality among RA patients. In this review we address the question of the impact of anti-rheumatic drugs currently used in RA, such as non-steroidal anti-inflammatory drugs (e.g. non-selective or cyclooxygenase-2 selective inhibitors), steroidal anti-inflammatory drugs (glucocorticoids), traditional disease-modifying anti-rheumatic drugs (e.g. methotrexate) or biologics (e.g. anti-tumour necrosis factor alpha anti-tumour necrosis factor alpha) on cardiovascular diseases in RA patients. We also discuss the specific mechanisms involved in the differential cardiovascular effects of these therapeutic agents.

Downregulation of Chicken Interleukin-17 Receptor A during Eimeria Infection

PubMed Central

Kim, Woo H.; Jeong, Jipseol; Park, Ae R.; Yim, Dongjean; Kim, Suk; Chang, Hong H.; Yang, Seung-Hak; Kim, Dong-Hee; Lillehoj, Hyun S.

2014-01-01

Both interleukin-17A (IL-17A) and IL-17F are proinflammatory cytokines that have an important role in intestinal homeostasis via receptor signaling. These cytokines have been characterized in chickens, but very little is known about their receptors and their functional activity. We provide here the first description of the sequence analysis, bioactivity, and comparative expression analysis of chicken IL-17RA (chIL-17RA) in chickens infected with Salmonella and Eimeria, two major infectious agents of gastrointestinal diseases of poultry of economic importance. A full-length chIL-17RA cDNA with a 2,568-bp coding region was identified from chicken thymus cDNA. chIL-17RA shares ca. 46% identity with mammalian homologues and 29.2 to 31.5% identity with its piscine counterparts. chIL-17RA transcript expression was relatively high in the thymus and in the chicken macrophage cell line HD11. The chIL-17RA-specific small interfering RNA inhibits interleukin-6 (IL-6), IL-8, and IL-1β mRNA expression in chicken embryo fibroblast cells (but not in DF-1 cells) stimulated with chIL-17A or chIL-17F. Interaction between chIL-17RA and chIL-17A was confirmed by coimmunoprecipitation. Downregulation of chIL-17RA occurred in concanavalin A- or lipopolysaccharide-activated splenic lymphocytes but not in poly(I·C)-activated splenic lymphocytes. In Salmonella- and Eimeria-infected chickens, the expression levels of the chIL-17RA transcript were downregulated in intestinal tissues from chickens infected with two Eimeria species, E. tenella or E. maxima, that preferentially infect the cecum and jejunum, respectively. However, chIL-17RA expression was generally unchanged in Salmonella infection. These results suggest that chIL-17RA has an important role in mucosal immunity to intestinal intracellular parasite infections such as Eimeria infection. PMID:24980970

Remote Data Retrieval for Bioinformatics Applications: An Agent Migration Approach

PubMed Central

Gao, Lei; Dai, Hua; Zhang, Tong-Liang; Chou, Kuo-Chen

2011-01-01

Some of the approaches have been developed to retrieve data automatically from one or multiple remote biological data sources. However, most of them require researchers to remain online and wait for returned results. The latter not only requires highly available network connection, but also may cause the network overload. Moreover, so far none of the existing approaches has been designed to address the following problems when retrieving the remote data in a mobile network environment: (1) the resources of mobile devices are limited; (2) network connection is relatively of low quality; and (3) mobile users are not always online. To address the aforementioned problems, we integrate an agent migration approach with a multi-agent system to overcome the high latency or limited bandwidth problem by moving their computations to the required resources or services. More importantly, the approach is fit for the mobile computing environments. Presented in this paper are also the system architecture, the migration strategy, as well as the security authentication of agent migration. As a demonstration, the remote data retrieval from GenBank was used to illustrate the feasibility of the proposed approach. PMID:21701677

Occupation and Risk of Developing Rheumatoid Arthritis: Results From a Population-Based Case-Control Study.

PubMed

Ilar, Anna; Alfredsson, Lars; Wiebert, Pernilla; Klareskog, Lars; Bengtsson, Camilla

2018-04-01

Environmental factors are of importance for the etiology of rheumatoid arthritis (RA), but much remains unknown concerning the contributions from distinct occupational hazards. We explored the association between occupation and the risk of anti-citrullinated protein antibody (ACPA)+ RA or ACPA- RA. We analyzed 3,522 cases and 5,580 controls from the Swedish population-based Epidemiological Investigation of Rheumatoid Arthritis case-control study. A questionnaire was used to obtain information on work history and lifestyle factors. Blood samples were drawn for serologic analyses. Unconditional logistic regression was used to calculate the odds ratio (OR) of RA associated with the last occupation before study inclusion. Analyses were performed with adjustments for known environmental exposures and lifestyle factors, including pack-years of cigarette smoking, alcohol use, body mass index, and education. Among men, bricklayers and concrete workers (OR 2.9, 95% confidence interval [95% CI] 1.4-5.7), material handling operators (OR 2.4, 95% CI 1.3-4.4), and electrical and electronics workers (OR 2.1, 95% CI 1.1-3.8) had an increased risk of ACPA+ RA. For ACPA- RA, bricklayers and concrete workers (OR 2.4, 95% CI 1.0-5.7) and electrical and electronics workers (OR 2.6, 95% CI 1.3-5.0) had an increased risk. Among women, assistant nurses and attendants had a moderately increased risk of ACPA+ RA (OR 1.3, 95% CI 1.1-1.6). No occupations were significantly associated with ACPA- RA among women. Mainly occupations related to potential noxious airborne agents were associated with an increased risk of ACPA+ or ACPA- RA, after adjustments for previously known confounders. © 2017, American College of Rheumatology.

[Guidelines in RA treatment: concepts on safety and recommendations using anti-TNF-alpha inhibitors. Grupo de Estudio de Nuevas Terapias de Enfermedades reumáticas (GENTE)].

PubMed

Díaz-Jouanen, Efraín; Abud-Mendoza, Carlos; Garza-Elizondo, Mario Alberto; Medrano-Ramírez, Gabriel; Burgos-Vargas, Rubén; Orozco-Alcalá, José Javier; Pacheco-Tena, César Francisco; Pineda, Carlos; Pozos-Espíndola, Juan Carlos; Ramos-Niembro, Francisco; Robles-San-Román, Manuel; Santana-Sahagún, Jesús Ernesto

2009-01-01

Recommendations for the use of Disease-Modifying Antirheumatic Drugs (DMARD) with both conventional and biological agents in Rheumatoid Arthritis (RA) must be based on their safety profile, adverse effects, risks, and advantages. With the purpose of presenting the most updated information about the safety of tumor necrosis factor alpha (TNFalpha) antagonists, in this article we summarize the literature published during the last three years about this sort of biological agents in specific clinical situations, such as risk of developing infections, cancer, cardiovascular diseases, and autoimmunity; as well as their administration to patients who will undergo surgical procedures, pregnant and/or breast-feeding women, and patients who need immunizations. Likewise, in this analysis we offer specific recommendations, based on evidence, for the best anti-TNF-alfa management.

Cellular alterations and enhanced induction of cleft palate after coadministration of retinoic acid and TCDD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abbott, B.D.; Birnbaum, L.S.

1989-06-15

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and retinoic acid (RA) are both teratogenic in mice. TCDD is a highly toxic, stable environmental contaminant, while RA is a naturally occurring form of vitamin A. Exposure to TCDD induces hydronephrosis and cleft palate, and exposure to RA induces limb defects and cleft palate. Teratology studies previously have shown that the incidence of clefting is higher after exposure to RA + TCDD than would be observed for the same doses of either compound given alone. This study examines the cellular effects which result in cleft palate, after po administration on gestation Day (GD) 10 or 12 ofmore » RA + TCDD in corn oil (10 ml/kg total volume). Exposure on GD 10 to 6 micrograms TCDD + 40 mg RA/kg inhibited early growth of the shelves and clefting was due to a failure of shelves to meet and fuse. This effect on mesenchyme was observed in previous studies to occur after exposure on GD 10 to 40 mg/kg RA alone, but not after TCDD alone. After exposure on GD 12 to 6 micrograms TCDD + 80 mg RA/kg, clefting was due to a failure of shelves to fuse after making contact, because the medial cells differentiated into an oral-like epithelium. This response was observed in previous studies to occur after exposure to TCDD alone, but RA alone on GD 12 resulted in differentiation toward nasal-like cells. The interaction between TCDD and RA results in RA-like clefting after exposure on GD 10 and TCDD-like clefting after exposure on GD 12, and this clefting occurs at higher incidences than would occur after the same levels of either agent alone. After exposure on either GD 10 or 12 to RA + TCDD, the programmed cell death of the medial cells does not occur, and these cells continue to express EGF receptors and to bind 125I-EGF. The effects of RA and TCDD may involve modulation of the cells responses to embryonic growth and differentiation factors.« less

Spatial Relationship of Focal Impulses, Rotors and Low Voltage Zones in Patients With Persistent Atrial Fibrillation.

PubMed

Schade, Anja; Nentwich, Karin; Costello-Boerrigter, Lisa C; Halbfass, Philipp; Mueller, Patrick; Roos, Markus; Barth, Sebastian; Krug, Joachim; Szoelloesi, Geza-Atilla; Lapp, Harald; Deneke, Thomas

2016-05-01

Focal impulses (FI) and rotors are sources associated with the initiation and maintenance of atrial fibrillation (AF). Their ablation results in a lower recurrence rate. The aim of this study was to characterize for the first time the spatial relationship between such sources and atrial low voltage zones (LVZ) representing fibrosis. Twenty-five consecutive patients undergoing their first ablation for persistent AF were included. Voltage mapping of both atria was done during AF. Endocardial mapping of FI and rotors (sources) was performed using a basket catheter and displayed using RhythmView(TM) (Topera Inc.) before ablation. Spatial relationship of LVZ and sources was analyzed. LVZs covered 13 ± 12% of right atrial (RA) endocardial surface and 33 ± 25% of left atrial (LA) endocardial surface. The median number of sources was 1 [1-3] in RA and 3 [1-4] in LA. Of LA sources, 18 (30%) were definitely not associated with LVZs or pulmonary vein (PV) antra. Of RA sources, 32 (84%) were remote from LVZ. During ablation of such sources substantial cycle length (CL) prolongation or AF conversion occurred in 11/23 patients (48%). Altogether, 8/11 (73%) of these pertinent sources were located remotely from LVZ and PV antra. There is a wide discrepancy in distribution of LVZ areas and sites of identified rotors. Site and incidence of FIRM sources appear to be unpredictable with atrial substrate mapping. Further prospective, randomized studies are necessary to elucidate the impact of additional ablation of such sources in patients with persistent or longstanding persistent AF. © 2016 Wiley Periodicals, Inc.

Multi-Agent Information Classification Using Dynamic Acquaintance Lists.

ERIC Educational Resources Information Center

Mukhopadhyay, Snehasis; Peng, Shengquan; Raje, Rajeev; Palakal, Mathew; Mostafa, Javed

2003-01-01

Discussion of automated information services focuses on information classification and collaborative agents, i.e. intelligent computer programs. Highlights include multi-agent systems; distributed artificial intelligence; thesauri; document representation and classification; agent modeling; acquaintances, or remote agents discovered through…

Effect of sealant agents on the color stability and surface roughness of nanohybrid composite resins.

PubMed

Dede, Doğu Ömür; Şahin, Onur; Koroglu, Aysegül; Yilmaz, Burak

2016-07-01

The effect of sealant agents on the surface roughness and color stability of nanohybrid composite resins is unknown. The purpose of this in vitro study was to evaluate the effect of sealant agents on the surface roughness and color stability of 4 nanohybrid composite resin materials. Forty disks (10×2 mm) were fabricated for each nanohybrid composite resin material (Z-550, Tetric EvoCeram, Clearfill Majesty, Ice) (N=160) and divided into 4 surface treatment groups: 1 conventional polishing (control) and 3 different sealant agent (Palaseal, Optiglaze, BisCover) coupling groups (n=10). The specimens were thermocycled, and surface roughness (Ra) values were obtained with a profilometer. Scanning electron microscope images were also recorded. CIELab color parameters of each specimen were measured with a spectrophotometer before and after 7 days of storage in a coffee solution. Color differences were calculated by the CIEDE 2000 (ΔE00) formula. The data were statistically analyzed by 2-way ANOVA and by the Tukey HSD test (α=.05). The surface treatment technique significantly affected the Ra values of the composite resins tested (P<.001). The interaction between the surface treatment technique and composite resin material was also significant for ΔE00 values (P<.05). Within the composite resin groups, significant decreases in Ra were observed only for the Palaseal agent coupled composite resin groups (except Ice) compared with the control groups (P<.05). Scanning electron microscope images revealed rougher surfaces with conventionally polished groups compared with test groups. Conventionally polished groups had the highest ΔE00 (3.09 to 3.49) values for each composite resin group, except for BisCover applied Clearfill Majesty (P<.05). Within the composite resin groups, significant differences were observed between the color change seen with BisCover and other sealants for Clearfill Majesty composite resin (P<.05). Using Palaseal agent on all tested composite resins except for Ice produced smoother surfaces. All surface sealant agents provided less discoloration of nanohybrid composite resins after coffee staining compared with conventional polishing except for BisCover applied Clearfill Majesty composite resin. Copyright © 2016 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Biologic therapies and bone loss in rheumatoid arthritis.

PubMed

Zerbini, C A F; Clark, P; Mendez-Sanchez, L; Pereira, R M R; Messina, O D; Uña, C R; Adachi, J D; Lems, W F; Cooper, C; Lane, N E

2017-02-01

Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures. Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of "small molecules of new agents." Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent's treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.

Increased prevalence of preeclampsia among women undergoing procedural intervention for renal artery fibromuscular dysplasia.

PubMed

Vance, Chardonnay J; Taylor, Robert N; Craven, Timothy E; Edwards, Matthew S; Corriere, Matthew A

2015-08-01

Renal artery fibromuscular dysplasia (RA-FMD) has a higher prevalence among women and a presumed hormonal etiology. Although preeclampsia has a clinical presentation similar to symptomatic RA-FMD and occurs exclusively in women, associations between these 2 diseases have not been characterized. To explore epidemiologic associations between RA-FMD and preeclampsia, we administered a validated screening instrument for preeclampsia to a cohort of women with a history of pregnancy who had previously been treated with procedural intervention for symptomatic RA stenosis. Women with a history of pregnancy who had previously undergone procedural intervention (including angioplasty and/or bypass) for symptomatic RA stenosis were identified from a prospectively maintained operative registry and screened for remote history of preeclampsia using a validated survey instrument. Univariable associations between RA-FMD and preeclampsia among participants with a history of pregnancy were evaluated using t-tests for continuous factors and chi-squared tests for dichotomous factors. Multivariable associations were evaluated using logistic regression models. A total of 144 women were identified who met the study inclusion criteria, including 94 with atherosclerotic RA stenosis and 50 with RA-FMD. Sixty-nine patients were contacted, 59 consented to participate, and 52 had a history of pregnancy (and therefore were at risk for preeclampsia). Participants completed the survey instrument at a mean of 7.1 ± 3.1 vs. 6.9 ± 3.6 years after RA procedural intervention, respectively. Survey responses indicated a history of preeclampsia in 19/52 (36.5%) of participants overall, including 14/27 (51.9%) with RA-FMD versus 5/20 (20.0%) with RA atherosclerosis (P = 0.02). Preeclampsia remained associated with FMD in a multivariable model adjusting for smoking status, age at time of surgery, and estimated glomerular filtration rate (odds ratio [OR] 9.51, 95% confidence interval [CI] 1.49-60.6, P = 0.017); age at the time of surgery (OR 2.78, 95% CI 1.04-7.42, P = 0.041) and estimated glomerular filtration rate (OR 3.31, 95% CI 1.29-8.52, P = 0.013) were also associated with FMD in the multivariable model. Women with a history of procedural intervention for symptomatic RA stenosis have an overall prevalence of preeclampsia which greatly exceeds that expected in the general population, and our results suggest that preeclampsia is specifically associated with RA-FMD. Further investigation is needed to characterize the mechanistic relationships between FMD and preeclampsia and may have potential to decrease related cardiovascular morbidity and mortality. Copyright © 2015 Elsevier Inc. All rights reserved.

Efficacy of Several Therapeutic Agents in a Murine Model of Dry Eye Syndrome

PubMed Central

Kilic, Servet; Kulualp, Kadri

2016-01-01

In the current study, we used 56 female BALB/c mice with induced dry eye syndrome to evaluate the therapeutic effects of formal saline (FS), sodium hyaluronate (SH), diclofenac sodium (DS), olopatadine (OP), retinoic acid (RA), fluoromethanole (FML), cyclosporine A (CsA), and doxycycline hyclate (DH). All subjects were kept in an evaporative ‘dry eye cabinet’ for the assessment of blink rate, tear production, tear break-up time, and impression cytology prior to (baseline) and during weeks 2, 4, and 6 of the study. The right eyes of all subjects were treated topically with 5 µL of the test agent twice daily during weeks 2 through 6. Impression cytology and tear break-up time differed between time points in all groups and differed between groups at weeks 4 and 6. Blink rate differed by time point only in the FS, FML, and DH groups. Tear production according to the phenol red cotton thread test differed by time point for all groups except RA, CsA, and DH and differed between groups only at week 6. Among the compounds tested in the present study, DS and CsA were the most effective therapeutic agents in our mouse model of dry eye syndrome; these agents likely exert their therapeutic effect through their antiinflammatory activity. PMID:27053565

Pulmonary fibrosis in rheumatoid arthritis: a review of clinical features and therapy.

PubMed

Roschmann, R A; Rothenberg, R J

1987-02-01

During the past four decades there has been a growing appreciation of the frequency of pulmonary abnormalities associated with RA. Approximately 30% to 40% of patients with RA demonstrate either radiographic or pulmonary function abnormalities indicative of interstitial fibrosis or restrictive lung disease. The severity of pulmonary fibrosis is not associated with rheumatologic symptoms or the duration of the associated RA, nor is there any clear relation to the extraarticular features of RA or serologic findings. Survival rates in patients with coexisting RA and pulmonary fibrosis are similar to those of patients with idiopathic pulmonary fibrosis. However, the spectrum of disease activity is quite variable. The majority of patients with progressive pulmonary symptomatology, when treated with corticosteroids, will have equivocal results. Some patients appear to respond to immunosuppressive or cytotoxic medications. The role of macrophages may be central to the injury to lung. Recent studies suggest a potential treatment role for cyclosporine, which may be able to interrupt lymphocyte-stimulated macrophage activation, and thus, fibroblast-mediated fibrosis in patients with pulmonary interstitial fibrosis. Bronchoalveolar lavage studies may delineate subgroups of patients who are more likely to respond to immunosuppressive agents, especially when treatment is started early.

Tolerability of clindamycin/tretinoin gel vs. tretinoin microsphere gel and adapalene gel.

PubMed

Leyden, James; Wortzman, Mitchell; Baldwin, Edward K

2009-04-01

Newer agents and formulations seek to improve the tolerability of topical retinoid therapy. Recently, a gel containing crystalline clindamycin 1.2% and tretinoin 0.025% (CLIN/RA) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of treating mild-to-moderate acne. This single-center, randomized, evaluator-blind phase 1 study compared the tolerability of CLIN/RA to 0.1% tretinoin gel or 0.1% adapalene gel. Forty-five patients applied CLIN/RA once daily to one side of their face every day for 21 days. Patients were randomized to either tretinoin 0.1% (n = 23) or adapalene 0.1% (n = 22) on the contralateral side. A clinical evaluator assessed degree of erythema and scaling; patients provided subjective evaluations of burning, stinging, and itching. CLIN/RA was significantly better tolerated than was 0.1% tretinoin gel, as evidenced by significantly reduced erythema (P < 0.04), scaling (P < 0.03), itching (P < 0.02), burning (P < 0.03) and stinging (P < 0.04). A trend for greater erythema, scaling, and subjective discomfort for 0.1% adapalene gel compared to CLIN/RA was also evident.

A Unified Approach to Model-Based Planning and Execution

NASA Technical Reports Server (NTRS)

Muscettola, Nicola; Dorais, Gregory A.; Fry, Chuck; Levinson, Richard; Plaunt, Christian; Norvig, Peter (Technical Monitor)

2000-01-01

Writing autonomous software is complex, requiring the coordination of functionally and technologically diverse software modules. System and mission engineers must rely on specialists familiar with the different software modules to translate requirements into application software. Also, each module often encodes the same requirement in different forms. The results are high costs and reduced reliability due to the difficulty of tracking discrepancies in these encodings. In this paper we describe a unified approach to planning and execution that we believe provides a unified representational and computational framework for an autonomous agent. We identify the four main components whose interplay provides the basis for the agent's autonomous behavior: the domain model, the plan database, the plan running module, and the planner modules. This representational and problem solving approach can be applied at all levels of the architecture of a complex agent, such as Remote Agent. In the rest of the paper we briefly describe the Remote Agent architecture. The new agent architecture proposed here aims at achieving the full Remote Agent functionality. We then give the fundamental ideas behind the new agent architecture and point out some implication of the structure of the architecture, mainly in the area of reactivity and interaction between reactive and deliberative decision making. We conclude with related work and current status.

Using Relational Agents to Promote Exercise and Sun Protection: Assessment of Participants’ Experiences With Two Interventions

PubMed Central

Lantini, Ryan

2018-01-01

Background Relational agents (RAs) are electronic computational figures designed to engage participants in the change process. A recent study, Project RAISE, tested the effectiveness of RAs, combined with existing computer-based interventions to increase regular exercise and sun protection behaviors. Results showed these interventions can be effective but need further development. Objective The purpose of this study was to examine participants’ experiences using RAs to increase participant engagement and promote behavior change . Methods A qualitative approach was primarily utilized. A 25-question interview guide assessed different components of participants’ experiences with the intervention, including motivation, engagement, satisfaction or dissatisfaction, quality of their interaction with the RA, and behavior change. Quantitative assessment of satisfaction was based on a scale of 1 to 10, with 1 representing least satisfied and 10 representing most satisfied. A summative analytic approach was used to assess individuals’ qualitative responses. A single analysis of variance (ANOVA) examined levels of satisfaction by gender. Results Of the original 1354 participants enrolled in Project RAISE, 490 of 1354 (36%) were assigned to the RA group. A sample of 216 out of 490 (44%) participants assigned to the RA group completed the interventions, and follow-up assessments were contacted to participate in the semistructured interview. A total of 34 out of 216 (16%) completed the interview. Participants were motivated by, and satisfied with, the intervention. Participants viewed the RA as supportive, informative, caring, and reported positive behavior change in both exercise and sun protection. Some participants (15/34, 44%) noted the RA was less judgmental and less “overbearing” compared with a human counselor; other participants (12/34, 35%) said that the interaction was sometimes repetitive or overly general. The majority of participants (22/34, 65%) viewed the RA as an important contributor to their behavior change for exercise, sun protection, or both. Levels of satisfaction ranged between 7 and 10. There were no gender differences noted in levels of satisfaction (P=.51). Conclusions RAs provide an innovative and attractive platform to increase exercise and sun protection behaviors and potentially other health behaviors. PMID:29415873

Modulation of Mycoplasma arthritidis-derived superantigen-induced cytokine gene expression by dexamethasone and interleukin-4.

PubMed Central

Mehindate, K; al-Daccak, R; Rink, L; Mecheri, S; Hébert, J; Mourad, W

1994-01-01

Activation of human monocytes or monocytic cell lines with all known stimuli coordinately induces the gene expression of various cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and the IL-1 receptor antagonist (IL-1Ra). In contrast, superantigens induce TNF-alpha and IL-1 beta but fail to affect IL-1Ra gene expression, suggesting that activation of monocytes via major histocompatibility complex class II is distinct from other signal transduction pathways. In the present study, we analyzed the regulation of the Mycoplasma arthritidis-derived superantigen (MAM)-induced IL-1 beta and TNF-alpha gene expression by studying the effects of two different anti-inflammatory agents: dexamethasone (DEX) and the T-cell-derived cytokine IL-4. Both agents contributed to the downregulation of MAM-induced IL-1 beta and TNF-alpha gene expression. They accelerated the normal decline of the gene expression of both MAM-induced cytokines by decreasing the stability of mRNAs via the induction or enhanced synthesis of one or more regulatory proteins. In addition, IL-4, but not DEX, induced a strong and rapid expression of IL-1Ra mRNA in MAM-stimulated and unstimulated THP-1 cells in a de novo protein synthesis-independent manner. The capacity of IL-4 to induce IL-1Ra gene expression reinforces its anti-inflammatory activity. This study illustrates some of the mechanisms by which MAM-induced proinflammatory monokine gene expression can be downregulated by IL-4 and DEX. Images PMID:7927746

An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase

DOE Office of Scientific and Technical Information (OSTI.GOV)

James, Lloyd R.A.; Xu, Zhi-Qiang; Sluyter, Ronald

Gold(I) complexes are an important tool in the arsenal of established approaches for treating rheumatoid arthritis (RA), while some recent studies have suggested that gold nanoparticles (Au NPs) may also be therapeutically efficacious. These observations prompted the current biological studies involving gold(I) anti-RA agents and Au NPs, which are aimed towards improving our knowledge of how they work. The cytotoxicity of auranofin, aurothiomalate, aurothiosulfate and Au NPs towards RAW264.7 macrophages was evaluated using the MTT assay, with the former compound proving to be the most toxic. The extent of cellular uptake of the various gold agents was determined using graphitemore » furnace atomic absorption spectrometry, while their distribution within macrophages was examined using microprobe synchrotron radiation X-ray fluorescence spectroscopy. The latter technique showed accumulation of gold in discrete regions of the cell, and co-localisation with sulfur in the case of cells treated with aurothiomalate or auranofin. Electrospray ionization mass spectrometry was used to characterize thioredoxin reductase (TrxR) in which the penultimate selenocysteine residue was replaced by cysteine. Mass spectra of solutions of TrxR and aurothiomalate, aurothiosulfate or auranofin showed complexes containing bare gold atoms bound to the protein, or protein adducts containing gold atoms retaining some of their initial ligands. These results support TrxR being an important target of gold(I) drugs used to treat RA, while the finding that Au NPs are incorporated into macrophages, but elicit little toxicity, indicates further exploration of their potential for treatment of RA is warranted.« less

GLP-1 agonists for type 2 diabetes: pharmacokinetic and toxicological considerations.

PubMed

Jespersen, Maria J; Knop, Filip K; Christensen, Mikkel

2013-01-01

Within recent years, glucagon-like peptide 1 receptor agonists (GLP-1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles. This review describes the pharmacokinetics and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration. GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable differences in risk between the available agents. Antibody formation and injection site reactions are more frequent with the exendin-4-based compounds. The efficacy with regard to Hb(A1c) reduction is superior with the longer-acting agonists, whereas the shorter-acting GLP-1-RA seems to provide greater postprandial glucose control and lower tolerability as a possible consequence of less induction of tachyphylaxis. The future place of these agents will depend on the added safety and efficacy data in the several ongoing cardiovascular outcome trials.

The efficiency of biologic therapy in a group of patients with rheumatoid arthritis.

PubMed

Gavrilă, B I; Ciofu, C; Stoica, V; Panaitescu, E

2015-01-01

The following study aims to evaluate the monotherapy with biologic agents: Infliximab (IFX), Etanercept (ETA), Adalimumab (ADA) and Rituximab (RTX) in patients diagnosed with rheumatoid arthritis (RA). To achieve these objectives, the database of "Dr. I. Cantacuzino" Clinical Hospital, Department of Internal Medicine and Rheumatology, was used. The study was retrospective and descriptive, covering 168 patients with RA, followed for 12 months, from January 2012 to January 2013. Admission criteria for the study were the following: patients diagnosed with RA according to ACR 1987/ EULAR 2010 criteria, disease activity score (DAS 28)> 5.1, positive inflammation tests, presence of RA refractory to classic remitting treatment administered at least 6 months prior to the initiation of biological therapy, on patients treated with RTX. They were considered non-responders after 6 months of treatment with anti tumor necrosis factor alpha (anti-TNF) and decided to switch agents with anti CD-20. Comparing values between any two points in time (baseline - 6 months -12 months) for any type of therapy, there were significant decreases in the values of erythrocyte sedimentation rate (ESR), reactive C protein (CRP) and disease activity score (DAS 28). There were no significant differences between therapies regarding ESR at 6 months (p = 0.070, ANOVA) and 12 months (p = 0.375, Kruskal-Wallis), significant differences were regarding CRP at 6 and 12 months (p = 0.000, Kruskal-Wallis) and DAS 28 at 6 months (p = 0.000, Kruskal- Wallis) and 12 months (p = 0.018, Kruskal-Wallis). All 4 therapies have proven efficient, prognostic markers decreasing gradually at 6 and 12 months.

Raddeanin A, a natural triterpenoid saponin compound, exerts anticancer effect on human osteosarcoma via the ROS/JNK and NF-κB signal pathway.

PubMed

Ma, Bo; Zhu, Jianwei; Zhao, Ang; Zhang, Jie; Wang, Yu; Zhang, Hang; Zhang, Lifang; Zhang, Qi

2018-05-27

Osteosarcoma (OS) is the most frequent and high mortality primary bone tumor in the adolescent. And it is well-known for poor prognosis due to high incidence of metastasis. Raddeanin A (RA), an active component of Anemone raddeana Regel, showed potential anti-cancer activities. However, the anti-tumor effect and molecular mechanism(s) of RA on osteosarcoma are still unclear. The present research is the first in vitro and in vivo investigate systematically anticancer of RA on human osteosarcoma. Our study demonstrated that RA induced mitochondria-dependent apoptosis in osteosarcoma cell lines and markedly suppressed the metastasis of osteosarcoma cells in vitro. And, RA treatment markedly inhibits tumor growth in vivo. Further mechanism study demonstrated that RA caused a significant enhance reactive oxygen species (ROS) level to stimulate phosphorylation of JNK. Moreover, RA led to decrease of p-IκBα level in the cytosol and reduction of p65 level in the nucleus, which was associated with the inhibition of NF-κB transcriptional activity. When NF-κB signaling was inhibited by siRNA targeting p65, a significant increase in cell apoptosis activity was observed. In addition, non-toxic RA concentrations (0.25, 0.5 and 1 μM) inhibited the migration and invasion of OS by suppressing MMP-2/9 expression associated with NF-κB-dependent transcription in vitro. The silencing of p65 increased the sensitivity of the osteosarcoma cells to RA suppressed migration and invasion. These findings suggest RA induces apoptosis and inhibits metastasis in OS cells, involved in provoking ROS/JNK and inhibiting NF-κB signaling pathways. Therefore, it may be a potential anti-metastatic and anti-proliferative therapeutic agent for human osteosarcoma. Copyright © 2017. Published by Elsevier Inc.

The effect of rosmarinic acid on 1,2-dimethylhydrazine induced colon carcinogenesis.

PubMed

Venkatachalam, Karthikkumar; Gunasekaran, Sivagami; Jesudoss, Victor Antony Santiago; Namasivayam, Nalini

2013-05-01

This study was carried out to investigate the chemopreventive potential of rosmarinic acid (RA) against 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the effect of RA on tumour formation, antioxidant enzymes, cytochrome P450 content, p-nitrophenol hydroxylase and GST activities. Rats were divided into six groups and fed modified pellet diet for the entire experimental period. Group 1 served as control, group 2 received RA (10 mg/kgb.w.). Groups 3-6 were induced colon cancer by injecting DMH (20 mg/kgb.w.) subcutaneously once a week for the first four weeks (groups 3-6). In addition, RA was administered at the doses of 2.5, 5 and 10 mg/kgb.w. to groups 4-6 respectively. DMH treated rats showed large number of colonic tumours; decreased lipid peroxidation; decreased antioxidant status; elevated CYP450 content and PNPH activities; and decreased GST activity in the liver and colon. Supplementation with RA (5 mgkg/b.w.) to DMH treated rats significantly decreased the number of polyps (50%); reversed the markers of oxidative stress (21.0%); antioxidant status (38.55%); CYP450 content (29.41%); and PNPH activities (21.9%). RA at the dose of 5 mg/kgb.w. showed a most pronounced effect and could be used as a possible chemopreventive agent against colon cancer. Copyright © 2011 Elsevier GmbH. All rights reserved.

Dosage effects of histamine-2 receptor antagonist on the primary prophylaxis of non-steroidal anti-inflammatory drug (NSAID)-associated peptic ulcers: a retrospective cohort study.

PubMed

He, Ying; Chan, Esther W; Man, Kenneth K C; Lau, Wallis C Y; Leung, Wai K; Ho, Lai M; Wong, Ian C K

2014-09-01

A histamine-2 receptor antagonist (H2RA) is one of the common gastroprotective co-therapies used with non-steroidal anti-inflammatory drugs (NSAIDs) for the prevention or treatment of peptic ulcers (PUs). To date, no study has directly compared the prophylactic effectiveness between high-dose and low-dose H2RA. Our objective was to compare the effectiveness of high-dose versus low-dose H2RAs in the primary prophylaxis of PUs among short-term NSAID users. A retrospective cohort study was conducted using the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong. Patients aged 18 years or above who received a single prescription of oral NSAID with oral H2RA were identified within the study period (1 January 2009-31 December 2012). Patients with a history of or risk factors for PU in the corresponding 2 years prior to the index date (of the first NSAID prescription) were excluded. Log binomial regression analysis was used to calculate the relative risk of PU among NSAID users with high-dose H2RA versus low-dose H2RA exposure. Among the NSAID cohort (n = 102,042), 77,509 (76 %) were on low-dose H2RA and 24,533 (24 %) were on high-dose H2RA. Of the total 69 PU cases identified during the drug exposure period, 64 (0.08 %) received low-dose-H2RA and five (0.02 %) received high-dose H2RA. The overall absolute risk of PUs for NSAID users whilst on H2RA was approximately 1 per 1,479 patients. The adjusted relative risk for NSAID users receiving high-dose H2RA versus low-dose H2RA was 0.32 (95 % confidence interval [CI] 0.13-0.79). Patients aged ≥65 years, receiving a longer duration of treatment, or with concomitant use of antiplatelet agents were found to be at higher risk of PU. High-dose H2RA showed greater effectiveness than low-dose H2RA in the primary prophylaxis of NSAID-associated PUs in short-term new users.

The Dynamic Duo–Inflammatory M1 macrophages and Th17 cells in Rheumatic Diseases

PubMed Central

Li, Jun; Hsu, Hui-Chen; Mountz, John D.

2014-01-01

The synovial tissue of Rheumatoid Arthritis (RA) patients is enriched with macrophages and T lymphocytes which are two central players in the pathogenesis of RA. Interaction between myeloid cells and T cells are essential for the initiation and progression of the inflammatory processes in the synovium. With the rapid evolution of our understanding of how these two cell types are involved in the regulation of immune responses, RA is emerging as an ideal disease model for investigating the cell-cell interactions and consequently introducing novel biologic agents that are designed to disrupt these processes. This review will discuss the bidirectional interaction between the IL-23+ inflammatory macrophages and IL-17+ GM-CSF+ CD4 T cells in rheumatic diseases as well as potential antirheumatic strategies via apoptosis induction in this context. PMID:25309946

Enabling private and public sector organizations as agents of homeland security

NASA Astrophysics Data System (ADS)

Glassco, David H. J.; Glassco, Jordan C.

2006-05-01

Homeland security and defense applications seek to reduce the risk of undesirable eventualities across physical space in real-time. With that functional requirement in mind, our work focused on the development of IP based agent telecommunication solutions for heterogeneous sensor / robotic intelligent "Things" that could be deployed across the internet. This paper explains how multi-organization information and device sharing alliances may be formed to enable organizations to act as agents of homeland security (in addition to other uses). Topics include: (i) using location-aware, agent based, real-time information sharing systems to integrate business systems, mobile devices, sensor and actuator based devices and embedded devices used in physical infrastructure assets, equipment and other man-made "Things"; (ii) organization-centric real-time information sharing spaces using on-demand XML schema formatted networks; (iii) object-oriented XML serialization as a methodology for heterogeneous device glue code; (iv) how complex requirements for inter / intra organization information and device ownership and sharing, security and access control, mobility and remote communication service, tailored solution life cycle management, service QoS, service and geographic scalability and the projection of remote physical presence (through sensing and robotics) and remote informational presence (knowledge of what is going elsewhere) can be more easily supported through feature inheritance with a rapid agent system development methodology; (v) how remote object identification and tracking can be supported across large areas; (vi) how agent synergy may be leveraged with analytics to complement heterogeneous device networks.

Patent foramen ovale: diagnosis with multidetector CT--comparison with transesophageal echocardiography.

PubMed

Kim, Young Jin; Hur, Jin; Shim, Chi-Young; Lee, Hye-Jeong; Ha, Jong-Won; Choe, Kyu Ok; Heo, Ji Hoe; Choi, Eui-Young; Choi, Byoung Wook

2009-01-01

To evaluate the clinical feasibility and accuracy of 64-section multidetector computed tomography (CT) compared with transesophageal echocardiography (TEE) for diagnosis of a patent foramen ovale (PFO). Institutional review board approval was obtained for this retrospective study. The study included 152 consecutive stroke patients (mean age, 61.7 years; 98 men, 54 women) who underwent both cardiac multidetector CT and TEE. Electrocardiographically gated cardiac CT was performed with a 64-section CT scanner by using a saline-chaser contrast agent injection technique. A contrast agent jet from the contrast agent-filled left atrium (LA) to the saline-filled right atrium (RA) and channel-like appearance of the interatrial septum (IAS) were evaluated on axial and oblique sagittal CT images. Two-dimensional and Doppler TEE were performed to detect PFO. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CT were obtained with TEE as the reference standard. A PFO was present in 26 patients at TEE. On CT images, a left-to-right contrast agent jet toward the inferior vena cava was noted in 21 patients (sensitivity, 73.1%; specificity, 98.4%; PPV, 90.5%; NPV, 94.7%). Channel-like appearance of the IAS was detected in 38 patients (sensitivity, 76.9%; specificity, 85.7%; PPV, 52.6%; NPV, 94.7%). Channel-like appearance of the IAS was noted in all patients who had a contrast agent jet. A contrast agent jet from LA to RA toward the inferior vena cava with channel-like appearance of the IAS on CT images confirms the presence of a PFO. (c) RSNA, 2008.

Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and seronegative spondyloarthritis: analysis from the MonitorNet database.

PubMed

Scirè, Carlo A; Caporali, Roberto; Sarzi-Puttini, Piercarlo; Frediani, Bruno; Di Franco, Manuela; Tincani, Angela; Sinigaglia, Luigi; Sfriso, Paolo; Tirri, Rosella; Bellis, Emanuela; Delsante, Giovanni; Porru, Giovanni; Salaffi, Fausto; Giuggioli, Dilia; Rossini, Maurizio; Todoerti, Monica; Bazzichi, Laura; Govoni, Marcello; Gerli, Roberto; Raschetti, Roberto; Minisola, Giovanni; Montecucco, Carlomaurizio; Todesco, Silvano

2013-01-01

To compare drug survival of different anti-TNF drugs (infliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicenter observational cohort study. All patients with RA or SpA registered in the MonitorNet database who started their first course of anti-TNF therapy were included. Overall drug survival was measured, along with specific reasons of discontinuation (inefficacy or adverse events). A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival. A second set of analyses stratified by diagnosis (RA and SpA) used INF as reference drug. Adjustment for confounders was performed. The results are presented as adjusted hazard ratios (adjHR) and 95% confidence intervals (95%CI). 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses. Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90). In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment. In RA, both ETA and ADA showed a significantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively]. Similar results were found in SpA. Drug survival for SpA is longer than that in RA mainly due to the AS subgroup. In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF.

Substance P ameliorates collagen II-induced arthritis in mice via suppression of the inflammatory response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Hyun Sook; Son, Youngsook, E-mail: ysson@khu.ac.kr

Highlights: • SP can increase IL-10 levels and reduce TNF-α and IL-17 levels in RA. • SP causes the increase in T{sub reg}, M2 macrophage, and MSCs in RA. • SP-induced immune suppression leads to the blockade of RA progression. • SP can be used as the therapeutics for autoimmune-related inflammatory diseases. - Abstract: Current rheumatoid arthritis (RA) therapies such as biologics inhibiting pathogenic cytokines substantially delay RA progression. However, patient responses to these agents are not always complete and long lasting. This study explored whether substance P (SP), an 11 amino acids long endogenous neuropeptide with the novel abilitymore » to mobilize mesenchymal stem cells (MSC) and modulate injury-mediated inflammation, can inhibit RA progression. SP efficacy was evaluated by paw swelling, clinical arthritis scoring, radiological analysis, histological analysis of cartilage destruction, and blood levels of tumor necrosis factor-alpha (TNF-α) interleukin (IL)-10, and IL-17 in vivo. SP treatment significantly reduced local inflammatory signs, mean arthritis scores, degradation of joint cartilage, and invasion of inflammatory cells into the synovial tissues. Moreover, the SP treatment markedly reduced the size of spleens enlarged by excessive inflammation in CIA, increased IL-10 levels, and decreased TNF-α and IL-17 levels. Mobilization of stem cells and induction of T{sub reg} and M2 type macrophages in the circulation were also increased by the SP treatment. These effect of SP might be associated with the suppression of inflammatory responses in RA and, furthermore, blockade of RA progression. Our results propose SP as a potential therapeutic for autoimmune-related inflammatory diseases.« less

Visceral leishmaniasis in a patient with rheumatoid arthritis treated with methotrexate.

PubMed

Loarce-Martos, Jesús; Garrote-Corral, Sandra; Gioia, Francesca; Bachiller-Corral, Javier

2017-09-25

A large number of complications have been associated with rheumatoid arthritis (RA), those of infectious etiology being of special relevance. Their high incidence is closely linked to the use of immunosuppressive medication. The spectrum of agents causing opportunistic infections in patients with RA is very broad; however, there are relatively few cases of Leishmania infection, especially in patients not being treated with biological drugs. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Adalimumab, etanercept, and infliximab utilization patterns and drug costs among rheumatoid arthritis patients.

PubMed

Carter, Chureen T; Changolkar, Arun K; Scott McKenzie, R

2012-01-01

To evaluate the utilization patterns of the anti-tumor necrosis factor (anti-TNF) agents Humira (adalimumab), Enbrel (etanercept), and Remicade (infliximab) in patients with rheumatoid arthritis (RA) and compare medication costs during the first year of treatment. (Humira is a registered trademark of Abbott Laboratories, IL; Enbrel is a registered trademark of Immunex Corporation, CA; and Remicade is a registered trademark of Janssen Biotech, Inc., PA). This retrospective analysis of medical and pharmacy claims included patients who were aged ≥18 years, had ≥2 RA diagnosis codes, and had ≥365 days of persistence with the index anti-TNF. Patients excluded had claims for anti-TNF agents within 6 months before the index date. Refill patterns for adalimumab and etanercept, number of infliximab infusions, time between infusions, and dose per infusion were analyzed for 12 months. Direct anti-TNF medication costs were compared among anti-TNFs for the initial treatment year. Infliximab-treated patients (n = 457) were significantly older than adalimumab- (n = 337) or etanercept-treated patients (n = 902). Time between refills was longer than recommended for 28% and 30% of adalimumab and etanercept refill periods, respectively. Potential cumulative time without therapy was 33 days for adalimumab and 43 days for etanercept. Statistically significant differences in mean per-patient anti-TNF medication costs for the first year were reported for adalimumab, etanercept, and infliximab ($14,991, $13,361, and $18,139, respectively; p < 0.0001); however, a cost assessment using labeled dosing of the anti-TNF agents with optimal treatment compliance yielded comparable annual medication costs. This analysis only evaluated utilization patterns for selected anti-TNF agents and was not inclusive of other medications that patients may have been using for RA. Absolute patient adherence could not be assessed due to lack of information on how patients were self-administering adalimumab and etanercept or if samples of the agents were made available. This study identified gaps in patients' refills compared with prescriber recommendations. The infliximab-treated group had infusion patterns consistent with prescribing information. Potential clinical and economic implications of dose attenuation with adalimumab and etanercept should be explored further.

Macrophages mediated diagnosis of rheumatoid arthritis using fibrin based magnetic nanoparticles as MRI contrast agents.

PubMed

Periyathambi, Prabu; Sastry, Thotapalli Parvathaleswara; Anandasadagopan, Suresh Kumar; Manickavasagam, Kanagavel

2017-01-01

A variety of bioimaging tools assists in the diagnosis and evaluation of rheumatoid arthritis (RA) and other osteoarthritis. However, detection of RA in the early stages by targeting its macrophages with suitable contrast agents will help in arresting the progression of the disease. In the present study, we investigated the effectiveness of using magnetic fibrin nanoparticles (MFNPs) conjugated with folic acid (FA-MFNPs) as a specific contrast agent to target the activated macrophages, which overexpress the folate receptors (FR) in the knee joints of rats with antigen-induced arthritis (AIA). FA-MFNPs were spherical with an average size of 18.3±1.6nm. In vitro studies have shown effective internalization of FA-MFNPs into the Raw264.7 macrophage cells. In vivo studies were carried out by injecting FA-MFNPs intravenously into the arthritic rats. The results showed enhanced MR imaging in the synovium of arthritic joints. Prussian blue histological staining confirmed uptake of FA-MFNPs by macrophages in the synovial tissue. The animal experiment results indicate that FA-MFNPs can be used as a specific MRI contrast agent in identifying phagocytic active macrophages in the synovial joints. Blood is the precursor source for synthesising the fibrin-based iron oxide (magnetic) nanoparticles (MFNPs) with diameters between 12 and 15nm. It has excellent superparamagnetic behaviour, biocompatibility, osteogenic potency, hemocompatibility, and biodegradable properties. MFNPs-based nanocomposites might be a promising contrast agent for bioimaging. Copyright © 2016 Elsevier B.V. All rights reserved.

Ultrastructural evaluation of enamel after dental bleaching associated with fluoride.

PubMed

Dominguez, John A; Bittencourt, Bruna; Michel, Milton; Sabino, Nilson; Gomes, João Carlos; Gomes, Osnara M M

2012-08-01

This study evaluated the effects on human enamel after two bleaching procedures: with a fluoridated bleaching agent and with topical fluoride application postbleaching. It used 43 enamel blocks (3 mm(2) ) that were ground flat (600-2,000 grit) and polished with polishing paste (one and one-fourth). Specimens were randomly divided into three groups according to the bleaching procedure: (1) control group, (2) hydrogen peroxide 35% (HPF) and topical application of fluoride 1.23%, and (3) HP 38% (OP) with fluoride in its composition. Bleaching agents were used according to the manufacturer's instructions. Three methodologies were used: nanoindentation, to observe surface hardness and elastic modulus; atomic force microscopy, to observe surface roughness (R(a) - R(z)); and scanning electron microscopy, to observe the enamel surface effects. Group OP had a decrease in the elastic modulus after bleaching, which was recovered at 14 days. An increased roughness (R(a); 32%) was observed on group HPF and had an increased erosion on enamel surface (67%). It was concluded that topical application of fluoride, after using the nonfluoridated whitening agent, increased the roughness values and erosion of enamel. Copyright © 2012 Wiley Periodicals, Inc.

Vectra DA for the objective measurement of disease activity in patients with rheumatoid arthritis.

PubMed

Segurado, O G; Sasso, E H

2014-01-01

Quantitative and regular assessment of disease activity in rheumatoid arthritis (RA) is required to achieve treatment targets such as remission and to optimize clinical outcomes. To assess inflammation accurately, predict joint damage and monitor treatment response, a measure of disease activity in RA should reflect the pathological processes resulting in irreversible joint damage and functional disability. The Vectra DA blood test is an objective measure of disease activity for patients with RA. Vectra DA provides an accurate, reproducible score on a scale of 1 to 100 based on the concentrations of 12 biomarkers that reflect the pathophysiologic diversity of RA. The analytical validity, clinical validity, and clinical utility of Vectra DA have been evaluated for patients with RA in registries and prospective and retrospective clinical studies. As a biomarker-based instrument for assessing disease activity in RA, the Vectra DA test can help monitor therapeutic response to methotrexate and biologic agents and assess clinically challenging situations, such as when clinical measures are confounded by non-inflammatory pain from fibromyalgia. Vectra DA scores correlate with imaging of joint inflammation and are predictive for radiographic progression, with high Vectra DA scores being associated with more frequent and severe progression and low scores being predictive for non-progression. In summary, the Vectra DA score is an objective measure of RA disease activity that quantifies inflammatory status. By predicting risk for joint damage more effectively than conventional clinical and laboratory measures, it has the potential to complement these measures and optimise clinical decision making.

Distribution of uranium and radium isotopes in an aquifer of a semi-arid region (Manouba-Essijoumi, Northern Tunisia).

PubMed

Added, A; Ben Mammou, A; Fernex, F; Rezzoug, S; Bernat, M

2005-01-01

Groundwaters from the Sebkhet Essijoumi drainage basin, situated in northern Tunisia, West of the city of Tunis, were sampled and analyzed for uranium and radium isotopes. Low (234)U/(238)U activity ratios coupled with relatively high (228)Ra and (238)U concentrations were found in the Manouba plain phreatic aquifer, at the northern part of the basin, where remote sensing has indicated that this plain corresponds to the main humid zone of the area. Low (234)U/(238)U ratios probably reflected short residence time for waters in the Manouba plain, and high ratios longer residence time in the south, where water reaching the phreatic aquifer seems to have previously circulated in rocks constituting the southern hills. Assuming that, in the Manouba plain aquifer, the groundwater flows downstream from the Oued Lill pass area to the South-West of the Sebkha, the difference in the (228)Ra/(226)Ra activity ratio suggests that the residence time of water has been 2.8 years longer near the Sebkha than upstream.

Epstein-Barr virus-associated lymphoproliferative disorder in a patient with rheumatoid arthritis on methotrexate and rofecoxib: idiosyncratic reaction or pharmacogenetics?

PubMed

Vincent, Simi; Slease, R Bradley; Rocca, Peter V

2002-12-01

Rheumatoid arthritis (RA) is an autoimmune disease associated with altered immunoregulation and resulting in a deforming polyarthritis. Methotrexate (MTX) is a commonly used second line agent for RA, and there have been several recent reports of Epstein-Barr virus (EBV)-associated polyclonal B cell lymphoproliferative disorder in MTX-treated RA patients. The patient in this report had long standing RA treated with MTX and had recently begun taking a cyclooxygenase-2 (COX-2) inhibitor. She developed a febrile illness associated with severe pancytopenia and leukocytoclastic vasculitic rash followed by diffuse adenopathy, with serologic and pathologic evidence of EBV infection. Previous studies have demonstrated the interaction of MTX and a variety of non-steroidal, anti-inflammatory drugs (NSAIDs) with various clinical manifestations including acute renal failure, pancytopenia, vomiting, diarrhea, elevated liver transaminases, jaundice, mucosal ulcerations, and pyrexia. However, we have not identified previous reports suggesting interaction between MTX and COX-2 inhibitors. We hypothesize that decreased renal elimination of MTX induced by the COX-2 inhibitor resulted in enhanced hematopoietic toxicity and immunosuppression causing the EBV-associated lymphoproliferative disease.

Antibodies to a strain-specific citrullinated Epstein-Barr virus peptide diagnoses rheumatoid arthritis.

PubMed

Trier, Nicole Hartwig; Holm, Bettina Eide; Heiden, Julie; Slot, Ole; Locht, Henning; Lindegaard, Hanne; Svendsen, Anders; Nielsen, Christoffer Tandrup; Jacobsen, Søren; Theander, Elke; Houen, Gunnar

2018-02-27

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Anti-citrullinated protein antibodies (ACPA) are crucial for the serological diagnosis of RA, where Epstein-Barr virus (EBV) has been suggested to be an environmental agent in triggering the onset of the disease. This study aimed to analyse antibody reactivity to citrullinated EBV nuclear antigen-2 (EBNA-2) peptides from three different EBV strains (B95-8, GD1 and AG876) using streptavidin capture enzyme-linked immunosorbent assay. One peptide, only found in a single strain (AG876), obtained a sensitivity and specificity of 77% and 95%, respectively and showed high sequence similarity to the filaggrin peptide originally used for ACPA detection. Comparison of antibody reactivity to commercial assays found that the citrullinated peptide was as effective in detecting ACPA as highly sensitive and specific commercial assays. The data presented demonstrate that the citrullinated EBNA-2 peptide indeed is recognised specifically by RA sera and that the single peptide is able to compete with assays containing multiple peptides. Furthermore, it could be hypothesized that RA may be caused by (a) specific strain(s) of EBV.

Molecular Mechanisms Underlying the Cardiovascular Benefits of SGLT2i and GLP-1RA.

PubMed

Khat, Dorrin Zarrin; Husain, Mansoor

2018-06-09

In addition to their effects on glycemic control, two specific classes of relatively new anti-diabetic drugs, namely the sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated reduced rates of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes (T2D) at high risk for cardiovascular disease (CVD). This review summarizes recent experimental results that inform putative molecular mechanisms underlying these benefits. SGLT2i and GLP-1RA exert cardiovascular effects by targeting in both common and distinctive ways (A) several mediators of macro- and microvascular pathophysiology: namely (A1) inflammation and atherogenesis, (A2) oxidative stress-induced endothelial dysfunction, (A3) vascular smooth muscle cell reactive oxygen species (ROS) production and proliferation, and (A4) thrombosis. These agents also exhibit (B) hemodynamic effects through modulation of (B1) natriuresis/diuresis and (B2) the renin-angiotensin-aldosterone system. This review highlights that while GLP-1RA exert direct effects on vascular (endothelial and smooth muscle) cells, the effects of SGLT2i appear to include the activation of signaling pathways that prevent adverse vascular remodeling. Both SGLT2i and GLP-1RA confer hemodynamic effects that counter adverse cardiac remodeling.

Development of Intra-Articular Drug Delivery to Alter Progression of Arthritis Following Joint Injury

DTIC Science & Technology

2012-04-01

2012Revised AnnualApril 2012 DESIGN: A novel injectable and in situ forming drug depot based on thermally-responsive elastin -like polypeptide (ELP) will... Elastin -like polypeptide, Drug Depot – technology allowing sustained release of biologically active agent , Active agents used include IL1Ra...The abstract has been removed and an appendix has been included. In brief this protocol explores the use of elastin like polypeptide (ELP) as a

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases.

PubMed

Rubbert-Roth, Andrea; Furst, Daniel E; Nebesky, Jan Michael; Jin, Angela; Berber, Erhan

2018-06-01

Tocilizumab (TCZ) is the first humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the long-term efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti-IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although long-term data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents.

Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis.

PubMed

Tsushima, Hiroshi; Morimoto, Shinji; Fujishiro, Maki; Yoshida, Yuko; Hayakawa, Kunihiro; Hirai, Takuya; Miyashita, Tomoko; Ikeda, Keigo; Yamaji, Ken; Takamori, Kenji; Takasaki, Yoshinari; Sekigawa, Iwao; Tamura, Naoto

2017-08-01

We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1 R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1 R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1 R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1 R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.

Rheumatoid Arthritis Treatment After Methotrexate: The Durability of Triple Therapy Versus Etanercept.

PubMed

Peper, Shana M; Lew, Robert; Mikuls, Ted; Brophy, Mary; Rybin, Denis; Wu, Hongseng; O'Dell, James

2017-10-01

Although it is common for rheumatologists to initiate biologic agents after failure of methotrexate monotherapy in rheumatoid arthritis (RA), ample data support the initial use of combinations of conventional therapies in this clinical scenario. Our study explores the durability of triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) versus methotrexate-etanercept in RA. RA patients with suboptimal response to methotrexate (n = 353) were randomized to either triple therapy or methotrexate-etanercept therapy in a 48-week, double-blinded, noninferiority trial. Patients without clinical improvement at 24 weeks were switched to the alternative treatment. Of the total, 289 participated in followup. We report treatment durability, Disease Activity Score in 28 joints (DAS28), and other measures during an open-label extension for an additional period up to 72 weeks. Mean ± SD duration of open-label followup was 11 ± 6 months. The likelihood of continuing conventional therapy at 1 year was 78% for triple therapy versus 63% for methotrexate-etanercept, with most treatment changes occurring at the start of followup. More patients changed from methotrexate-etanercept to triple therapy than from triple therapy to methotrexate-etanercept (P = 0.005). DAS28 scores and other disease activity measures were not different for the 2 treatments and were stable during followup. In RA patients with suboptimal methotrexate response randomized to receive triple therapy or methotrexate-etanercept, the former was found to be significantly more durable. Given cost differences and similar outcomes, the variable durability demonstrated provides additional evidence supporting conventional combinations over biologic agent combinations as the first choice after methotrexate inadequate response. © 2017, American College of Rheumatology.

Influence of route of administration/drug formulation and other factors on adherence to treatment in rheumatoid arthritis (pain related) and dyslipidemia (non-pain related).

PubMed

Fautrel, Bruno; Balsa, Alejandro; Van Riel, Piet; Casillas, Marta; Capron, Jean-Philippe; Cueille, Carine; de la Torre, Inmaculada

2017-07-01

A comprehensive review was performed to investigate the effect of route of administration on medication adherence and persistence in rheumatoid arthritis (RA) and to compare adherence/persistence with oral medications between RA and a non-painful disease (dyslipidemia). Comprehensive database searches were performed to identify studies investigating medication adherence and/or persistence in adults with RA receiving conventional synthetic or biologic agents. Similar searches were performed for studies of patients with dyslipidemia receiving statins. Studies had to be published after 1998 in English and involve ≥6 months' follow up. Adherence and persistence were compared between the different routes of drug administration in RA, and between the two diseases for oral medications. A total of 35 and 28 papers underwent data extraction for RA and dyslipidemia, respectively. Within the constraints of the analysis, adherence and persistence rates appeared broadly similar for the different routes of drug administration in RA. Adherence to oral medications was also broadly similar across the two diseases, but persistence was lower in dyslipidemia. Poor adherence has clinical consequences in both diseases: greater disease activity and risk of flare in RA, and increased serum cholesterol levels and risk of heart and cerebrovascular disease in dyslipidemia. Over 1-3 years, poor adherence to biologic RA medications led to increased resource use and medical costs but lower total direct costs due to reduced biologic drug costs. Conversely, poor adherence to dyslipidemia medications resulted in increased total direct costs. In both diseases, adherence improved with patient education/support. The route of drug administration and the symptomatic (pain) nature of the disease do not appear to be dominant factors for drug adherence or persistence in RA. The wide range of adherence and persistence values and definitions across studies made comparisons between drug formulations and diseases difficult.

Comparative analysis of disease activity measures, use of biologic agents, body mass index, radiographic features, and bone density in psoriatic arthritis and rheumatoid arthritis patients followed in a large U.S. disease registry.

PubMed

Reddy, Soumya M; Anandarajah, Allen P; Fisher, Mark C; Mease, Philip J; Greenberg, Jeffrey D; Kremer, Joel M; Reed, George; Chen, Rui; Messing, Susan; Kaukeinen, Kimberly; Ritchlin, Christopher T

2010-12-01

To compare disease activity, radiographic features, and bone density in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) matched cohorts. Disease activity and radiographic data in the Consortium of Rheumatology Researchers of North America database from 2001 to 2008 were compared for 2481 patients with PsA and 17,107 patients with RA subsequently matched for age, gender, and disease duration. Radiographic outcomes included presence of erosions, and joint deformity. In addition, bone mineral density (BMD) scores for lumbar spine (L-spine) and femoral neck were compared using the same matching criteria plus weight and smoking status. Tender (4.5 vs 3.4, p < 0.001) and swollen (4.4 vs 2.9, p < 0.012) joint counts, and modified Health Assessment Questionnaire scores were significantly higher (0.4 vs 0.3, p < 0.001) in patients with RA compared with patients with PsA. Patient general health and pain scores were also higher in patients with RA vs patients with PsA. Joint erosions (47.4% vs 37.6%, p = 0.020) and deformity (25.2% vs 21.6%, p = 0.021) were more prevalent in RA than PsA. In multivariate analysis, a reduced prevalence of erosions in PsA vs RA was noted (OR 0.609, p < 0.001). After matching, T-scores for L-spine (-0.54 vs -0.36, p = 0.077) and femoral neck (-0.88 vs -0.93, p = 0.643) were similar in patients with RA and patients with PsA, although body weight was a major confounder. The level of disease activity and radiographic damage was significantly higher for RA vs PsA subjects, although the magnitude of differences was relatively small. BMD levels were comparable between cohorts. Outcomes in patients with PsA and patients with RA may be more similar than previously reported.

A multicenter report of biologic agents for the treatment of secondary amyloidosis in Turkish rheumatoid arthritis and ankylosing spondylitis patients.

PubMed

Pamuk, Ömer Nuri; Kalyoncu, Umut; Aksu, Kenan; Omma, Ahmet; Pehlivan, Yavuz; Çağatay, Yonca; Küçükşahin, Orhan; Dönmez, Salim; Çetin, Gözde Yıldırım; Mercan, Rıdvan; Bayındır, Özün; Çefle, Ayşe; Yıldız, Fatih; Balkarlı, Ayşe; Kılıç, Levent; Çakır, Necati; Kısacık, Bünyamin; Öksüz, Mustafa Ferhat; Çobankara, Veli; Onat, Ahmet Mesut; Sayarlıoğlu, Mehmet; Öztürk, Mehmet Akif; Pamuk, Gülsüm Emel; Akkoç, Nurullah

2016-07-01

In this multicenter, retrospective study, we evaluated the efficacy and safety of biologic therapies, including anti-TNFs, in secondary (AA) amyloidosis patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). In addition, the frequency of secondary amyloidosis in RA and AS patients in a single center was estimated. Fifty-one AS (39M, 12F, mean age: 46.7) and 30 RA patients (11M, 19F, mean age: 51.7) with AA amyloidosis from 16 different centers in Turkey were included. Clinical and demographical features of patients were obtained from medical charts. A composite response index (CRI) to biologic therapy-based on creatinine level, proteinuria and disease activity-was used to evaluate the efficacy of treatment. The mean annual incidence of AA amyloidosis in RA and AS patients was 0.23 and 0.42/1000 patients/year, respectively. The point prevalence in RA and AS groups was 4.59 and 7.58/1000, respectively. In RA group with AA amyloidosis, effective response was obtained in 52.2 % of patients according to CRI. RA patients with RF positivity and more initial disease activity tended to have higher response rates to therapy (p values, 0.069 and 0.056). After biologic therapy (median 17 months), two RA patients died and two developed tuberculosis. In AS group, 45.7 % of patients fulfilled the criteria of good response according to CRI. AS patients with higher CRP levels at the time of AA diagnosis and at the beginning of anti-TNF therapy had higher response rates (p values, 0.011 and 0.017). During follow-up after anti-TNF therapy (median 38 months), one patient died and tuberculosis developed in two patients. Biologic therapy seems to be effective in at least half of RA and AS patients with AA amyloidosis. Tuberculosis was the most important safety concern.

Preparation and properties of calcium-silicate filled resins for dental restoration. Part I: chemical-physical characterization and apatite-forming ability.

PubMed

Profeta, Andrea Corrado

2014-11-01

The aim of this study was to measure dimensional changes due to hygroscopic expansion and the bioactivity of two experimental methacrylate-based dental adhesives either incorporating Bioglass 45S5 (3-E&RA/BG) or MTA (3-E&RA/WMTA). 3-E&RA/BG, 3-E&RA/WMTA and a control filler-free resin blend (3-E&RA) were formulated from commercially available monomers. Water sorption (WS) and solubility (SL) behaviour were evaluated by weighing material disks at noted intervals; the relationship between degree of hydration and the glass transition temperature (Tg) was investigated by using differential scanning calorimetry (DSC). In vitro apatite-forming ability as a function of soaking time in phosphate-containing solutions was also determined. Kruskal-Wallis analysis of variance (ANOVA) was used to evaluate differences between groups for maximum WS, SL, net water uptake and the percentage change in Tg values. Post-ANOVA pair-wise comparisons were conducted using Mann-Whitney-U tests. 3-E&RA/BG and 3-E&RA/WMTA exhibited values of maximum WS and net water uptake that were significantly higher when compared to 3-E&RA. However, no statistically significant differences were observed in terms of SL between all the adhesives. The addition of the Bioglass 45S5 and MTA to the 3-E&RA showed no reduction of the Tg after 60 days of storage in deionized water. ATR Fourier Transform Infrared Spectroscopy (ATR-FTIR) of the filled resin disks soaked in DPBS for 60 days showed the presence of carbonate ions in different chemical phases. Dentine bonding agents comprising calcium-silicates are not inert materials in a simulated oral environment and apatite formation may occur in the intra-oral conditions. A bioactive dental material which forms apatite on the surface would have several benefits including closure of gaps forming at the resin-dentine interface and potentially better bond strength over time (less degradation of bond).

Curing APL through PML/RARA degradation by As2O3.

PubMed

Lallemand-Breitenbach, Valerie; Zhu, Jun; Chen, Zhu; de Thé, Hugues

2012-01-01

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the PML/RARA oncogene. The prognosis for patients with APL was revolutionized by two treatments: retinoic acid (RA) and As(2)O(3) (arsenic trioxide). These were both shown a posteriori to target PML/RARA, explaining their exquisite specificity for APL. Arsenic, as a single agent, cures up to 70% of patients, whereas APL patients treated with the combination of RA and As(2)O(3) reach a stunning 90% cure rate. Recent physiopathological models highlight the key role of RA- and As(2)O(3)-triggered PML/RARA degradation, and the molecular mechanisms underlying As(2)O(3)-induced PML/RARA degradation have been recently clarified. As discussed below, arsenic binding, oxidation, sumoylation on PML nuclear bodies, and RNF4-mediated ubiquitination all contribute to the As(2)O(3)-triggered catabolism of PML/RARA. Copyright © 2011 Elsevier Ltd. All rights reserved.

"Old drugs" for the treatment of rheumatoid arthritis: will the cholinergic anti-inflammatory pathway and anti-nociceptive pathway work?

PubMed

Pan, Xiaohua; Yu, Xiaowei; Qin, Ling; Zhang, Peng

2010-12-01

Based on the newly discovered cholinergic anti-inflammatory pathway, on the anti-nociceptive pathway and on our preliminary research, we raise a new strategy for the treatment of rheumatoid arthritis (RA) which mainly focuses on the application of old drugs that can activate both of the above mentioned pathways. It has been reported that nicotinic receptor agonists used for the treatment of neurological diseases were expected to be applied to the therapy of inflammatory diseases (RA). Therefore, it is promising that old drugs available in clinics may exert new functions for the treatment of RA, which may greatly reduce the expense of such treatment, once applied. These currently-used old drugs should be considered as another new resource in exploring anti-rheumatic agents under the guidance of the newly discovered cholinergic anti-inflammatory pathway and the anti-nociceptive pathway.

Effect of at-home whitening strips on the surface roughness and color of a composite and an ormocer restorative material.

PubMed

Gurbuz, Ayhan; Ozkan, Pelin; Yilmaz, Kerem; Yilmaz, Burak; Durkan, Rukiye

2013-01-01

Oxygenating agents like carbamide peroxide or H(2) O(2) are commonly used whitening agents. They have varying influence on the color and surface roughness of resin-based restorative materials and teeth. The aim of this study was to evaluate the effect of an at-home peroxide whitening agent applied through a whitening strip on the color and surface roughness of a nanofilled composite resin and an ormocer-based resin. Disc-shaped (2 mm thick, 10 mm diameter) nanofilled resin composite (n = 10) and ormocer (n = 10) specimens were prepared. All specimens were treated with a whitening strip. Whitening procedures were performed applying a 6.5% hydrogen peroxide whitening strip (Crest White Strips Professional) for 30 minutes twice each day for a period of 21 consecutive days. During the test intervals, the specimens were rinsed under running distilled water for 1 minute to remove the whitening agents and immersed in 37°C distilled water until the next treatment. Surface roughness and color of the specimens were measured with a profilometer and a colorimeter, respectively, before and after whitening. Color changes were calculated (ΔE) using L*, a*, and b* coordinates. Repeated measures of variance analysis and Duncan test were used for statistical evaluation (α= 0.05). The average surface roughness of composite increased from 1.4 Ra to 2.0 Ra, and from 0.8 Ra to 0.9 Ra for the ormocer material; however, these changes in roughness after whitening were not significant (p > 0.05). Also, when two materials were compared, the surface roughness of restorative materials was not different before and after whitening (p > 0.05). L* and b* values for each material changed significantly after whitening (p < 0.05). ΔE values (before/after whitening) calculated for composite (11.9) and ormocer (16.1) were not significantly different from each other (p > 0.05). The tested whitening agent did not affect the surface roughness of either resin-based restorative material. Both materials became brighter after whitening. The behavior of the materials in the yellow/blue axis was opposite to each other after whitening. Each material had clinically unacceptable color change after whitening (ΔE > 5.5); however, the magnitude of the color change of materials was similar (p > 0.05). According to the results of this study, with the use of materials tested, patients should be advised that existing composite restorations may bleach along with the natural teeth, and replacement of these restorations after whitening may not be required. © 2012 by the American College of Prosthodontists.

A regional audit of the use of COX-2 selective non-steroidal anti-inflammatory drugs (NSAIDs) in rheumatology clinics in the West Midlands, in relation to NICE guidelines.

PubMed

Price-Forbes, A N; Callaghan, R; Allen, M E; Rowe, I F

2005-07-01

Whilst all non-steroidal anti-inflammatory drugs (NSAIDs) can cause adverse gastrointestinal events, COX-2-selective inhibitors (COX-2) may have improved gastrointestinal safety compared with non-selective NSAIDs (NSNSAIDs). In 2001, the National Institute for Clinical Excellence (NICE) published guidance on the use of the COX-2 agents celecoxib, rofecoxib, meloxicam and etodolac for rheumatoid arthritis (RA) and osteoarthritis (OA). This study aimed to audit the appropriateness of NSAID use in relation to NICE guidance in rheumatology out-patients. Questionnaires were completed for all patients attending clinics in 18 rheumatology units in the West Midlands over a 2-week period. Data collected included patient demographics, NSAID type, indications, duration of use (> or =3 months was considered prolonged), and concomitant prescription of corticosteroids, warfarin and gastroprotective agents. Data were collected on 2846 patients; 1164 (41%) were taking NSAIDs (791 NSNSAIDs, 373 COX-2). Of the 1164 NSAID users, 753 (65%) had a diagnosis of RA or OA (483 NSNSAIDs, 270 COX-2). Overall, 37% of NSAID prescriptions were appropriate. Of the NSNSAID users, 92% had at least one risk factor for adverse gastrointestinal events and were therefore inappropriately treated. Prolonged use (in 89%) and age > or =65 yr (in 23%) were the most frequent risk factors identified. Of the COX-2 users, 97% had one or more risk factors and were appropriately treated. Analysis of the RA/OA subgroup revealed similar findings. Thirty-six per cent were taking NSAIDs appropriately; 97% of NSNSAID use was inappropriate and 97% of COX-2 use was appropriate treatment. In the whole cohort, gastroprotective agents were used in 26% of NSNSAID users, 56% of gastroprotective agents being proton pump inhibitors. Ninety-two per cent of patients attending rheumatology clinics who were taking NSNSAIDs should have been prescribed a COX-2-selective agent in relation to NICE guidance. Duration of use and age > or =65 yr emerged numerically as the most important risk factors. Significant numbers of patients taking NSNSAIDs may be at risk from adverse gastrointestinal events and clinicians may wish to review their prescribing patterns. Conversely, 97% of patients taking COX-2 agents were treated appropriately. Although practice overall conformed poorly with NICE guidance, NSAID prescribing also needs to be considered in the context of recent concerns regarding the cardiovascular risks of COX-2 agents.

Cancer Risk-Assessment of Radiation Damage in Ataxia Telangiectasia Heterozygous Human Breast Epithelial Cell Cultures

NASA Technical Reports Server (NTRS)

Applewhite, Lisa C.

2002-01-01

This paper describes the study of the markers of cellular changes that are found during the onset of carcinogenesis. Several of the biological factors are markers of stress response, oncoprotein expression, and differentiation factors. Oxidative stress response agents such as heat shock proteins (HSPs) protect cells from oxidative stresses such as ionizing radiation. The onocoprotein HER-2/neu, a specific breast cancer marker, indicates early onset of cancer. Additional structural and morphogenetic markers of differentiation were considered in order to determine initial cellular changes at the initial onset of cancer. As an additional consideration, all-trans retinoic acid (RA), a differentiation agent, was considered because of its known role in regulating normal differentiation and inhibiting tumor proliferation via specific nuclear receptors. This paper discusses study and results of the preliminary analyses of gamma irradiation of AT heterozygous human breast epithelial cells (WH). Comparisons are also made of the effects various RA concentrations post-irradiation.

Retinoic acid and nitric oxide promote cell proliferation and differentially induce neuronal differentiation in vitro in the cnidarian Renilla koellikeri.

PubMed

Estephane, Djoyce; Anctil, Michel

2010-10-01

Retinoic acid (RA) and nitric oxide (NO) are known to promote neuronal development in both vertebrates and invertebrates. Retinoic acid receptors appear to be present in cnidarians and NO plays various physiological roles in several cnidarians, but there is as yet no evidence that these agents have a role in neural development in this basal metazoan phylum. We used primary cultures of cells from the sea pansy Renilla koellikeri to investigate the involvement of these signaling molecules in cnidarian cell differentiation. We found that 9-cis RA induce cell proliferation in dose- and time-dependent manners in dishes coated with polylysine from the onset of culture. Cells in cultures exposed to RA in dishes devoid of polylysine were observed to differentiate into epithelium-associated cells, including sensory cells, without net gain in cell density. NO donors also induce cell proliferation in polylysine-coated dishes, but induce neuronal differentiation and neurite outgrowth in uncoated dishes. No other cell type undergoes differentiation in the presence of NO. These observations suggest that in the sea pansy (1) cell adhesion promotes proliferation without morphogenesis and this proliferation is modulated positively by 9-cis RA and NO, (2) 9-cis RA and NO differentially induce neuronal differentiation in nonadherent cells while repressing proliferation, and (3) the involvement of RA and NO in neuronal differentiation appeared early during the evolutionary emergence of nervous systems. 2010 Wiley Periodicals, Inc.

Protease-degradable PEG-maleimide coating with on-demand release of IL-1Ra to improve tissue response to neural electrodes

PubMed Central

Gutowski, Stacie M.; Shoemaker, James T.; Templeman, Kellie L.; Wei, Yang; Latour, Robert A.; Bellamkonda, Ravi V.; LaPlaca, Michelle C.; García, Andrés J.

2015-01-01

Neural electrodes are an important part of brain-machine interface devices that can restore functionality to patients with sensory and movement disorders. Chronically implanted neural electrodes induce an unfavorable tissue response which includes inflammation, scar formation, and neuronal cell death, eventually causing loss of electrode function. We developed a poly(ethylene glycol) hydrogel coating for neural electrodes with non-fouling characteristics, incorporated an anti-inflammatory agent, and engineered a stimulus-responsive degradable portion for on-demand release of the anti-inflammatory agent in response to inflammatory stimuli. This coating reduces in vitro glial cell adhesion, cell spreading, and cytokine release compared to uncoated controls. We also analyzed the in vivo tissue response using immunohistochemistry and microarray qRT-PCR. Although no differences were observed among coated and uncoated electrodes for inflammatory cell markers, lower IgG penetration into the tissue around PEG+IL-1Ra coated electrodes indicates an improvement in blood-brain barrier integrity. Gene expression analysis showed higher expression of IL-6 and MMP-2 around PEG+IL-1Ra samples, as well as an increase in CNTF expression, an important marker for neuronal survival. Importantly, increased neuronal survival around coated electrodes compared to uncoated controls was observed. Collectively, these results indicate promising findings for an engineered coating to increase neuronal survival and improve tissue response around implanted neural electrodes. PMID:25617126

VSF Measurements and Inversion for RaDyO

DTIC Science & Technology

2012-09-30

near-surface waters, including the surf zone. APPROACH MASCOT (Multi-Angle SCattering Optical Tool) has a 30 mW 658 nm laser diode source...in Santa Barbara Channel are provided in Fig. 1. Despite the widespread use of polarized laser sources across a diversity of Navy applications, this...operations that rely on divers, cameras, laser imaging systems, and active and passive remote sensing systems. These include mine countermeasures, harbor

Rosmarinic acid suppresses adipogenesis, lipolysis in 3T3-L1 adipocytes, lipopolysaccharide-stimulated tumor necrosis factor-α secretion in macrophages, and inflammatory mediators in 3T3-L1 adipocytes

PubMed Central

Rui, Yehua; Tong, Lingxia; Cheng, Jinbo; Wang, Guiping; Qin, Liqiang; Wan, Zhongxiao

2017-01-01

ABSTRACT Background: Rosmarinic acid (RA) is a natural phenol carboxylic acid with many promising biological effects. It may be a suitable candidate for improving obesity-related adipose tissue dysfunction. Objective: We aimed to investigate the therapeutic use of RA as an anti-obesity agent by measuring its effects on adipogenesis, lipolysis, and messenger RNA (mRNA) expression of major adipokines in 3T3-L1 adipocytes; and its effects on lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) secretion in macrophages and inflammatory mediators in 3T3-L1 adipocytes incubated with macrophage-conditioned medium (MCM). Methods: 3T3-L1 preadipocytes were used to explore how RA affects adipogenesis, as well as the involvement of phosphorylated extracellular signal-regulated kinase-1/2 (p-ERK1/2) and mothers against decapentaplegic homolog 3 (p-Smad3). 3T3-L1 preadipocytes were also differentiated into mature adipocytes to explore how RA affects basal and isoproterenol- and forskolin-stimulated lipolysis; and how RA affects key adipokines’ mRNA expression. RAW 264.7 macrophages were stimulated with LPS in the absence or presence of RA to explore RA’s effects on TNF-α secretion. MCM was collected and 3T3-L1 adipocytes were incubated with MCM to explore RA’s effects on interleukin-6 (IL-6), IL-1β, monocyte chemoattractant protein-1 (MCP-1), and RANTES mRNA expression. Results: During the preadipocyte differentiation process, RA suppressed peroxisome proliferator-activated receptor-γ and CCAAT/enhancer binding protein-α, and activated p-ERK1/2 and p-Smad3; inhibition of adipogenesis by RA was partially restored following treatment with p-ERK1/2 and p-Smad3 inhibitors. In mature adipocytes, RA inhibited basal lipolysis; phosphodiesterase-3 inhibitor reversed this. RA also inhibited isoproterenol- and forskolin-stimulated glycerol and free fatty acid release, and the phosphorylation of hormone-sensitive lipase and perilipin. RA had no effects on leptin, adiponectin, resistin, or visfatin mRNA expression. RA suppressed TNF-α mRNA expression and secretion in LPS-stimulated RAW 264.7 macrophages; and reduced LPS-MCM-induced IL-6, IL-1β, MCP-1, and RANTES mRNA expression in 3T3-L1 adipocytes. Conclusions: RA exerts inhibitory effects on adipogenesis, lipolysis, and inflammation. RA could be a promising natural product for improving adipose mobilization in obesity. PMID:28659738

[Pharmacological management of rheumatoid arthritis: the state of the art and the future perspective].

PubMed

Kameda, Hideto; Takeuchi, Tsutomu

2013-07-01

Pharmacological management of rheumatoid arthritis (RA) has been rapidly progressed in recent years, which is appeared in the "treat to target" movement and the recommendations developed by some established international/domestic rheumatology associations. The baseline evaluation of poor prognostic factors as well as disease activity with composite measures is necessary for a personalized management. Methotrexate is currently the anchor drug, and other conventional or biological antirheumatic drugs should be added to it for refractory patients. The development of various novel agents including signal transduction inhibitors should promote further advances in the management of RA and other systemic autoimmune and/or inflammatory diseases.

Costs associated with failure to respond to treatment among patients with rheumatoid arthritis initiating TNFi therapy: a retrospective claims analysis.

PubMed

Grabner, Michael; Boytsov, Natalie N; Huang, Qing; Zhang, Xiang; Yan, Tingjian; Curtis, Jeffrey R

2017-05-15

Tumor necrosis factor inhibitors (TNFi) are common second-line treatments for rheumatoid arthritis (RA). This study was designed to compare the real-world clinical and economic outcomes between patients with RA who responded to TNFi therapy and those who did not. For this retrospective cohort analysis we used medical and pharmacy claims from members of 14 large U.S. commercial health plans represented in the HealthCore Integrated Research Database. Adult patients (aged ≥18 years) diagnosed with RA and initiating TNFi therapy (index date) between 1 January 2007 and 30 April 2014 were included in the study. Treatment response was assessed using a previously developed and validated claims-based algorithm. Patients classified as treatment responders in the 12 months postindex were matched 1:1 to nonresponders on important baseline characteristics, including sex, age, index TNFi agent, and comorbidities. The matched cohorts were then compared on their all-cause and RA-related healthcare resource use, and costs were assessed from a payer perspective during the first, second, and third years postindex using parametric tests, regressions, and a nonparametric bootstrap. A total of 7797 patients met the study inclusion criteria, among whom 2337 (30%) were classified as treatment responders. The responders had significantly lower all-cause hospitalizations, emergency department visits, and physical/occupational therapy visits than matched nonresponders during the first-year postindex. Mean total all-cause medical costs were $5737 higher for matched nonresponders, largely driven by outpatient visits and hospitalizations. Mean all-cause pharmacy costs (excluding costs of biologics) were $354 higher for matched nonresponders. Mean RA-related pharmacy costs (conventional synthetic and biologic drugs), however, were $8579 higher in the responder cohort, driven by higher adherence to their index TNFi agent (p < 0.01 for all comparisons). A similar pattern of cost differentiation was observed over years 2 and 3 of follow-up. In this real-world study we found that, compared with matched nonresponders, patients who responded to TNFi treatments had lower all-cause medical, pharmacy, and total costs (excluding biologics) up to 3 years from initiation of TNFi therapy. These cost differences between the two cohorts provide a considerable offset to the cost of RA medications and should encourage close monitoring of treatment response to minimize disease progression with appropriate therapy choices.

Immunosuppressive agents are associated with peptic ulcer bleeding.

PubMed

Tomizawa, Minoru; Shinozaki, Fuminobu; Hasegawa, Rumiko; Shirai, Yoshinori; Motoyoshi, Yasufumi; Sugiyama, Takao; Yamamoto, Shigenori; Ishige, Naoki

2017-05-01

Peptic ulcer bleeding can be fatal. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and immunosuppressive agents are administered for long-term usage. The present study assessed the association between peptic ulcer bleeding and administration of NSAIDs, corticosteroids and immunosuppressive agents. Furthermore, the efficacy of lowering the risk of peptic ulcer bleeding with proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) was evaluated. Medical records were retrospectively analyzed for patients subjected to an upper gastrointestinal (GI) endoscopy performed at the National Hospital Organization Shimoshizu Hospital (Yotsukaido, Japan) from October 2014 to September 2015. During this period, a total of 1,023 patients underwent an upper GI endoscopy. A total of 1,023 patients, including 431 males (age, 68.1±12.9 years) and 592 females (age, 66.4±12.3 years), who had been administered NSAIDs, corticosteroids, immunosuppressive agents, PPIs and H2RAs, were respectively enrolled. Endoscopic findings of the patients were reviewed and their data were statistically analyzed. Logistic regression analysis was used to determine the odds ratio of peptic ulcer bleeding for each medication; immunosuppressive agents had an odds ratio of 5.83, which was larger than that for NSAIDs (4.77). The Wald test was applied to confirm the correlation between immunosuppressive agents and peptic ulcer bleeding. Furthermore, χ 2 tests were applied to the correlation between peptic ulcer bleeding and administration of PPIs or H2RAs. Immunosuppressive agents had the largest χ 2 , and the P-value was 0.03. Administration of PPIs was significantly correlated with non-peptic ulcer bleeding (P=0.02); furthermore, a tendency toward non-peptic ulcer bleeding with administration of H2RA was indicated, but it was not statistically significant (P=0.12). In conclusion, immunosuppressive agents were correlated with peptic ulcer bleeding and PPIs were effective at lowering the risk of peptic ulcer bleeding.

Immunosuppressive agents are associated with peptic ulcer bleeding

PubMed Central

Tomizawa, Minoru; Shinozaki, Fuminobu; Hasegawa, Rumiko; Shirai, Yoshinori; Motoyoshi, Yasufumi; Sugiyama, Takao; Yamamoto, Shigenori; Ishige, Naoki

2017-01-01

Peptic ulcer bleeding can be fatal. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and immunosuppressive agents are administered for long-term usage. The present study assessed the association between peptic ulcer bleeding and administration of NSAIDs, corticosteroids and immunosuppressive agents. Furthermore, the efficacy of lowering the risk of peptic ulcer bleeding with proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) was evaluated. Medical records were retrospectively analyzed for patients subjected to an upper gastrointestinal (GI) endoscopy performed at the National Hospital Organization Shimoshizu Hospital (Yotsukaido, Japan) from October 2014 to September 2015. During this period, a total of 1,023 patients underwent an upper GI endoscopy. A total of 1,023 patients, including 431 males (age, 68.1±12.9 years) and 592 females (age, 66.4±12.3 years), who had been administered NSAIDs, corticosteroids, immunosuppressive agents, PPIs and H2RAs, were respectively enrolled. Endoscopic findings of the patients were reviewed and their data were statistically analyzed. Logistic regression analysis was used to determine the odds ratio of peptic ulcer bleeding for each medication; immunosuppressive agents had an odds ratio of 5.83, which was larger than that for NSAIDs (4.77). The Wald test was applied to confirm the correlation between immunosuppressive agents and peptic ulcer bleeding. Furthermore, χ2 tests were applied to the correlation between peptic ulcer bleeding and administration of PPIs or H2RAs. Immunosuppressive agents had the largest χ2, and the P-value was 0.03. Administration of PPIs was significantly correlated with non-peptic ulcer bleeding (P=0.02); furthermore, a tendency toward non-peptic ulcer bleeding with administration of H2RA was indicated, but it was not statistically significant (P=0.12). In conclusion, immunosuppressive agents were correlated with peptic ulcer bleeding and PPIs were effective at lowering the risk of peptic ulcer bleeding. PMID:28565788

A Comparison of Patient Characteristics and Outcomes in Selected European and U.S. Rheumatoid Arthritis Registries

PubMed Central

Curtis, Jeffrey R; Jain, Archana; Askling, Johan; Bridges, Lou; Carmona, Loreto; Dixon, William; Finckh, Axel; Hyrich, Kimme; Greenberg, Jeffrey; Kremer, Joel; Listing, Joachim; Michaud, Kaleb; Mikuls, Ted; Shadick, Nancy; Solomon, Daniel H; Wolfe, Fred; Zink, Angela

2010-01-01

Purpose To provide a qualitative comparison of selected US and European rheumatoid arthritis (RA) biologics registries and cohorts including ARTIS, BIOBADASER, BSRBR, BRASS, CLEAR, CORRONA, NDB, RABBIT, SCQM, and VARA. Randomized controlled trials (RCTs) have demonstrated the efficacy of biologic agents in treatment of rheumatic diseases. However, results from RCTs may not be generalizable to clinical practice because of their strict inclusion and exclusion criteria. Assessment of safety using RCT data also is limited by short duration of follow-up and relatively small sample sizes which generally preclude analysis of longer-term outcomes and rare adverse events. In rheumatology, various observational cohorts and registries have been created to complement information obtained from RCTs, some with the primary purpose of monitoring effectiveness and safety of biologic agents. Most registries are either drug based or disease based. These registries include patients with a variety of rheumatic diseases including RA. A careful comparison of these registries, as provided in this article, can provide a basis for understanding the many similarities and differences inherent in their design, as well as societal context and content, all of which can significantly impact their results and comparisons across registers. Summary The increasing use of biologic agents for treatment of rheumatic diseases has raised important questions about cost, safety and effectiveness of these agents. The unique and variable features of patient populations and registry designs in Europe and the U.S. provide valuable and complementary data on comparative effectiveness and safety of biologic agents to what can be derived from RCTs. PMID:20674669

Direct and indirect healthcare costs of rheumatoid arthritis patients in Turkey.

PubMed

Hamuryudan, Vedat; Direskeneli, Haner; Ertenli, Ihsan; Inanc, Murat; Karaaslan, Yasar; Oksel, Fahrettin; Ozbek, Suleyman; Pay, Salih; Terzioglu, Ender; Balkan Tezer, Dilara; Hacibedel, Basak; Akkoc, Nurullah

2016-01-01

To estimate the annual cost of rheumatoid arthritis (RA) in Turkey by obtaining real-world data directly from patients. In this cross-sectional study, RA patients from the rheumatology outpatient clinics of 10 university hospitals were interviewed with a standardised questionnaire on RA-related healthcare care costs. The study included 689 RA patients (565 females) with a mean age of 51.2±13.2 years and mean disease duration of 9.4±7.8 years. The mean scores of the Routine Assessment of Patient Index Data 3 and the Health Assessment Questionnaire-Disability Index (5.08±2.34 and 1.08±0.68, respectively) indicated moderate disease activity and severity for the whole group. One-third of the patients were on biologic agents and 12% had co-morbid conditions. The mean number of annual outpatient visits was 11.7±9.6 per patient. Of the patients, 15% required hospitalisation and 4% underwent surgery. The mean annual direct cost was € 4,954 (median, € 1,805), whereas the mean annual indirect cost was € 2,802 (median, € 608). Pharmacy costs accounted for the highest expenditure (mean, € 2,777; median, € 791), followed by the RA-related consultations and expenses (mean, € 1,600; median, € 696). RA has a substantial economic burden in Turkey, direct costs being higher than indirect costs. Although both direct and indirect costs are lower in Turkey than in Europe with respect to nominal Euro terms, they are higher from the perspectives of purchasing power parity and gross domestic product. Early diagnosis and treatment of RA may positively affect the national economy considering the positive correlation between health care utilisations and increased cost with disease severity.

The 23-valent pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis: a double-blinded, randomized, placebo-controlled trial.

PubMed

Izumi, Yasumori; Akazawa, Manabu; Akeda, Yukihiro; Tohma, Shigeto; Hirano, Fuminori; Ideguchi, Haruko; Matsumura, Ryutaro; Miyamura, Tomoya; Mori, Shunsuke; Fukui, Takahiro; Iwanaga, Nozomi; Jiuchi, Yuka; Kozuru, Hideko; Tsutani, Hiroshi; Saisyo, Kouichirou; Sugiyama, Takao; Suenaga, Yasuo; Okada, Yasumasa; Katayama, Masao; Ichikawa, Kenji; Furukawa, Hiroshi; Kawakami, Kenji; Oishi, Kazunori; Migita, Kiyoshi

2017-01-25

Pneumococcal pneumonia is the most frequent form of pneumonia. We herein assessed the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in the prevention of pneumonia overall in rheumatoid arthritis (RA) patients at risk for infections. We hypothesized that PPSV23 vaccination is superior in preventing pneumococcal pneumonia compared with placebo in RA patients. A prospective, multicenter, double-blinded, randomized, placebo-controlled (1:1) trial was conducted across departments of rheumatology in Japanese National Hospital Organization hospitals. RA patients (n = 900) who had been treated with biological or immunosuppressive agents were randomly assigned PPSV23 or placebo (sodium chloride). The primary endpoints were the incidences of all-cause pneumonia and pneumococcal pneumonia. The secondary endpoint was death from pneumococcal pneumonia, all-cause pneumonia, or other causes. Cox regression models were used to estimate the risk of pneumonia overall for the placebo group compared with the vaccine group. Seventeen (3.7%) of 464 patients in the vaccine group and 15 (3.4%) of 436 patients in the placebo group developed pneumonia. There was no difference in the rates of pneumonia between the two study groups. The overall rate of pneumonia was 21.8 per 1000 person-years for patients with RA. The presence of interstitial pneumonia (hazard ratio: 3.601, 95% confidence interval: 1.547-8.380) was associated with an increased risk of pneumonia in RA patients. PPSV23 does not prevent against pneumonia overall in RA patients at relative risk for infections. Our results also confirm that the presence of interstitial lung disease is associated with pneumonia in Japanese patients with RA. UMIN-CTR UMIN000009566 . Registered 17 December 2012.

Curcumin inhibits osteoclastogenic potential in PBMCs from rheumatoid arthritis patients via the suppression of MAPK/RANK/c-Fos/NFATc1 signaling pathways.

PubMed

Shang, Wei; Zhao, Ling-Jie; Dong, Xiao-Lei; Zhao, Zhi-Ming; Li, Jing; Zhang, Bei-Bei; Cai, Hui

2016-10-01

The aim of the present study was to determine the effects of curcumin on the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs) obtained from patients with rheumatoid arthritis (RA), and to investigate the underlying molecular mechanisms. PBMCs from patients with RA (n=12) and healthy controls (n=10) were cultured to assess osteoclastogenic potential. The number of tartrate‑resistant acid phosphatase‑positive osteoclasts differentiated from PBMCs isolated from patients with RA was significantly increased compared with that of the healthy controls. In addition, the osteoclast number in patients with RA was correlated with the clinical indicators, Sharp score (r=0.810; P=0.001) and lumbar T‑score (r=‑0.685; P=0.014). Furthermore, the resorption area was increased in the RA group compared with the healthy controls. The mRNA and protein expression levels in PBMC‑derived osteoclasts treated with curcumin were measured by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. Curcumin inhibited the osteoclastogenic potential of PBMCs, potentially by suppressing activation of extracellular signal‑regulated kinases 1 and 2, p38 and c‑Jun N‑terminal kinase, and inhibiting receptor activator of nuclear factor κB (RANK), c‑Fos and nuclear factor of activated T cells (NFATc1) expression. The results of the present study demonstrated that curcumin may inhibit the osteoclastogenic potential of PBMCs from patients with RA through the suppression of the mitogen‑activated protein kinase/RANK/c‑Fos/NFATc1 signaling pathways, and that curcumin may be a potential novel therapeutic agent for the treatment of bone deterioration in inflammatory diseases such as RA.

Curcumin inhibits osteoclastogenic potential in PBMCs from rheumatoid arthritis patients via the suppression of MAPK/RANK/c-Fos/NFATc1 signaling pathways

PubMed Central

Shang, Wei; Zhao, Ling-Jie; Dong, Xiao-Lei; Zhao, Zhi-Ming; Li, Jing; Zhang, Bei-Bei; Cai, Hui

2016-01-01

The aim of the present study was to determine the effects of curcumin on the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs) obtained from patients with rheumatoid arthritis (RA), and to investigate the underlying molecular mechanisms. PBMCs from patients with RA (n=12) and healthy controls (n=10) were cultured to assess osteoclastogenic potential. The number of tartrate-resistant acid phosphatase-positive osteoclasts differentiated from PBMCs isolated from patients with RA was significantly increased compared with that of the healthy controls. In addition, the osteoclast number in patients with RA was correlated with the clinical indicators, Sharp score (r=0.810; P=0.001) and lumbar T-score (r=−0.685; P=0.014). Furthermore, the resorption area was increased in the RA group compared with the healthy controls. The mRNA and protein expression levels in PBMC-derived osteoclasts treated with curcumin were measured by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Curcumin inhibited the osteoclastogenic potential of PBMCs, potentially by suppressing activation of extracellular signal-regulated kinases 1 and 2, p38 and c-Jun N-terminal kinase, and inhibiting receptor activator of nuclear factor κB (RANK), c-Fos and nuclear factor of activated T cells (NFATc1) expression. The results of the present study demonstrated that curcumin may inhibit the osteoclastogenic potential of PBMCs from patients with RA through the suppression of the mitogen-activated protein kinase/RANK/c-Fos/NFATc1 signaling pathways, and that curcumin may be a potential novel therapeutic agent for the treatment of bone deterioration in inflammatory diseases such as RA. PMID:27572279

The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9.

PubMed

Sánchez-Blázquez, Pilar; Pozo-Rodrigálvarez, Andrea; Merlos, Manuel; Garzón, Javier

2018-06-01

The glutamate N-methyl-D-aspartate receptor (NMDAR) plays an essential role in the excitotoxic neural damage that follows ischaemic stroke. Because the sigma-1 receptor (σ1R) can regulate NMDAR transmission, exogenous and putative endogenous regulators of σ1R have been investigated using animal models of ischaemic stroke. As both agonists and antagonists provide some neural protection, the selective involvement of σ1Rs in these effects has been questioned. The availability of S1RA (E-52862/MR309), a highly selective σ1R antagonist, prompted us to explore its therapeutic potential in an animal model of focal cerebral ischaemia. Mice were subjected to right middle cerebral artery occlusion (MCAO), and post-ischaemic infarct volume and neurological deficits were determined across a range of intervals after the stroke-inducing surgery. Intracerebroventricular or intravenous treatment with S1RA significantly reduced the cerebral infarct size and neurological deficits caused by permanent MCAO (pMCAO). Compared with the control/sham-operated mice, the neuroprotective effects of S1RA were observed when delivered up to 5 h prior to surgery and 3 h after ischaemic onset. Interestingly, neither mice with the genetic deletion of σ1R nor wild-type mice that were pre-treated with the σ1R agonist PRE084 showed beneficial effects after S1RA administration with regard to stroke infarction. S1RA-treated mice showed faster behavioural recovery from stroke; this finding complements the significant decreases in matrix metalloproteinase-9 (MMP-9) expression and reactive astrogliosis surrounding the infarcted cortex. Our data indicate that S1RA, via σ1R, holds promising potential for clinical application as a therapeutic agent for ischaemic stroke.

RaPToRS Sample Delivery System

NASA Astrophysics Data System (ADS)

Henchen, Robert; Shibata, Kye; Krieger, Michael; Pogozelski, Edward; Padalino, Stephen; Glebov, Vladimir; Sangster, Craig

2010-11-01

At various labs (NIF, LLE, NRL), activated material samples are used to measure reaction properties. The Rapid Pneumatic Transport of Radioactive Samples (RaPToRS) system quickly and safely moves these radioactive samples through a closed PVC tube via airflow. The carrier travels from the reaction chamber to the control and analysis station, pneumatically braking at the outlet. A reversible multiplexer routes samples from various locations near the shot chamber to the analysis station. Also, the multiplexer allows users to remotely load unactivated samples without manually approaching the reaction chamber. All elements of the system (pneumatic drivers, flow control valves, optical position sensors, multiplexers, Geiger counters, and release gates at the analysis station) can be controlled manually or automatically using a custom LabVIEW interface. A prototype is currently operating at NRL in Washington DC. Prospective facilities for Raptors systems include LLE and NIF.

Remote controlled robot assisted cardiac navigation: feasibility assessment and validation in a porcine model.

PubMed

Ganji, Yusof; Janabi-Sharifi, Farrokh; Cheema, Asim N

2011-12-01

Despite the recent advances in catheter design and technology, intra-cardiac navigation during electrophysiology procedures remains challenging. Incorporation of imaging along with magnetic or robotic guidance may improve navigation accuracy and procedural safety. In the present study, the in vivo performance of a novel remote controlled Robot Assisted Cardiac Navigation System (RACN) was evaluated in a porcine model. The navigation catheter and target sensor were advanced to the right atrium using fluoroscopic and intra-cardiac echo guidance. The target sensor was positioned at three target locations in the right atrium (RA) and the navigation task was completed by an experienced physician using both manual and RACN guidance. The navigation time, final distance between the catheter tip and target sensor, and variability in final catheter tip position were determined and compared for manual and RACN guided navigation. The experiments were completed in three animals and five measurements recorded for each target location. The mean distance (mm) between catheter tip and target sensor at the end of the navigation task was significantly less using RACN guidance compared with manual navigation (5.02 ± 0.31 vs. 9.66 ± 2.88, p = 0.050 for high RA, 9.19 ± 1.13 vs. 13.0 ± 1.00, p = 0.011 for low RA and 6.77 ± 0.59 vs. 15.66 ± 2.51, p = 0.003 for tricuspid valve annulus). The average time (s) needed to complete the navigation task was significantly longer by RACN guided navigation compared with manual navigation (43.31 ± 18.19 vs. 13.54 ± 1.36, p = 0.047 for high RA, 43.71 ± 11.93 vs. 22.71 ± 3.79, p = 0.043 for low RA and 37.84 ± 3.71 vs. 16.13 ± 4.92, p = 0.003 for tricuspid valve annulus. RACN guided navigation resulted in greater consistency in performance compared with manual navigation as evidenced by lower variability in final distance measurements (0.41 vs. 0.99 mm, p = 0.04). This study demonstrated the safety and feasibility of the RACN system for cardiac navigation. The results demonstrated that RACN performed comparably with manual navigation, with improved precision and consistency for targets located in and near the right atrial chamber. Copyright © 2011 John Wiley & Sons, Ltd.

Aerodynamic roughness length estimation with lidar and imaging spectroscopy in a shrub-dominated dryland

USGS Publications Warehouse

Li, Aihua; Zhao, Wenguang; Mitchell, Jessica J; Glenn, Nancy F.; Germino, Matthew; Sankey, Joel B.; Allen, Richard G

2017-01-01

The aerodynamic roughness length (Z0 m) serves an important role in the flux exchange between the land surface and atmosphere. In this study, airborne lidar (ALS), terrestrial lidar (TLS), and imaging spectroscopy data were integrated to develop and test two approaches to estimate Z0 m over a shrub dominated dryland study area in south-central Idaho, USA. Sensitivity of the two parameterization methods to estimate Z0 m was analyzed. The comparison of eddy covariance-derived Z0 m and remote sensing-derived Z0 m showed that the accuracy of the estimated Z0 m heavily depends on the estimation model and the representation of shrub (e.g., Artemisia tridentata subsp. wyomingensis) height in the models. The geometrical method (RA1994) led to 9 percent (~0.5 cm) and 25% (~1.1 cm) errors at site 1 and site 2, respectively, which performed better than the height variability-based method (MR1994) with bias error of 20 percent and 48 percent at site 1 and site 2, respectively. The RA1994 model resulted in a larger range of Z0 m than the MR1994 method. We also found that the mean, median and 75th percentiles of heights (H75) from ALS provides the best Z0 m estimates in the MR1994 model, while the mean, median, and MLD (Median Absolute Deviation from Median Height), as well as AAD (Mean Absolute Deviation from Mean Height) heights from ALS provides the best Z0 m estimates in the RA1994 model. In addition, the fractional cover of shrub and grass, distinguished with ALS and imaging spectroscopy data, provided the opportunity to estimate the frontal area index at the pixel-level to assess the influence of grass and shrub on Z0m estimates in the RA1994 method. Results indicate that grass had little effect on Z0 m in the RA1994 method. The Z0 m estimations were tightly coupled with vegetation height and its local variance for the shrubs. Overall, the results demonstrate that the use of height and fractional cover from remote sensing data are promising for estimating Z0 m, and thus refining land surface models at regional scales in semiarid shrublands.

Optimal responses in disease activity scores to treatment in rheumatoid arthritis: Is a DAS28 reduction of >1.2 sufficient?

PubMed

Mian, Aneela N; Ibrahim, Fowzia; Scott, David L; Galloway, James

2016-06-16

The overall benefit of intensive treatment strategies in rheumatoid arthritis (RA) remains uncertain. We explored how reductions in disability and improvements in quality of life scores are affected by alternative assessments of reductions in disease activity scores for 28 joints (DAS28) in two trials of intensive treatment strategies in active RA. One trial (CARDERA) studied 467 patients with early active RA receiving 24 months of methotrexate monotherapy or steroid and disease-modifying anti-rheumatic drug (DMARD) combinations. The other trial (TACIT) studied 205 patients with established active RA; they received 12 months of treatment with DMARD combinations or biologic agents. We compared changes in the health assessment questionnaire (HAQ) and Euroqol-5D (EQ5D) at trial endpoints in European League Against Rheumatism (EULAR) good and moderate EULAR responders in patients in whom complete endpoint data were available. In the CARDERA trial 98 patients (26 %) were good EULAR responders and 160 (32 %) were EULAR moderate responders; comparable data in TACIT were 66 (35 %) and 86 (46 %) patients. The magnitude of change in the HAQ and EQ5D was greater in both trials in EULAR good responders than in EULAR moderate responders. HAQ scores had a difference in of -0.49 (95 % CI -0.66, -0.32) in the CARDERA and -0.31 (95 % CI -0.47, -0.13) in the TACIT trial. With the EQ5D comparable differences were 0.12 (95 % CI 0.04, 0.19) and 0.15 (95 % CI 0.05, 0.25). Both exceeded minimum clinically important differences in HAQ and EQ5D scores. We conclude that achieving a good EULAR response with DMARDs and biologic agents in active RA results in substantially improved mean HAQ and EQ5D scores. Patients who achieve such responses should continue on treatment. However, continuing such treatment strategies is more challenging when only a moderate EULAR response is achieved. In these patients evidence of additional clinically important benefits in measures such as the HAQ should also be sought.

In vitro anticoagulant and antioxidant activities of Jatropha gossypiifolia L. (Euphorbiaceae) leaves aiming therapeutical applications.

PubMed

Félix-Silva, Juliana; Souza, Thiago; Camara, Rafael Barros Gomes; Cabral, Bárbara; Silva-Júnior, Arnóbio Antônio; Rebecchi, Ivanise Marina Moretti; Zucolotto, Silvana Maria; Rocha, Hugo Alexandre Oliveira; Fernandes-Pedrosa, Matheus de Freitas

2014-10-20

Jatropha gossypiifolia L. (Euphorbiaceae) is a medicinal plant largely used in folk medicine. Teas from the leaves are popularly used as an antithrombotic agent and the branches are frequently employed as a "thick blood" agent. Considering that the anticoagulant activity associated with antioxidant properties could be beneficial for various cardiovascular diseases, this study's aim is the evaluation of anticoagulant and antioxidant activities of J. gossypiifolia leaves, seeking new therapeutic purposes for this plant. The aqueous leaf crude extract (CE) was prepared by decoction and was fractionated by liquid-liquid partition with solvents of increasing polarity. The phytochemical analysis was performed by thin layer chromatography (TLC) and by the spectrophotometric quantification of sugars, proteins and phenolic compounds. The anticoagulant activity was evaluated by prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests. The capacity to act in the fibrinolytic system (fibrinolytic and fibrinogenolytic activities) was also assessed. The antioxidant activity was evaluated by total antioxidant capacity, reducing power, copper chelating activity, iron chelating activity, hydroxyl radical scavenging activity and superoxide radical scavenging assays. The potential toxicity was evaluated using hemolytic assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay on HEK-293 cells. CE showed significant anticoagulant activity in aPTT test, while no action was observed in PT test, suggesting a preferential action toward the intrinsic and/or common pathway of coagulation. No effect was observed in the fibrinolytic system. Using the aPTT test, it was observed that the residual aqueous (RA) fraction was the most active, being two times more active than CE. RA presented very significant antioxidant activity in all models tested comparable to or even higher than CE. Regarding the safety, CE and RA did not produce significant cytotoxicity in both tests employed. Phytochemical analysis revealed the presence of alkaloids, flavonoids, proteins, tannins, steroids and/or terpenoids and sugars. CE and RA possessed significant anticoagulant and antioxidant activity and absence of cytotoxic effect in vitro, thus showing the potential of the plant, especially RA fraction, as a new source of bioactive molecules for therapeutic purposes, with particular emphasis on the treatment of cardiovascular diseases.

A double-blind, randomized, bilateral comparison of skin irritancy following application of the combination acne products clindamycin/tretinoin and benzoyl peroxide/adapalene.

PubMed

Goreshi, Renato; Samrao, Aman; Ehst, Benjamin D

2012-12-01

The use of topical medications for acne vulgaris is often limited by their irritant properties. Newer combination preparations are available and offer convenience, but irritant potential may still be a hindrance, perhaps more so with the combination of 2 agents. Few studies have compared these formulations directly for tolerability. We sought to compare the tolerability of 2 combination topical acne products, clindamycin 1.2%-tretinoin 0.025% (CLIN/RA) gel and benzoyl peroxide 2.5%-adapalene 0.1% (BPO/ADA) gel. CLIN/RA and BPO/ADA were applied daily to opposite sides of a subject's face for 21 days in a double-blinded fashion. Investigators' Global Assessments and study subject self-assessments of burning/stinging, itching, erythema, and dryness/scaling were collected. Transepidermal water loss (TEWL) was also measured as an objective measure of skin irritation. A mixed model analysis and repeated-measures analysis of variance were used to compare outcomes for both acne formulations. CLIN/RA produced significantly less burning/stinging than BPO/ADA (P<.001) as well as significantly less pruritus than BPO/ ADA (P<.001). BPO/ADA caused significantly more TEWL than CLIN/RA (P=.005). There was no significant difference in the amount of erythema or the amount of dryness/scaling caused by either formulation. CLIN/RA produced significantly less skin irritancy and TEWL than BPO/ADA.

Retinoic acid‐induced glandular differentiation of the oesophagus

PubMed Central

Chang, Chih‐Long; Lao‐Sirieix, Pierre; Save, Vicki; De La Cueva Mendez, Guillermo; Laskey, Ron; Fitzgerald, Rebecca C

2007-01-01

Background Retinoic acid (RA) is a powerful differentiation agent. Barrett's oesophagus occurs when duodeno‐gastro‐oesophageal reflux causes squamous epithelium (SE) tissue to become columnar epithelium tissue by an unknown mechanism. The bile acid lithocholic acid (LCA) competes for the retinoid X receptor retinoid binding site. Hence, RA pathways may be implicated in Barrett's oesophagus. Methods RA activity in tissues and cell lines treated with all‐trans retinoic acid (ATRA) with or without LCA was assessed using a reporter. Expression of p21 was determined by real‐time PCR in Barrett's oesophagus cell lines with or without LCA. SE and Barrett's oesophagus biopsy specimens were exposed to 100 μM of ATRA or 20 mM of a RA inhibitor, citral, in organ culture for >72 h. Characteristics of treated specimens, compared with untreated controls, were analysed by immunohistochemical analysis (cytokeratins (CKs), vimentin) and RT‐PCR (CKs). Confocal microscopy assessed temporal changes in co‐localisation of CK8/18 and vimentin. Cell proliferation was assessed by bromo‐deoxyuridine incorporation and immunohistochemical analysis for Ki67 and p21. Results RA biosynthesis was increased in Barrett's oesophagus compared with SE (p<0.001). LCA and ATRA caused a synergistic increase in RA signalling as shown by increased p21 (p<0.01). Morphological and molecular analysis of SE exposed to ATRA showed columnar differentiation independent of proliferation. Metaplasia could be induced from the stromal compartment alone and vimentin expression co‐localised with CK8/18 at 24 h, which separated into CK8/18‐positive glands and vimentin‐positive stroma by 48 h. Citral‐treated Barrett's oesophagus led to phenotypic and immunohistochemical characteristics of SE, which was independent of proliferation. Conclusion RA activity is increased in Barrett's oesophagus and is induced by LCA. Under conditions of altered RA activity and an intact stroma, the oesophageal phenotype can be altered independent of proliferation. PMID:17185354

Usage of skin care products and risk of rheumatoid arthritis: results from the Swedish EIRA study

PubMed Central

2012-01-01

Introduction The aim of this study was to investigate the association between exposure to cosmetics, often containing mineral oil, and the risk of developing rheumatoid arthritis (RA). The study was performed against the background that occupational exposure to mineral oil has recently been shown to be associated with an increased risk for RA in man, and that injection of or percutaneous exposure to mineral-oil-containing cosmetics can induce arthritis in certain rat strains. Methods A population-based case-control study of incident cases of RA was performed among the population aged 18 to 70 years in a defined area of Sweden during May 1996 to December 2003. A case was defined as an individual from the study base, who received for the first time a diagnosis of RA according to the 1987 American College of Rheumatology criteria. Controls were randomly selected from the study base with consideration taken for age, gender and residential area. Cases (n = 1,419) and controls (n = 1,674) answered an extensive questionnaire regarding environmental and lifestyle factors including habits of cosmetic usage. The relative risk of developing RA was calculated for subjects with different cosmetic usage compared with subjects with low or no usage. Analysis was also performed stratifying the cases for presence/absence of rheumatoid factor and antibodies to citrulline-containing peptides. Results The relative risks of developing RA associated with use of cosmetics were all close to one, both for women and men, for different exposure categories, and in relation to different subgroups of RA. Conclusion This study does not support the hypothesis that ordinary usage of common cosmetics as body lotions, skin creams, and ointments, often containing mineral oil, increase the risk for RA in the population in general. We cannot exclude, however, that these cosmetics can contribute to arthritis in individuals carrying certain genotypes or simultaneously being exposed to other arthritis-inducing environmental agents. PMID:22455933

Are RA patients from a non-endemic HCV population screened for HCV? A cross-sectional analysis of three different settings.

PubMed

Skinner-Taylor, Cassandra Michelle; Erhard-Ramírez, Alejandro; Garza-Elizondo, Mario Alberto; Esquivel-Valerio, Jorge Antonio; Abud-Mendoza, Carlos; Martínez-Martínez, Marco Ulises; Vega-Morales, David; Arana-Guajardo, Ana

In Mexico, other risk factors are associated with hepatitis C virus (HCV): prior heroin users, living alone, widower, and northern region residence. Rheumatoid arthritis (RA) patients are considered immunosuppressed and HCV testing is recommended before treatment. The aim of the study was to describe the characteristics of HCV testing in RA patients in three different medical care settings in a non-endemic area. A retrospective observational study was performed using medical records from 960 RA patients describing the indications for HCV testing. The test was performed in 28.6% and the HCV overall frequency was 0.36%. Population characteristics were not associated with an increased risk of HCV infection; therefore, anti-HCV positivity was low. The main reason for testing was before starting biological agents. Due to the low pre-test probability, testing for HCV infection should be personalized; i.e., according to disease prevalence in a particular geographical location and the individual risk factors. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

The promotion of hair regrowth by topical application of a Perilla frutescens extract through increased cell viability and antagonism of testosterone and dihydrotestosterone.

PubMed

Li, Jing-Jie; Li, Zheng; Gu, Li-Juan; Choi, Kang-Ju; Kim, Dong-Seon; Kim, Ho-Kyoung; Sung, Chang-Keun

2018-01-01

This study investigated the potential hair regrowth effects associated with a plant extract of Perilla frutescens, which was selected due to its putative hair regrowth activity. Extracts were prepared from dried P. frutescens suspended in distilled water, where the resultant aqueous suspension was fractionated sequentially using hexane, ethyl acetate, n-butanol, and distilled water. We observed that the n-butanol fraction resulted in the highest hair regrowth activity. The n-butanol soluble fraction of P. frutescens extract (BFPE) was further separated using AB-8 macroporous resin and silica gel chromatography to obtain rosmarinic acid (RA), which demonstrated effective hair growth regeneration potential. BFPE also showed in vivo anti-androgenic activity following the use of a hair growth assay in testosterone-sensitive male C57Bl/6NCrSlc mice. Furthermore, the effects of cell viability promotion were investigated following an in vitro analysis in primary hair follicle fibroblast cells (PHFCs) treated with RA. The results suggested that RA was the active compound in P. frutescens that triggers hair growth, and RA could be a potential therapeutic agent for the promotion of hair growth and prevention of androgenetic alopecia (AGA).

Treatment with biologic agents improves the prognosis of patients with rheumatoid arthritis and amyloidosis.

PubMed

Kuroda, Takeshi; Tanabe, Naohito; Kobayashi, Daisuke; Sato, Hiroe; Wada, Yoko; Murakami, Shuichi; Saeki, Takako; Nakano, Masaaki; Narita, Ichiei

2012-07-01

Reactive amyloid A (AA) amyloidosis is a serious and life-threatening systemic complication of rheumatoid arthritis (RA). We evaluated the safety of therapy with anti-tumor necrosis factor and anti-interleukin 6 biologic agents in RA patients with reactive AA amyloidosis, together with prognosis and hemodialysis (HD)-free survival, in comparison with patients with AA amyloidosis without such therapy. One hundred thirty-three patients with an established diagnosis of reactive AA amyloidosis participated in the study. Clinical data were assessed from patient records at the time of amyloid detection and administration of biologics. Survival was calculated from the date when amyloid was first demonstrated histologically or the date when biologic therapy was started until the time of death or to the end of 2010 for surviving patients. Patients who had started HD were selected for inclusion only after the presence of amyloid was demonstrated. Fifty-three patients were treated with biologic agents (biologic group) and 80 were not (nonbiologic group). Survival rate was significantly higher in the biologic group than in the nonbiologic group. Nine patients in the biologics group and 33 in the nonbiologic group started HD. Biologic therapy had a tendency for reduced risk of initiation of HD without any statistical significance. Patients with amyloidosis have a higher mortality rate, but the use of biologic agents can reduce risk of death. The use of biologics may not significantly influence the HD-free survival rate.

Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST-RA database.

PubMed

Sokka, T; Kautiainen, H; Pincus, T; Toloza, S; da Rocha Castelar Pinheiro, G; Lazovskis, J; Hetland, M L; Peets, T; Immonen, K; Maillefert, J F; Drosos, A A; Alten, R; Pohl, C; Rojkovich, B; Bresnihan, B; Minnock, P; Cazzato, M; Bombardieri, S; Rexhepi, S; Rexhepi, M; Andersone, D; Stropuviene, S; Huisman, M; Sierakowski, S; Karateev, D; Skakic, V; Naranjo, A; Baecklund, E; Henrohn, D; Gogus, F; Badsha, H; Mofti, A; Taylor, P; McClinton, C; Yazici, Y

2009-11-01

To analyse associations between the clinical status of patients with rheumatoid arthritis (RA) and the gross domestic product (GDP) of their resident country. The Quantitative Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST-RA) cohort includes clinical and questionnaire data from 6004 patients who were seen in usual care at 70 rheumatology clinics in 25 countries as of April 2008, including 18 European countries. Demographic variables, clinical characteristics, RA disease activity measures, including the disease activity score in 28 joints (DAS28), and treatment-related variables were analysed according to GDP per capita, including 14 "high GDP" countries with GDP per capita greater than US$24,000 and 11 "low GDP" countries with GDP per capita less than US$11,000. Disease activity DAS28 ranged between 3.1 and 6.0 among the 25 countries and was significantly associated with GDP (r = -0.78, 95% CI -0.56 to -0.90, r(2) = 61%). Disease activity levels differed substantially between "high GDP" and "low GDP" countries at much greater levels than according to whether patients were currently taking or not taking methotrexate, prednisone and/or biological agents. The clinical status of patients with RA was correlated significantly with GDP among 25 mostly European countries according to all disease measures, associated only modestly with the current use of antirheumatic medications. The burden of arthritis appears substantially greater in "low GDP" than in "high GDP" countries. These findings may alert healthcare professionals and designers of health policy towards improving the clinical status of patients with RA in all countries.

13-cis Retinoic Acid Inhibits Development and Progression of Chronic Allograft Nephropathy

PubMed Central

Adams, Judith; Kiss, Eva; Arroyo, Ana B.V.; Bonrouhi, Mahnaz; Sun, Qiang; Li, Zhen; Gretz, Norbert; Schnitger, Anna; Zouboulis, Christos C.; Wiesel, Manfred; Wagner, Jürgen; Nelson, Peter J.; Gröne, Hermann-Josef

2005-01-01

Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflammatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher344→Lewis transplantation model. In 13cRA animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating mononuclear cells and their proliferative activity were significantly diminished. The mRNA expression of chemokines (MCP-1/CCL2, MIP-1α/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-β1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRA-treated rats showed a pronounced decrease in protein secretion of inflammatory cytokines (eg, tumor necrosis factor-α, interleukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 × 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-κB binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. In summary, 13cRA acted as a potent immunosuppressive and anti-fibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy. PMID:15972972

Validation of ERS-1 environmental data products

NASA Technical Reports Server (NTRS)

Goodberlet, Mark A.; Swift, Calvin T.; Wilkerson, John C.

1994-01-01

Evaluation of the launch-version algorithms used by the European Space Agency (ESA) to derive wind field and ocean wave estimates from measurements of sensors aboard the European Remote Sensing satellite, ERS-1, has been accomplished through comparison of the derived parameters with coincident measurements made by 24 open ocean buoys maintained by the National Oceanic and Atmospheric Administration). During the period from November 1, 1991 through February 28, 1992, data bases with 577 and 485 pairs of coincident sensor/buoy wind and wave measurements were collected for the Active Microwave Instrument (AMI) and Radar Altimeter (RA) respectively. Based on these data, algorithm retrieval accuracy is estimated to be plus or minus 4 m/s for AMI wind speed, plus or minus 3 m/s for RA wind speed and plus or minus 0.6 m for RA wave height. After removing 180 degree ambiguity errors, the AMI wind direction retrieval accuracy was estimated at plus or minus 28 degrees. All of the ERS-1 wind and wave retrievals are relatively unbiased. These results should be viewed as interim since improved algorithms are under development. As final versions are implemented, additional assessments should be conducted to complete the validation.

Microwave Radiometer Technology Acceleration Mission (MiRaTA): Advancing Weather Remote Sensing with Nanosatellites

NASA Astrophysics Data System (ADS)

Cahoy, K.; Blackwell, W. J.; Bishop, R. L.; Erickson, N.; Fish, C. S.; Neilsen, T. L.; Stromberg, E. M.; Bardeen, J.; Dave, P.; Marinan, A.; Marlow, W.; Kingsbury, R.; Kennedy, A.; Byrne, J. M.; Peters, E.; Allen, G.; Burianek, D.; Busse, F.; Elliott, D.; Galbraith, C.; Leslie, V. V.; Osaretin, I.; Shields, M.; Thompson, E.; Toher, D.; DiLiberto, M.

2014-12-01

The Microwave Radiometer Technology Acceleration (MiRaTA) is a 3U CubeSat mission sponsored by the NASA Earth Science Technology Office (ESTO). Microwave radiometer measurements and GPS radio occultation (GPSRO) measurements of all-weather temperature and humidity provide key contributions toward improved weather forecasting. The MiRaTA mission will validate new technologies in both passive microwave radiometry and GPS radio occultation: (1) new ultra-compact and low-power technology for multi-channel and multi-band passive microwave radiometers, and (2) new GPS receiver and patch antenna array technology for GPS radio occultation retrieval of both temperature-pressure profiles in the atmosphere and electron density profiles in the ionosphere. In addition, MiRaTA will test (3) a new approach to spaceborne microwave radiometer calibration using adjacent GPSRO measurements. The radiometer measurement quality can be substantially improved relative to present systems through the use of proximal GPSRO measurements as a calibration standard for radiometric observations, reducing and perhaps eliminating the need for costly and complex internal calibration targets. MiRaTA will execute occasional pitch-up maneuvers so that the radiometer and GPSRO observations sound overlapping volumes of atmosphere through the Earth's limb. To validate system performance, observations from both microwave radiometer (MWR) and GPSRO instruments will be compared to radiosondes, global high-resolution analysis fields, other satellite observations, and to each other using radiative transfer models. Both the radiometer and GPSRO payloads, currently at TRL5 but to be advanced to TRL7 at mission conclusion, can be accommodated in a single 3U CubeSat. The current plan is to launch from an International Space Station (ISS) orbit at ~400 km altitude and 52° inclination for low-cost validation over a ~90-day mission to fly in 2016. MiRaTA will demonstrate high fidelity, well-calibrated radiometric sensing from a nanosatellite platform, thereby enabling new architectural approaches for mission implementation at lower cost and risk with more flexible access to space.

CoCoRaHS: A Community Science Program Providing Valuable Precipitation Data to Guide Decision Making

NASA Astrophysics Data System (ADS)

Robinson, D. A.; Doesken, N.

2017-12-01

CoCoRaHS is an acronym for the Community Collaborative Rain, Hail and Snow Network. It is long-running, community-based network of volunteers working together to measure and map precipitation (rain, hail and snow). Precipitation is an ideal element for public engagement because it affects everyone, it is so variable in time and space and it impacts so many things. By using a standard precipitation gauge, stressing training and education, utilizing an interactive website, and having observations undergo quality assurance, the CoCoRaHS program provides high-quality data for natural resource, education and research applications. The program currently operates in all states, Canada and the Bahamas. It originated with the Colorado Climate Center at Colorado State University in 1998 due in part to the Fort Collins flood a year prior. Upwards of 12,000 observers submit observations each day. Observations meet federal guidelines and are archived at the U.S. National Centers for Environmental Information. Because of excellent spatial coverage, data quality, practical relevance, and accessibility, CoCoRaHS observations are used by a wide variety of organizations and individuals. The U.S. National Weather Service, hydrologists, emergency managers, city utilities (water supply, storm water), insurance adjusters, the U.S. Department of Agriculture, engineers, mosquito control commissions, ranchers and farmers, outdoor and recreation interests, teachers and students are just some examples of those who use CoCoRaHS data in making well-informed, meaningful decisions. Some examples of community applications and the science utility of CoCoRaHS observations include storm warnings, water supply and demand forecasts, disaster declarations (drought, winter storm, etc.), drought and food production assessments, calibration/validation of remote sensing, infrastructure evaluation and potential redesign (ice and snow loading, bridge, storm and sewer design), recreation planning, and environmental education. This presentation will demonstrate a growing trust in volunteered data and that the CoCoRaHS program succeeds in striking a balance between education, local interest, community service and service to science.

Visually induced changes in components of the retinoic acid system in fundal layers of the chick.

PubMed

Bitzer, M; Feldkaemper, M; Schaeffel, F

2000-01-01

Eye growth is visually regulated via messengers that are released from the retina. The retina involves a yet unknown algorithm to analyse the projected image so that the appropriate growth rates for the back of the eye are ensured. One biochemical candidate that could act as a growth controller, is retinoic acid (RA). Previous work (Seko, Shimokawa and Tokoro, 1996; Mertz et al., 1999) has shown that retinal and choroidal RA levels are indeed predictably changed by visual conditions that cause myopia or hyperopia, respectively. We have studied in which fundal tissues aldehyde dehydrogenase-2 (AHD2) and retinaldehyde dehydrogenase-2 (RALDH2), enzymes involved in RA synthesis, are expressed and at which levels the effects of vision on RA levels may be controlled. Using Northern blot analysis, we have found that the retinal mRNA level of the AHD2 is up-regulated after 3 days of treatment with negative lenses (negative lenses place the image behind the retina). The abundance of the retinal mRNA of a RA receptor, RAR-beta, was up-regulated already after 6 hr of treatment with positive lenses (positive lenses place the image in front of the retina). The up-regulation persisted for at least 1 week. Finally, we have studied the effects of an inhibitor of RA synthesis, disulfiram, on the visual control of eye growth. We found inhibition of myopia as induced by frosted goggles ('deprivation myopia') but no significant inhibitory effects on refractive errors induced by +7D or -7D lenses. Our results are in line with the hypothesis that RA may play a role in the visual control of eye growth. The RA system differs from a number of other candidates (dopamine, cholinergic agents, opiates) in that it distinguishes between positive and negative defocus, similar to the immediate early gene ZENK (Stell et al., 1999). The exact time kinetics of the changes have still to be worked out since it is possible that the changes in RA relate to already occurring changes in growth rather than to initial steps of the signaling cascade. Copyright 2000 Academic Press.

Inflammation-mediated muscle metabolic dysregulation local and remote to the site of major abdominal surgery.

PubMed

Varadhan, Krishna K; Constantin-Teodosiu, Dumitru; Constantin, Despina; Greenhaff, Paul L; Lobo, Dileep N

2017-11-02

Postoperative hyperglycaemia is common in patients having major surgery and is associated with adverse outcomes. This study aimed to determine whether bacteraemia contributed to postoperative systemic inflammation, and whether increases in the expression of muscle mRNAs and proteins reflecting increased muscle inflammation, atrophy and impaired carbohydrate oxidation were evident at the time of surgery, and both local and distant to the site of trauma, and could be associated with impaired glucoregulation. Fifteen adult patients without diabetes undergoing major abdominal surgery participated in this observational study set in a university teaching hospital. Arterialised-venous blood samples and muscle biopsies were obtained before and after major elective abdominal surgery, from sites local (rectus abdominis - RA) and remote to the site of surgery (vastus lateralis - VL). The main outcome measures included blood glucose concentrations, gut permeability and changes in expression of muscle mRNAs and proteins linked to inflammation and glucose regulation. Immediately postoperatively, RA demonstrated markedly increased mRNA expression levels of cathepsin-L (7.5-fold, P < 0.05), FOXO1 (10.5-fold, P < 0.05), MAFbx (11.5-fold, P < 0.01), PDK4 (7.8-fold, P < 0.05), TNF-α (16.5-fold, P < 0.05) and IL-6 (1058-fold, P < 0.001). A similar, albeit blunted, response was observed in VL. Surgery also increased expression of proteins linked to inflammation (IL-6; 6-fold, P < 0.01), protein degradation (MAFbx; 4.5-fold, P < 0.5), and blunted carbohydrate oxidation (PDK4; 4-fold, P < 0.05) in RA but not VL. Increased systemic inflammation (TNF-α, P < 0.05; IL-6, P < 0.001), and impaired postoperative glucose tolerance (P < 0.001), but not bacteraemia (although gut permeability was increased significantly, P < 0.05) or increased plasma cortisol, were noted 48 h postoperatively. A systemic postoperative proinflammatory response was accompanied by muscle inflammation and metabolic dysregulation both local and remote to the site of surgery, and was not accompanied by bacteraemia. Registered at http://clinicaltrials.gov (NCT01134809). Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effects of retinoids on ultraviolet-induced carcinogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Epstein, J.H.

The evidence for effects of the retinoids on UV-induced carcinogenesis is sparse. Clinical observations indicate that topical RA can cause significant regression of premalignant actinic keratoses. Also there is some evidence that this agent can cause dissolution of some basal cell epitheliomas. However this latter effect does not appear to be of therapeutic value. Systemic retinoids are of little value in the treatment of premalignant and malignant cutaneous lesions though 13-cis-retinoic acid might be of use in the basal cell nevus syndrome. Examination of the influence of the retinoids on photocarcinogenesis essentially has been confined to RA and animal experimentation.more » RA in nontoxic concentrations can both stimulate and inhibit photocarcinogenesis depending upon the circumstances of the study. The mechanisms of these responses are not clear. Influences on DNA synthesis directly and/or indirectly or on immune responses may be involved in both effects. Preliminary studies with oral 13-cis-retinoic acid have not demonstrated any effects to date on UV-induced skin cancer formation.« less

Review of Matters Related to the Sexual Assault of Lance Corporal Maria Lauterbach, U.S. Marine Corps

DTIC Science & Technology

2011-10-18

her then supervisory agent directed the inclusion . Physical Assault Complaint. The NCIS Investigative Manual requires agents interview and take...lations and pr ocedu ra l de fi ciencies described 1n t he report . Clea rly corrective action is r equ ired in t his casa , as both a !"leans to...misconduct. Also , i mmedia t ely after identifying the proble~s ~ithin this inves t iga tion , NCIS init ia t ed ~ number of organizationa l measures des

Long-Wave Infrared (LWIR) Polarimetric and Radiometric Analysis for a Variety of Thermal and Electromagnetic Suppressing Materials

DTIC Science & Technology

2014-08-01

polarimetry for remote sensing applications. Appl Opt. 2006;45(22):5453–5469. 5. Kudenov M, Pezzaniti L, Gerhart G. Microbolometer-infrared imaging...infrared imaging polarimetry . In: Photonics for Port and Harbor Security, DeWeert MJ, Saito TT, editors. Proceedings of SPIE; 2005;5780. 13. Hecht E...metrology. In: Polarimetry : Radar, Infrared, Visible, Ultraviolet, and X-Ray, Chipman RA, Morris JW, editors. Proceedings of SPIE; 1990;1317:280

Platelet-Associated CD40/CD154 Mediates Remote Tissue Damage After Mesenteric Ischemia/Reperfusion Injury

DTIC Science & Technology

2012-02-27

aggregates form in the mesenteric vasculature in patients with ulcerative colitis . Eur J Gastroenterol Hepatol 20: 283 289. 37. Franks ZG, Campbell RA...in these mice [8,33]. Moreover, increased levels of activated platelets and platelet derived factors have also been found in patients with...inflammatory bowel disease [12,34 36] and with ischemic stroke [37 40]. CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily, and is

Measures of rheumatoid arthritis disease activity in Australian clinical practice.

PubMed

Taylor, Andrew; Bagga, Hanish

2011-01-01

Objectives. To investigate which rheumatoid arthritis (RA) disease activity measures are being collected in patients receiving glucocorticoids, non-biologic or biologic disease-modifying antirheumatic drugs (DMARDs) in Australian rheumatology practice. Methods. A retrospective audit of medical records was conducted from eight rheumatology practices around Australia. Each rheumatologist recruited 30 consecutive eligible patients into the review, 10 of whom must have been receiving a biological agent for rheumatoid arthritis. Disease activity measures and radiographic assessments were collected from each patient's last consultation. For biologic patients, disease activity measures were also collected from when the patient was first initiated on the biological agent. Results. At last consultation, the disease measures that were recorded most often were ESR (89.2%), haemoglobin (87.5%), and CRP (84.2%). DAS28 was infrequently recorded (16.3%). The rate of recording disease activity measures for patients receiving biologic DMARDs decreased over time (mean 27 months). Conclusion. This review has shown inconsistency of RA activity measures being recorded in Australian rheumatology clinical practice. An accurate assessment of the disease process is necessary to effectively target rheumatoid arthritis patients to treat in order to achieve optimal outcomes.

Positive impacts on rural and regional workforce from the first seven cohorts of James Cook University medical graduates.

PubMed

Sen Gupta, T; Woolley, T; Murray, R; Hays, R; McCloskey, T

2014-01-01

The regionally-based James Cook University (JCU) School of Medicine aims to meet its mission to address the health needs of the region by combining selection and curriculum strategies shown to increase rural career recruitment outcomes. The School has graduated 536 students in its first seven cohorts from 2005 to 2011. This paper presents the early career practice locations and the specialty training undertaken by these cohorts, and describes the association between later practice location with both hometown at application and internship location. Hometown at application' data for JCU Bachelor of Medicine, Bachelor of Surgery (MBBS) graduates was retrieved from administrative databases held by the university, while postgraduate location and career data were obtained either from personal contact via email, telephone, Facebook or electronically from the Australian Health Practitioner Regulation Authority website. Practice location was described across Australian Standard Geographical Classification Remoteness Area (RA) categories. Data for the primary practice location of 536 JCU MBBS graduates across postgraduate years (PGY) 1 to 7 is 99% complete. A total of 65% of JCU graduates undertook their internship in non-metropolitan locations including 20% in RA 2 and 44% in RA 3-5, a pattern of practice different to that of other Australian clinicians. For the internship year, 'non-metropolitan-origin' JCU MBBS graduates predominantly worked in RA 2-5 locations, while 'metropolitan origin' graduates were more likely to work in major cities. However, by PGY 7, the distribution of 'rural' and 'metropolitan' origin JCU graduates across RA categories was similar. The RA category of internship location - either 'metropolitan (RA 1) or 'non-metropolitan' (RA 2-5) - was associated with the location of subsequent practice across PGY 2-7. This comprehensive data set provides the first real evidence from one of Australia's new medical schools on actual postgraduate practice location, as compared to 'intent to practice'. The geographic profile by RA of JCU graduates' hometown and patterns of postgraduate practice is different to that of other Australian medical students and doctors. This early evidence supports the JCU model of distributed non-metropolitan medical education, and suggests more regionally-located internship and specialty training places would further increase the medical workforce in northern and/or rural Australia. The workforce impact of the seven cohorts of graduates in this study is starting to be felt in rural and regional Australia, and, if these trends continue, will result in significant workforce improvements over the next decade. These results support further investment in regional and rural medical education.

Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study.

PubMed

Sokka, Tuulikki; Kautiainen, Hannu; Pincus, Theodore; Verstappen, Suzanne M M; Aggarwal, Amita; Alten, Rieke; Andersone, Daina; Badsha, Humeira; Baecklund, Eva; Belmonte, Miguel; Craig-Müller, Jürgen; da Mota, Licia Maria Henrique; Dimic, Alexander; Fathi, Nihal A; Ferraccioli, Gianfranco; Fukuda, Wataru; Géher, Pál; Gogus, Feride; Hajjaj-Hassouni, Najia; Hamoud, Hisham; Haugeberg, Glenn; Henrohn, Dan; Horslev-Petersen, Kim; Ionescu, Ruxandra; Karateew, Dmitry; Kuuse, Reet; Laurindo, Ieda Maria Magalhaes; Lazovskis, Juris; Luukkainen, Reijo; Mofti, Ayman; Murphy, Eithne; Nakajima, Ayako; Oyoo, Omondi; Pandya, Sapan C; Pohl, Christof; Predeteanu, Denisa; Rexhepi, Mjellma; Rexhepi, Sylejman; Sharma, Banwari; Shono, Eisuke; Sibilia, Jean; Sierakowski, Stanislaw; Skopouli, Fotini N; Stropuviene, Sigita; Toloza, Sergio; Valter, Ivo; Woolf, Anthony; Yamanaka, Hisashi

2010-01-01

Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries. The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses. At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score. Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.

Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA Study

PubMed Central

2010-01-01

Introduction Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries. Methods The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses. Results At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score. Conclusions Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA. PMID:20226018

The Efficacy and Safety of Mainstream Medications for Patients With cDMARD-Naïve Rheumatoid Arthritis: A Network Meta-Analysis.

PubMed

Cai, Weiyan; Gu, Youyi; Cui, Huanqin; Cao, Yinyin; Wang, Xiaoliang; Yao, Yi; Wang, Mingyu

2018-01-01

Background: The mainstream medications for rheumatoid arthritis (RA) include conventional disease-modifying antirheumatic drugs (cDMARDs), which mostly are methotrexate (MTX), and biologic agents such as adalimumab (ADA), certolizumab (CZP), etanercept (ETN), golimumab (GOL), infliximab (IFX), and tocilizumab (TCZ). This network meta-analysis was aimed at evaluating the efficacy and safety of the medications above and interventions combining cDMARDs and biologic agents for patients with RA. Methods: PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched systematically for eligible randomized controlled trials (RCTs). Outcomes concerning efficacy and safety were evaluated utilizing odds ratios (ORs) and 95% credible intervals ( CrI ). The outcomes of efficacy would be evaluated through remission and American College of Rheumatology (ACR) scores. The surface under the cumulative ranking curve (SUCRA) was calculated to rank each treatment on each index. Results: A total of 20 RCTs with 9,047 patients were included, and the efficacy and safety of the concerning interventions for RA were evaluated. Compared with cDMARDs alone, TCZ+MTX, ETN+MTX, IFX+MTX, TCZ, and ADA+MTX showed significant statistical advantage on ACR20, ACR50, and ACR70. Apart from that, as for remission, TCZ+MTX, IFX+MTX, TCZ, and CZP+MTX performed better compared to cDMARDs alone. The SUCRA ranking also indicated that TCZ+MTX was the intervention with best ranking in the entire four efficacy indexes followed by ETX+MTX and IFX+MTX. However, there was no obvious difference among these medications compared with cDMARDs when it comes to safety, which need more specific studies on that. Conclusion: TCZ+MTX was potentially the most recommended combination of medications for RA due to its good performance in all outcomes of efficacy. ETX+MTX and IFX+MTX, which also performed well, could be introduced as alternative treatments. However, considering the adverse events, the treatments concerning should be introduced with caution.

Evolution of the earliest mantle caused by the magmatism-mantle upwelling feedback: Implications for the Moon and the Earth

NASA Astrophysics Data System (ADS)

Ogawa, M.

2017-12-01

The two most important agents that cause mantle evolution are magmatism and mantle convection. My earlier 2D numerical models of a coupled magmatism-mantle convection system show that these two agents strongly couple each other, when the Rayleigh number Ra is sufficiently high: magmatism induced by a mantle upwelling flow boosts the upwelling flow itself. The mantle convection enhanced by this positive feedback (the magmatism-mantle upwelling, or MMU, feedback) causes vigorous magmatism and, at the same time, strongly stirs the mantle. I explored how the MMU feedback influences the evolution of the earliest mantle that contains the magma ocean, based on a numerical model where the mantle is hot and its topmost 1/3 is partially molten at the beginning of the calculation: The evolution drastically changes its style, as Ra exceeds the threshold for onset of the MMU feedback, around 107. At Ra < 107, basaltic materials generated by the initial widespread magmatism accumulate in the deep mantle to form a layer; the basaltic layer is colder than the overlying shallow mantle. At Ra > 107, however, the mantle remains compositionally more homogeneous in spite of the widespread magmatism, and the deep mantle remains hotter than the shallow mantle, because of the strong convective stirring caused by the feedback. The threshold value suggests that the mantle of a planet larger than Mars evolves in a way substantially different from that in the Moon does. Indeed, in my earlier models, magmatism makes the early mantle compositionally stratified in the Moon, but the effects of strong convective stirring overwhelms that of magmatism to keep the mantle compositionally rather homogeneous in Venus and the Earth. The MMU feedback is likely to be a key to understanding why vestiges of the magma ocean are so scarce in the Earth.

Prophylaxis of radiation-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials.

PubMed

Li, Wing S; van der Velden, Joanne M; Ganesh, Vithusha; Vuong, Sherlyn; Raman, Srinivas; Popovic, Marko; Lam, Henry; Wong, Kam H; Ngan, Roger K; Burbach, J P Maarten; DeAngelis, Carlo; Xxxx, Rachel McDonald; Chow, Edward

2017-04-01

The aim of this article was to systematically review the efficacy and safety of various antiemetics in prophylaxis of radiation-induced nausea and vomiting (RINV). A literature search of Ovid MEDLINE, EMBASE and Cochrane CENTRAL was performed to identify randomized controlled trials (RCTs) that evaluated the efficacy of prophylaxis for RINV in patients receiving radiotherapy to abdomen/pelvis, including total body irradiation (TBI). Primary endpoints were complete control of nausea and complete control of vomiting during acute and delayed phases. Secondary endpoints included use of rescue medication, quality of life (QoL) and incidence of adverse events. Seventeen RCTs were identified. Among patients receiving radiotherapy to abdomen/pelvis, our meta-analysis showed that prophylaxis with a 5-hydroxytryptamine-3 receptor antagonist (5HT3 RA) was significantly more efficacious than placebo and dopamine receptor antagonists in both complete control of vomiting [OR 0.49; 95% confidence interval (CI): 0.33-0.72 and OR 0.17; 95% CI: 0.05-0.58 respectively] and complete control of nausea (OR 0.43; 95% CI: 0.26-0.70 and OR 0.46; 95% CI: 0.24-0.88 respectively). 5HT3 RAs were also more efficacious than rescue therapy and dopamine receptor antagonists plus dexamethasone. The addition of dexamethasone to 5HT3 RA compared to 5HT3 RA alone provides a modest improvement in prophylaxis of RINV. Among patients receiving TBI, 5HT3 RA was more effective than other agents (placebo, combination of metoclopramide, dexamethasone and lorazepam). 5HT3 RAs are more effective than other antiemetics for prophylaxis of RINV in patients receiving radiotherapy to abdomen/pelvis and TBI. Future RCTs should investigate the efficacy of newer agents such as substance P neurokinin 1 receptor antagonists in addition to 5HT3 RAs in prophylaxis of RINV during both acute and delayed phases.

Comparative magnitude and kinetics of human cytomegalovirus-specific CD4⁺ and CD8⁺ T-cell responses in pregnant women with primary versus remote infection and in transmitting versus non-transmitting mothers: Its utility for dating primary infection in pregnancy.

PubMed

Fornara, Chiara; Furione, Milena; Arossa, Alessia; Gerna, Giuseppe; Lilleri, Daniele

2016-07-01

To discriminate between primary (PI) and remote (RI) human cytomegalovirus (HCMV) infection, several immunological parameters were monitored for a 2-year period in 53 pregnant women with PI, and 33 pregnant women experiencing HCMV PI at least 5 years prior. Cytokine (IFN-γ and IL-2) production by and phenotype (effector/memory CD45RA(+)) of HCMV-specific CD4(+) and CD8(+) T-cells as well as the lymphoproliferative responses (LPR) were evaluated, with special reference to the comparison between a group of women transmitting (T) and a group of non-transmitting (NT) the infection to fetus. While HCMV-specific CD4(+) T-cells reached at 90 days post-infection (p.i.) values comparable to RI, CD8(+) T-cells reached at 60 days p.i. levels significantly higher and persisting throughout the entire follow-up. Instead, IL-2 production and lymphoproliferative responses were lower in PI than RI for the entire follow-up period. Effector memory CD45RA(+) CD4(+) and CD8(+) HCMV-specific T-cells increased until 90 days p.i., reaching and maintaining levels higher than RI. The comparison between T and NT women showed that, at 30 days p.i., in NT women there was a significantly higher IL-2 production by HCMV-specific CD4(+) T-cells, and at 60 days p.i. a significantly higher frequency of both specific CD4(+) and CD8(+) CD45RA(+) T-cells. HCMV T-cell response appears to correlate with virus transmission to fetus and some parameters (CD4(+) lymphoproliferation, and frequency of HCMV-specific CD8(+) IL2(+) T-cells) may help in dating PI during pregnancy. © 2015 Wiley Periodicals, Inc.

Assessing information needs and use of online resources for disease self-management in patients with rheumatoid arthritis: a qualitative study.

PubMed

des Bordes, Jude K A; Gonzalez, Elsa; Lopez-Olivo, Maria A; Shethia, Maithili; Nayak, Pratibha; Suarez-Almazor, Maria E

2018-07-01

To explore the information needs of patients with rheumatoid arthritis (RA) and their acceptance of online resources and Facebook in particular, as a source of information, interaction, and support among peers. Participants were adults with RA of ≤ 10 years duration, had ongoing or prior treatment with disease-modifying anti-rheumatic drugs or biologic agents, and internet access. We conducted 20 in-depth interviews using semi-structured interview guide to explore: (1) RA information needs, (2) use of self-management health behaviors, (3) use of internet resources for disease management, (4) role of peer support in health self-management, and (5) use of social networking sites (SNS) such as Facebook in disease management. Data were analyzed using content analysis and constant comparative methods. Participants were mainly female (85%), White (70%), and over 50 years old (70%). Specific information needs included knowledge regarding medications, disease course, pain control, diet, and exercise. Most participants had a narrow perception of SNS as a tool for disease management. However, they found SNS acceptable and were open to participating in a support group on Facebook with reasonable assurance of privacy. Although the overarching theme was RA information needs, the other themes contribute in supporting the robust emergence of Internet media in informing patients about their health and support systems. Our findings can inform the choice and format of materials to be considered for online education on self-management and social networking for RA patients.

Recent advances in the treatment of rheumatoid arthritis.

PubMed

Mahajan, Tina D; Mikuls, Ted R

2018-05-01

Therapies for rheumatoid arthritis (RA) continue to expand rapidly. The purpose of this review is to discuss novel treatment options, including biosimilars, that are available, as well as to highlight promising agents in development. The purpose is also to discuss new emerging safety signals associated with these drugs and to discuss strategies in tapering therapy. There are several novel RA therapies. These include the interleukin-6 (IL-6) receptor blocker sarilumab, which was approved in 2017. In aggregate, the sarilumab studies show that it is effective in RA, including patients with incomplete responses to methotrexate and anti-tumor necrosis factor inhibitor, and showing superior efficacy when used in higher dose (200 mg every 2 weeks) to standard-dose adalilumab. Other drugs that are currently being studied include the IL-6 cytokine blocker sarikumab, the small targeted molecule filgotinib, and many new biosimilars. Baracitinib failed to achieve approval by the Food and Drug Administration primarily over perceived safety concerns. The two biosimilar drugs currently approved are CT-P13 and SB2, which are based on the reference product infliximab. Although this review summarizes trials examining biologic tapering, additional data are needed to guide clinicians in regards to treatment de-escalation in RA. With the greatly expanded armamentarium of RA treatment options available, it is important for clinicians to understand the data regarding drug efficacy and safety. With remission increasingly attainable, effective drug tapering strategies are needed. Although tapering trials do exist, more studies will be needed to help guide clinical practice.

Effect of certolizumab pegol with methotrexate on home and work place productivity and social activities in patients with active rheumatoid arthritis.

PubMed

Kavanaugh, Arthur; Smolen, Josef S; Emery, Paul; Purcaru, Oana; Keystone, Edward; Richard, Lance; Strand, Vibeke; van Vollenhoven, Ronald F

2009-11-15

To assess the impact of certolizumab pegol (CZP), a novel PEGylated anti-tumor necrosis factor, in combination with methotrexate (MTX) on productivity outside and within the home, and on participation in family, social, and leisure activities in adult patients with rheumatoid arthritis (RA). The efficacy and safety of CZP (200 mg and 400 mg) plus MTX were assessed in 2 phase III, multicenter, double-blind, placebo-controlled trials (Rheumatoid Arthritis Prevention of Structural Damage [RAPID] 1 and RAPID 2). The novel, validated, RA-specific Work Productivity Survey (WPS-RA) was used to assess work place and home productivity. WPS-RA responses were collected at baseline and every 4 weeks until withdrawal/study completion. At baseline, 41.6% and 39.8% of subjects were employed outside the home in RAPID 1 and RAPID 2, respectively. Compared with placebo plus MTX, CZP plus MTX significantly reduced work absenteeism and presenteeism among patients working outside the home. Significant reductions in number of household days lost, household days with productivity reduced by >/=50%, and days lost due to RA for participation in family, social, and leisure activities were reported by patients in active treatment relative to placebo plus MTX. Improvements in all measures were observed with CZP plus MTX as early as week 4, and maintained until the study end (12 months in RAPID 1, 6 months in RAPID 2). Findings were consistent with clinical improvements with CZP plus MTX in both trials. CZP plus MTX improved productivity outside and within the home and resulted in more participation in social activities compared with placebo plus MTX. These observations suggest that considerable indirect cost gains might be achieved with this therapeutic agent in RA.

Decoy receptor 3 suppresses B cell functions and has a negative correlation with disease activity in rheumatoid arthritis.

PubMed

Chen, Ming-Han; Liu, Po-Chun; Chang, Chien-Wen; Chen, Yi-Ann; Chen, Ming-Huang; Liu, Chun-Yu; Leu, Chuen-Miin; Lin, Hsiao-Yi

2014-01-01

The decoy receptor 3 (DcR3) is a member of the tumour necrosis factor (TNF) receptor superfamily and may regulate inflammation. The aim of this study was to investigate the role of DcR3 in B cell functions and its correlation to disease activity in patients with rheumatoid arthritis (RA). The concentrations of DcR3 and TNF-α were measured by ELISA. B cell proliferation was assessed by quantification of 3H-thymidine uptake. Staphylococcus aureus Cowan (SAC) strain were used to stimulate B cell proliferation and TNF-α production. Compared to the osteoarthritis (OA) patients, the RA group had higher synovial DcR3 levels (3273.6±1623.2 vs. 1594.8±1190.0 pg/ml, p=0.003), which were negatively correlated with the serum erythrocyte sedimentation rate and Disease Activity Score using 28 joint counts (DAS28) scores (r=-0.560, p=0.002; r=-0.579, p<0.001, respectively). Although the RA B cells have more active characteristics, B cell proliferation induced by SAC was successfully suppressed by recombinant DcR3.Fc fusion protein with an average inhibition of 44.8%. Moreover, DcR3.Fc fusion protein was found to suppress SAC-induced TNF-α production by B cells in 8 RA patients (average inhibition 47.0%). The results of our study indicated that the inhibition of B cell functions by DcR3 may partially explain the negative correlation between DcR3 level and disease activity in RA patients. Our findings imply that DcR3 may be used as a biomarker for disease activity and a potential therapeutic agent in the treatment of RA.

Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST–RA database

PubMed Central

Sokka, T; Kautiainen, H; Pincus, T; Toloza, S; da Rocha Castelar Pinheiro, G; Lazovskis, J; Hetland, M L; Peets, T; Immonen, K; Maillefert, J F; Drosos, A A; Alten, R; Pohl, C; Rojkovich, B; Bresnihan, B; Minnock, P; Cazzato, M; Bombardieri, S; Rexhepi, S; Rexhepi, M; Andersone, D; Stropuviene, S; Huisman, M; Sierakowski, S; Karateev, D; Skakic, V; Naranjo, A; Baecklund, E; Henrohn, D; Gogus, F; Badsha, H; Mofti, A; Taylor, P; McClinton, C; Yazici, Y

2009-01-01

Objective: To analyse associations between the clinical status of patients with rheumatoid arthritis (RA) and the gross domestic product (GDP) of their resident country. Methods: The Quantitative Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST–RA) cohort includes clinical and questionnaire data from 6004 patients who were seen in usual care at 70 rheumatology clinics in 25 countries as of April 2008, including 18 European countries. Demographic variables, clinical characteristics, RA disease activity measures, including the disease activity score in 28 joints (DAS28), and treatment-related variables were analysed according to GDP per capita, including 14 “high GDP” countries with GDP per capita greater than US$24 000 and 11 “low GDP” countries with GDP per capita less than US$11 000. Results: Disease activity DAS28 ranged between 3.1 and 6.0 among the 25 countries and was significantly associated with GDP (r  =  −0.78, 95% CI −0.56 to −0.90, r2  =  61%). Disease activity levels differed substantially between “high GDP” and “low GDP” countries at much greater levels than according to whether patients were currently taking or not taking methotrexate, prednisone and/or biological agents. Conclusions: The clinical status of patients with RA was correlated significantly with GDP among 25 mostly European countries according to all disease measures, associated only modestly with the current use of antirheumatic medications. The burden of arthritis appears substantially greater in “low GDP” than in “high GDP” countries. These findings may alert healthcare professionals and designers of health policy towards improving the clinical status of patients with RA in all countries. PMID:19643759

Origin and evolution of rare amphibole-bearing mantle peridotites from Wilcza Góra (SW Poland), Central Europe

NASA Astrophysics Data System (ADS)

Matusiak-Małek, Magdalena; Puziewicz, Jacek; Ntaflos, Theodoros; Grégoire, Michel; Kukuła, Anna; Wojtulek, Piotr Marian

2017-08-01

Mantle xenoliths in the 20 Ma Wilcza Góra basanite (Lower Silesia, NE Bohemian Massif) are mostly harzburgites, some with amphibole which is exceptional in the region. Forsterite content in olivine defines two Groups of peridotites: Group A (Fo89.1-91.5) and Group B (Fo84.2-89.2). Hornblende-clinopyroxenite, websterite and one composite xenolith consisting of dunite, olivine-hornblendite and pyroxene-hornblende-peridotite contain olivine with Fo77.3-82.5 and are classified as Group C. Group A xenoliths contain Al-poor orthopyroxene and some contain LREE-enriched clinopyroxene with negative Ti, Zr-Hf and Nb-Ta anomalies. Spinel (Cr# 0.57-0.68) is scarce in Group A, and Cr-rich pargasite occurs in only two xenoliths. Group B xenoliths contain less magnesian orthopyroxene and clinopyroxene. The REE patterns of Group B clinopyroxene are convex downward, less enriched in LREE and have smaller negative Ti, Zr-Hf and Nb-Ta anomalies than those in Group A. The Cr# in Group B spinel is 0.26-0.56, while pargasite is Ti-rich and Cr-poor. Clinopyroxene from Group C is low magnesian, slightly enriched in LREE and has no negative Ti, Zr-Hf and Nb-Ta anomalies. Group C pargasite is rich in Ti and poor in Cr. Equilibration temperatures recorded in all groups vary within the range of 905-970 °C. Xenoliths from Wilcza Góra record a polyphase lithospheric mantle evolution, starting with melting which extracted ca. 30% melt from the protolith and left a harzburgite residuum depleted in Al, lacking clinopyroxene and containing rare Cr-rich spinel. This residuum was later overprinted by chromatographic metasomatism by carbonated hydrous silicate melt related to Cenozoic volcanism. The metasomatic agent was locally hydrous enough to enable amphibole to crystallize. The Group C pyroxenites formed directly from the metasomatic melt or during peridotite-melt reactions at high melt-rock ratio. The melt is inferred to have percolated through the wall-rock peridotite, decreasing its amount and changing composition (and that of the crystallizing clinopyroxene and amphibole) as it differentiated chromatographically from Groups B to A. Enrichment in carbonatite component occurred in the further parts of a chromatographic column. Group B peridotites closest to the source of the metasomatic agent were percolated by an iron-rich melt. The latter, aside from crystallizing clinopyroxene and amphibole, caused Fe-enrichment in the host harzburgite. Such a metasomatic history is typical for the lithospheric mantle located beneath the northern margin of the Bohemian Massif, but Wilcza Góra is the only locality, where activity of a hydrous metasomatic agent is recorded. Thus, the lithospheric mantle in this area was affected by mafic silicate metasomatic agents of variable compositions.

A web service framework for astronomical remote observation in Antarctica by using satellite link

NASA Astrophysics Data System (ADS)

Jia, M.-h.; Chen, Y.-q.; Zhang, G.-y.; Jiang, P.; Zhang, H.; Wang, J.

2018-07-01

Many telescopes are deployed in Antarctica as it offers excellent astronomical observation conditions. However, because Antarctica's environment is harsh to humans, remote operation of telescope is necessary for observation. Furthermore, communication to devices in Antarctica through satellite link with low bandwidth and high latency limits the effectiveness of remote observation. This paper introduces a web service framework for remote astronomical observation in Antarctica. The framework is based on Python Tornado. RTS2-HTTPD and REDIS are used as the access interface to the telescope control system in Antarctica. The web service provides real-time updates through WebSocket. To improve user experience and control effectiveness under the poor satellite link condition, an agent server is deployed in the mainland to synchronize the Antarctic server's data and send it to domestic users in China. The agent server will forward the request of domestic users to the Antarctic master server. The web service was deployed and tested on Bright Star Survey Telescope (BSST) in Antarctica. Results show that the service meets the demands of real-time, multiuser remote observation and domestic users have a better experience of remote operation.

Prescription practice of biological drugs in rheumatoid arthritis during the first 3 years of post-marketing use in Denmark and Norway: criteria are becoming less stringent

PubMed Central

Hjardem, E; Hetland, M; Ostergaard, M; Krogh, N; Kvien, T

2005-01-01

Objective: To investigate changes in prescription practice during the first 3 years of post-marketing use of biological drugs, and to determine the proportion of patients who would not have received tumour necrosis factor (TNF) blocking agents if the prescription guidelines of the UK and the Netherlands had been applied. Methods: Patients with rheumatoid arthritis (RA) receiving TNF blocking agents from Denmark (n = 823, median age 56.0, 72.2% women) and Norway (n = 371, median age 52.5, 75.4% women) were studied. Prescription guidelines in the UK and the Netherlands were applied to the data. Results: Baseline disease activity and number of previous DMARDs declined significantly during the 3 years (median baseline DAS28 decreased from 5.8 to 5.2 in Denmark (p<0.001) and from 6.0 to 5.6 in Norway (p<0.01)). 47.9% and 41.3% of the Norwegian and Danish patients, respectively, did not meet the UK criteria for using TNF blocking agents, and 10.5% and 5.7% did not meet the Dutch criteria. Conclusion: Danish and Norwegian prescription practices of biological treatments in RA were similar, and became less stringent from 2000 to 2003. Prescriptions agreed well with the Dutch guidelines, but almost half the patients did not meet the UK guidelines. PMID:15640272

Bleaching agent action on color stability, surface roughness and microhardness of composites submitted to accelerated artificial aging.

PubMed

Rattacaso, Raphael Mendes Bezerra; da Fonseca Roberti Garcia, Lucas; Aguilar, Fabiano Gamero; Consani, Simonides; de Carvalho Panzeri Pires-de-Souza, Fernanda

2011-04-01

The purpose of this study was to evaluate the bleaching agent action on color stability, surface roughness and microhardness of composites (Charisma, Filtek Supreme and Heliomolar - A2) submitted to accelerated artificial aging (AAA). A Teflon matrix (12 x 2 mm) was used to fabricate 18 specimens (n=6) which, after polishing (Sof-Lex), were submitted to initial color reading (ΔE), Knoop microhardness (KHN) (50 g/15 s load) and roughness (R(a)) (cut-off 0.25 mm) tests. Afterwards, the samples were submitted to AAA for 384 hours and new color, microhardness and roughness readings were performed. After this, the samples were submitted to daily application (4 weeks) of 16% Carbamide Peroxide (NiteWhite ACP) for 8 hours and kept in artificial saliva for 16 hours. New color, microhardness and roughness readings were made at the end of the cycle, and 15 days after bleaching. Comparison of the ΔE means (2-way ANOVA, Bonferroni, P<.05) indicated clinically unacceptable color alteration for all composites after AAA, but without significant difference. Statistically significant increase in the KHN values after AAA was observed, but without significant alterations 15 days after bleaching. For R(a) there was no statistically significant difference after AAA and 15 days after bleaching. The alterations promoted by the bleaching agent and AAA are material dependent.

Using multiple pharmacoeconomic methods to conduct a cost-effectiveness analysis of histamine H2-receptor antagonists.

PubMed

McCoy, S; Blayney-Chandramouli, J; Mutnick, A

1998-12-15

A formulary decision at a health care institution was studied by using two pharmacoeconomic methods. A pharmacoeconomic study was undertaken to assess the impact of a 1995 formulary decision to designate cimetidine as the primary histamine H2-receptor antagonist (H2RA) and to restrict the use of famotidine. Consecutive patients receiving either i.v. cimetidine or famotidine for stress ulcer prophylaxis were reviewed during a two-month period in 1997, and information on demographics, dosage and duration of H2RA therapy, admission date, laboratory test values, and adverse drug reactions was collected. Data for 62 patients (43 cimetidine recipients and 19 famotidine recipients) were evaluated. Therapy was categorized as successful or failed, and the data were then evaluated by decision analysis to evaluate the cost-effectiveness of the agents and by multiattribute utility theory (MAUT) to incorporate a humanistic evaluation of the treatments, namely, the number of doses administered and the number of times dosages were changed. The decision tree revealed that the average cost of receiving cimetidine was $82.01 and the average cost of famotidine therapy was $92.45. The MAUT analysis showed that cimetidine was the preferred agent as long as cost was valued at greater than 60% of the decision-making process and efficacy remained equal between the two agents. Two pharmacoeconomic methods lent support to a formulary decision at a health care institution.

Low plasma levels of cholecalciferol and 13-cis-retinoic acid in tuberculosis: implications in host-based chemotherapy.

PubMed

Srinivasan, Anand; Syal, Kirtimaan; Banerjee, Dibyajyoti; Hota, Debasish; Gupta, Dheeraj; Kaul, Deepak; Chakrabarti, Amitava

2013-10-01

The aim of this study was to estimate the concentration of cholecalciferol and 13-cis-retinoic acid (RA) in the plasma and pleural fluid of patients with tuberculosis (TB) against controls. Plasma levels of cholecalciferol and 13-cis-RA were measured in 22 patients with TB and healthy controls and their pleural fluids levels were measured in 6 TB patients and diseased controls by established high-performance liquid chromatography-based procedure. Cholecalciferol levels in plasma and pleural fluid of patients with TB and healthy controls were 67.45 (10.71) nmol/L and 21.40 (8.58) nmol/L compared with 117.43 (18.40) nmol/L (P < 0.001) and 94.73 (33.34) nmol/L (P = 0.0049), respectively. 13-cis-RA level in the plasma of patients with TB and healthy controls were 1.51 (0.72) nmol/L and 6.67 (0.81) nmol/L (P < 0.001), respectively. 13-cis-RA was not detectable in pleural fluid. The levels of both the agents were lower in patients with TB than in controls. It was observed that in patients with TB there is a combined deficiency of cholecalciferol and 13-cis-RA compared with healthy volunteers. Because cholecalciferol and 13-cis-RA are in equilibrium with active ingredients of vitamins A and D, we feel that there is a combined deficiency of these vitamins in patients with TB. There is an evidence that concomitant vitamin A and D supplementation can kill intracellular Mycobacterium tuberculosis in vitro. Therefore, the observations made in this study can pave the path for a trial of combined supplementation of available formulations of vitamin A and D (cholecalciferol and 13-cis-RA) for novel anti-tubercular drug therapy. Because such an approach is host-based it has potential to treat even multidrug-resistant and extensively drug-resistant forms of TB. Copyright © 2013 Elsevier Inc. All rights reserved.

A Novel Highly Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis Patients: A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group Study.

PubMed

Amalraj, Augustine; Varma, Karthik; Jacob, Joby; Divya, Chandradhara; Kunnumakkara, Ajaikumar B; Stohs, Sidney J; Gopi, Sreeraj

2017-10-01

Rheumatoid arthritis (RA) is an autoimmune, chronic systemic inflammatory disorder. The long-term use of currently available drugs for the treatment of RA has many potential side effects. Natural phytonutrients may serve as alternative strategies for the safe and effective treatment of RA, and curcuminoids have been used in Ayurvedic medicine for the treatment of inflammatory conditions for centuries. In this study, a novel, highly bioavailable form of curcumin in a completely natural turmeric matrix was evaluated for its ability to improve the clinical symptoms of RA. A randomized, double-blind, placebo-controlled, three-arm, parallel-group study was conducted to evaluate the comparative efficacy of two different doses of curcumin with that of a placebo in active RA patients. Twelve patients in each group received placebo, 250 or 500 mg of the curcumin product twice daily for 90 days. The responses of the patients were assessed using the American College of Rheumatology (ACR) response, visual analog scale (VAS), C-reactive protein (CRP), Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) values. RA patients who received the curcumin product at both low and high doses reported statistically significant changes in their clinical symptoms at the end of the study. These observations were confirmed by significant changes in ESR, CPR, and RF values in patients receiving the study product compared to baseline and placebo. The results indicate that this novel curcumin in a turmeric matrix acts as an analgesic and anti-inflammatory agent for the management of RA at a dose as low as 250 mg twice daily as evidenced by significant improvement in the ESR, CRP, VAS, RF, DAS28, and ACR responses compared to placebo. Both doses of the study product were well tolerated and without side effects.

Silver Nanoparticles: Two-Faced Neuronal Differentiation-Inducing Material in Neuroblastoma (SH-SY5Y) Cells.

PubMed

Abdal Dayem, Ahmed; Lee, Soo Bin; Choi, Hye Yeon; Cho, Ssang-Goo

2018-05-15

We have previously demonstrated the potential of biologically synthesized silver nanoparticles (AgNP) in the induction of neuronal differentiation of human neuroblastoma, SH-SY5Y cells; we aimed herein to unveil its molecular mechanism in comparison to the well-known neuronal differentiation-inducing agent, all-trans-retinoic acid (RA). AgNP-treated SH-SY5Y cells showed significantly higher reactive oxygen species (ROS) generation, stronger mitochondrial membrane depolarization, lower dual-specificity phosphatase expression, higher extracellular-signal-regulated kinase (ERK) phosphorylation, lower AKT phosphorylation, and lower expression of the genes encoding the antioxidant enzymes than RA-treated cells. Notably, pretreatment with N -acetyl-l-cysteine significantly abolished AgNP-induced neuronal differentiation, but not in that induced by RA. ERK inhibition, but not AKT inhibition, suppresses neurite growth that is induced by AgNP. Taken together, our results uncover the pivotal contribution of ROS in the AgNP-induced neuronal differentiation mechanism, which is different from that of RA. However, the negative consequence of AgNP-induced neurite growth may be high ROS generation and the downregulation of the expression of the genes encoding the antioxidant enzymes, which prompts the future consideration and an in-depth study of the application of AgNP-differentiated cells in neurodegenerative disease therapy.

The effect of differentiation agents on inflammatory and oxidative responses of the human neuroblastoma cell line SK-N-SH.

PubMed

Niewiarowska-Sendo, Anna; Patrzalek, Katarzyna; Kozik, Andrzej; Guevara-Lora, Ibeth

2015-01-01

Obtaining a suitable experimental cellular model is a major problem for neuroscience studies. Neuroblastoma cell lines have been often applied in studies related to pathological disorders of nervous system. However, in the search for an ideal model, these cells must be differentiated to cancel their tumor character. The subsequent reactions that are caused by differentiation are not always indifferent to the same model. We evaluated the effect of two well known substances, used for SH-N-SK cell line differentiation, retinoic acid (RA) and phorbol-12-myristate-13-acetate (PMA), on the induction of pro-inflammatory and pro-oxidative reactions in these cells. Cells differentiated with PMA were able to produce significantly higher amounts of pro-inflammatory cytokines whereas the release of nitric oxide radicals was similar to that in undifferentiated cells. On the contrary, in RA-differentiated cells no significant changes in cytokine production were observed and the nitric oxide release was decreased. Additionally, the RA-differentiated neuronal model was more sensible to lipopolysaccharide stimulation, producing pro-inflammatory cytokines abundantly. These results suggest that RA-differentiated SH-N-SK cells provide a more suitable experimental model for the study of molecular and cellular mechanisms of the inflammation and oxidative stress in neuronal cells.

Identification and suppression of epidermal growth factor receptor variant III signaling in fibroblast-like synoviocytes from aggressive rheumatoid arthritis by the mimotope.

PubMed

Niu, Jianying; Li, Changhong; Jin, Yinji; Xing, Rui; Sun, Lin; Yu, Ruohan; Jian, Leilei; Liu, Xiangyuan; Yang, Lin

2018-06-01

Epidermal growth factor receptor (EGFR) signaling has been reported to play a vital role in the pathogenesis of rheumatoid arthritis (RA). In current study, we sought to observe whether the active immunization induced by the mimotope could recognize EGFR, inhibit their signaling and disrupt the pathogenic behavior of fibroblast-like synoviocytes (FLS) from RA patients. We prepared a linked EGFR mimotope and performed series of experiments to detect whether the mimotope could induce the desired immune responses. To our surprises, we detected the expression of EGFR variant III (EGFRvIII), but not EGFR in the synovial tissues and FLS from patients with aggressive RA by the linked EGFR mimotope-induced antibodies (LEMIA). Meanwhile, LEMIA could inhibit the signaling caused by the autophosphorylation of EGFRvIII in the FLS. The proliferation, migration, invasion and anti-apoptosis capabilities of the EGFRvIII-expressed FLS were disrupted by LEMIA. These results suggest that EGFRvIII signaling may participate in the malignant behaviors of FLS from aggressive RA. Meanwhile, the linked EGFR mimotope could be used to detect the expression of EGFRvIII and developed to be a potential therapy agent against the aggressive FLS. Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Synergistic induction of 1,25-dihydroxyvitamin D(3)- and all-trans-retinoic acid-induced differentiation of HL-60 leukemia cells by yomogin, a sesquiterpene lactone from Artemisia princeps.

PubMed

Kim, Seung Hyun; Kim, Tae Sung

2002-10-01

Many anti-inflammatory agents are known to significantly enhance the terminal differentiation of some cancer cells such as leukemia cells. In this study, the effect of yomogin, a eudesmane sesquiterpene lactone isolated from Artemisia princeps with anti-inflammatory activity, was investigated in human promyelocytic leukemia HL-60 cells. Yomogin by itself induced small increases in cell differentiation, with less than 19 % of the cells attaining a differentiated phenotype. Importantly, yomogin synergistically enhanced differentiation of HL-60 cells in a dose-dependent manner when combined with either 5 nM 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2) D(3)] or 50 nM all- trans retinoic acid (all- trans RA). Cytofluorometric analysis and morphologic studies indicated that the combinations of yomogin and 1,25-(OH)(2) D(3) stimulated differentiation to monocytes whereas the combinations of yomogin and all- trans RA stimulated differentiation to granulocytes. These results suggest that yomogin may be useful in combination with 1,25-(OH)(2) D(3) or all- trans-RA in the differentiation therapy for myeloid leukemias. Abbreviations. 1,25-(OH)(2) D(3) :1,25-dihydroxyvitamin D(3) FITC:fluorescein isothiocyanate NBT:nitroblue tetrazolium RA:retinoic acid PE:phytoerythrin

Sexually transmitted diseases of the anus and rectum: Causal agents, coinfections, HIV infection and high-risk sexual behaviour.

PubMed

Morgado-Carrasco, Daniel; Alsina Gibert, Mercè; Bosch Mestres, Jordi; Álvarez Martínez, Miriam; Blanco Arévalo, José Luís; Fuertes de Vega, Irene

2018-04-18

Sexually transmitted infections of the rectum and anus (STI-RA) mainly affect men who have sex with men (MSM). The incidence of STI-RA among them has increased in recent years. Retrospective study in patients with diagnoses of STI-RA in an STI unit during the years 2014 and 2015. Epidemiological, clinical and microbiological data were collected. We included 95 patients, all of whom were MSM; 88.42% were HIV+; 67.17% did not use a condom during their most recent sexual intercourse; 17.91% had had sex with sex workers and 72.22% had used drugs during sexual intercourse during the previous year. A percentage of 32.92 reported symptoms that had lasted longer than 30 days. Lymphogranuloma venereum (LGV) was diagnosed in 54.73% of the patients. All patients who presented with proctitis and perianal ulcers were diagnosed with LGV infection. All those who presented perianal ulcers without proctitis were diagnosed with syphilis. All the patients affected by STI-RA were MSM, most of them HIV+, had engaged in high-risk sexual behaviour and had suffered prolonged symptomatology. Clinical and microbiological characteristics of STI-AR could help adjust the empiric therapy. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

Human and Computer Control of Undersea Teleoperators

DTIC Science & Technology

1978-07-15

j ’Al.• /i•.f IAII•lU•I .p.ra i- . AWL• u~/K ftI&i. . .................... L HUMAN AND COMPUTER CONTROL / OF UNDERSEA TELEOPERATORS, .9 . - - I... UNDERSEA TELEOPERATORS 15 Mar 1977-14 June 1978 6. PERFORMING ORO. REPORT NUMBER,- J ". AUTHOR(e) S. CONTRACT OR GRANT NUMBER(*) Thomas B. Sheridan and...y ad Identify by block >w his is a review of factors p ertaining to man-machine interaction in remote control of undersea vehicles, especially their

Efficacy of some colloidal silver preparations and silver salts against Proteus bacteria, one possible cause of rheumatoid arthritis.

PubMed

Disaanayake, D M B T; Faoagali, Joan; Laroo, Hans; Hancock, Gerald; Whitehouse, Michael

2014-04-01

There has been increased interest in the role of anti-Proteus antibodies in the aetiology of rheumatoid arthritis (RA) and whether chemotherapeutic agents active against Proteus species might reduce the risk and/or exacerbations of RA. We examined the in vitro antibacterial effects of ten different silver preparations which were either ionic silver [Ag(I)] solutions or nanoparticulate silver (NPS) (Ag(0)) suspensions against ATCC and two wild (clinical) strains of Proteus. The data establish the low minimum inhibitory concentration and minimum bactericidal concentration of all the silver formulations tested against these four Proteus strains. In a pilot study, a potent NPS preparation ex vivo showed long-lasting anti-Proteus activity in a normal human volunteer.

LASER CAPTURE MICRODISSECTION AND GENE ARRAY ANALYSIS OF PALATAL EPITHELIAL AND MESENCHYMAL CELLS EXPOSED TO TCDD

EPA Science Inventory

Palatal shelves from embryos exposed on gestation day (GD) 12 to either retinoic acid (RA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) contact but fail to fuse. It is of interest to know if diverse agents that induce clefting via the same etiology also activate the same biochem...

Controlled teleportation of an arbitrary n-qubit quantum information using quantum secret sharing of classical message

NASA Astrophysics Data System (ADS)

Zhang, Zhan-Jun

2006-03-01

I present a scheme which allows an arbitrary 2-qubit quantum state teleportation between two remote parties with control of many agents in a network. Comparisons between the present scheme and the existing scheme proposed recently [F.G. Deng, et al., Phys. Rev. A 72 (2005) 022338] are made. It seems that the present scheme is much simpler and more economic. Then I generalize the scheme to teleport an arbitrary n-qubit quantum state between two remote parties with control of agents in a network.

Deterministic Teleportation of Multi-qudit States in a Network via Various Probabilistic Channels

NASA Astrophysics Data System (ADS)

Zhang, Ti-Hang; Jiang, Min; Huang, Xu; Wan, Min

2014-04-01

In this paper, we present a generalized approach to faithfully teleport an unknown state of a multi-qudit system involving multi spatially remote agents via various probabilistic channels. In a quantum teleportation network, there are generally multi spatially remote relay agents between a sender and a distant receiver. With the assistance of the relay agents, it is possible to directly construct a deterministic channel between the sender and the distant receiver. In our scheme, different from previous probabilistic teleportation protocols, the integrity of the unknown multi-qudit state could be maintained even when the construction of faithful channel fails. Our results also show that the required auxiliary particle resources, local operations and classical communications are considerably reduced for the present purpose.

Ambient agents: embedded agents for remote control and monitoring using the PANGEA platform.

PubMed

Villarrubia, Gabriel; De Paz, Juan F; Bajo, Javier; Corchado, Juan M

2014-07-31

Ambient intelligence has advanced significantly during the last few years. The incorporation of image processing and artificial intelligence techniques have opened the possibility for such aspects as pattern recognition, thus allowing for a better adaptation of these systems. This study presents a new model of an embedded agent especially designed to be implemented in sensing devices with resource constraints. This new model of an agent is integrated within the PANGEA (Platform for the Automatic Construction of Organiztions of Intelligent Agents) platform, an organizational-based platform, defining a new sensor role in the system and aimed at providing contextual information and interacting with the environment. A case study was developed over the PANGEA platform and designed using different agents and sensors responsible for providing user support at home in the event of incidents or emergencies. The system presented in the case study incorporates agents in Arduino hardware devices with recognition modules and illuminated bands; it also incorporates IP cameras programmed for automatic tracking, which can connect remotely in the event of emergencies. The user wears a bracelet, which contains a simple vibration sensor that can receive notifications about the emergency situation.

Ambient Agents: Embedded Agents for Remote Control and Monitoring Using the PANGEA Platform

PubMed Central

Villarrubia, Gabriel; De Paz, Juan F.; Bajo, Javier; Corchado, Juan M.

2014-01-01

Ambient intelligence has advanced significantly during the last few years. The incorporation of image processing and artificial intelligence techniques have opened the possibility for such aspects as pattern recognition, thus allowing for a better adaptation of these systems. This study presents a new model of an embedded agent especially designed to be implemented in sensing devices with resource constraints. This new model of an agent is integrated within the PANGEA (Platform for the Automatic Construction of Organiztions of Intelligent Agents) platform, an organizational-based platform, defining a new sensor role in the system and aimed at providing contextual information and interacting with the environment. A case study was developed over the PANGEA platform and designed using different agents and sensors responsible for providing user support at home in the event of incidents or emergencies. The system presented in the case study incorporates agents in Arduino hardware devices with recognition modules and illuminated bands; it also incorporates IP cameras programmed for automatic tracking, which can connect remotely in the event of emergencies. The user wears a bracelet, which contains a simple vibration sensor that can receive notifications about the emergency situation. PMID:25090416

[Investigation of Epstein-Barr virus and herpes simplex virus markers by serological and molecular methods in patients with rheumatoid arthritis and systemic lupus erythematosus].

PubMed

Us, Tercan; Cetin, Esin; Kaşifoğlu, Nilgün; Kaşifoğlu, Timuçin; Akgün, Yurdanur

2011-10-01

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) which are autoimmune diseases usually questioned for their association with many infectious agents have etiopathogenesis related to genetic, immunologic, hormonal and even environmental factors. The most commonly attributed etiologic agents are herpes group viruses. The aim of this study was to investigate the role of Epstein-Barr virus (EBV) and herpes simplex (HSV) viruses in the etiology of RA and SLE. A total of 137 patients (87 RA and 50 SLE; mean age: 33 ± 12 years) who were admitted to Eskisehir Osmangazi University Medical Faculty Rheumatology Department between January 2007-January 2008 and diagnosed according to 1987 ACR (American College of Rheumatology) criteria have been included in the study, together with 50 healthy blood donors (mean age: 35 ± 14 years) as control group. Serum samples obtained from all of the cases were tested for EBV VCA-IgG, VCA-IgM, EA/D-IgG and EBNA-IgG (Trinity Biotech, USA); IgM and IgG antibodies against HSV-1 and HSV-2 by ELISA method (Dia-Pro Diagnostic, Italy), and the presence of viral nucleic acids in blood samples were investigated by real-time quantitative polymerase chain reaction (RTPCR; Qiagen, USA). EBV VCA-IgM was negative in all of the RA, SLE and control group patients. VCA-IgG positivity were 98% and 96%, and for EBNA-IgG 98.5% and 100%, in patient and control groups, respectively. There was no statistically significant difference between the groups regarding VCA-IgG and EBNA- IgG positivity (p> 0.05). On the other hand, EBV EA/D-IgG positivity rate found in the SLE group (34%) was significantly higher than RA (7%) and control (12%) groups (p< 0.001 and p< 0.05, respectively). There was no significant difference between RA and control groups in terms of EA/D-IgG positivity (p> 0.05). Regarding herpes simplex virus serology, HSV1-IgG seropositivity were 99% and 94% and HSV2-IgG positivity were 8% and 12% in the patient and control groups, respectively. There was no statistically significant difference between the groups according to the positivity rates of IgM and IgG specific for HSV-1 and HSV-2 (p> 0.05). All of the cases were found negative in terms of EBV, HSV-1 and HSV- 2 DNAs according to double-checked RT-PCR results. In conclusion, no significant difference was determined for EBV and HSV serologic markers in RA and SLE patients compared to the control group. However, significantly higher rate of EBV EA/D-IgG positivity in SLE patients might have indicated a possible association between SLE and EBV infection. Larger scale, prospective studies including examination of the synovial fluid/tissue samples are required to enlighten the association between SLE and EBV.

Remote detection of chem/bio hazards via coherent anti-Stokes Raman spectroscopy

DTIC Science & Technology

2017-09-12

hour per response, including the time for reviewing lnstnJctions, searching existing data sources, gathering and maintaining the data needed, and... time remote detection of hazardous microparticles in atmosphere and to evaluate the range of distances for typical species and the parameters of laser...detectable photons from a prototype molecule at a distance. 1S. SUBJECT TERMS Stimulated Raman scattering, Remote detection, biochemical agents, explosives

Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study.

PubMed

Sokka, Tuulikki; Toloza, Sergio; Cutolo, Maurizio; Kautiainen, Hannu; Makinen, Heidi; Gogus, Feride; Skakic, Vlado; Badsha, Humeira; Peets, Tõnu; Baranauskaite, Asta; Géher, Pál; Ujfalussy, Ilona; Skopouli, Fotini N; Mavrommati, Maria; Alten, Rieke; Pohl, Christof; Sibilia, Jean; Stancati, Andrea; Salaffi, Fausto; Romanowski, Wojciech; Zarowny-Wierzbinska, Danuta; Henrohn, Dan; Bresnihan, Barry; Minnock, Patricia; Knudsen, Lene Surland; Jacobs, Johannes Wg; Calvo-Alen, Jaime; Lazovskis, Juris; Pinheiro, Geraldo da Rocha Castelar; Karateev, Dmitry; Andersone, Daina; Rexhepi, Sylejman; Yazici, Yusuf; Pincus, Theodore

2009-01-01

Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA). The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents. Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies. In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.

Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study

PubMed Central

Sokka, Tuulikki; Toloza, Sergio; Cutolo, Maurizio; Kautiainen, Hannu; Makinen, Heidi; Gogus, Feride; Skakic, Vlado; Badsha, Humeira; Peets, Tõnu; Baranauskaite, Asta; Géher, Pál; Újfalussy, Ilona; Skopouli, Fotini N; Mavrommati, Maria; Alten, Rieke; Pohl, Christof; Sibilia, Jean; Stancati, Andrea; Salaffi, Fausto; Romanowski, Wojciech; Zarowny-Wierzbinska, Danuta; Henrohn, Dan; Bresnihan, Barry; Minnock, Patricia; Knudsen, Lene Surland; Jacobs, Johannes WG; Calvo-Alen, Jaime; Lazovskis, Juris; Pinheiro, Geraldo da Rocha Castelar; Karateev, Dmitry; Andersone, Daina; Rexhepi, Sylejman; Yazici, Yusuf; Pincus, Theodore

2009-01-01

Introduction Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA). Methods The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents. Results Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies. Conclusions In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself. PMID:19144159

Brief Report: Risk of Gastrointestinal Perforation Among Rheumatoid Arthritis Patients Receiving Tofacitinib, Tocilizumab, or Other Biologic Treatments.

PubMed

Xie, Fenglong; Yun, Huifeng; Bernatsky, Sasha; Curtis, Jeffrey R

2016-11-01

To evaluate gastrointestinal (GI) perforation in rheumatoid arthritis (RA) patients receiving tofacitinib, tocilizumab, or other biologic agents. Using health plan data from 2006 through 2014, RA patients without prior GI perforation were identified. Those in whom treatment with tofacitinib or a biologic agent was being initiated were followed up for incident GI perforation with hospitalization. Crude incidence rates were calculated by exposure. Adjusted Cox proportional hazards models were used to evaluate the association between GI perforation and exposures. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated. A cohort of 167,113 RA patients was analyzed. Among them, 4,755 began treatment with tofacitinib, 11,705 with tocilizumab, 115,047 with a tumor necrosis factor inhibitor (TNFi), 31,214 with abatacept, and 4,392 with rituximab. Compared to TNFi recipients, abatacept recipients were older, tofacitinib and rituximab recipients were younger, and tocilizumab recipients were similar in age. Patients beginning treatment with a non-TNFi agent were more likely to have previously received biologic agents than patients beginning treatment with a TNFi. The incidence of GI perforation per 1,000 patient-years was 0.86 (tofacitinib), 1.55 (tocilizumab), 1.07 (abatacept), 0.73 (rituximab), and 0.83 (TNFi). Most perforations occurred in the lower GI tract: the incidence of lower GI tract perforation per 1,000 patient-years was 0.86 (tofacitinib), 1.26 (tocilizumab), 0.76 (abatacept), 0.48 (rituximab), and 0.46 (TNFi). Lower GI tract perforation risk was significantly elevated with tocilizumab treatment, and numerically elevated with tofacitinib treatment, versus treatment with TNFi. Adjusted HRs were 2.51 (95% CI 1.31-4.80) for tocilizumab and 1.94 (95% CI 0.49-7.65) for tofacitinib. Older age (HR 1.16 per 5 years [95% CI 1.10-1.22]), diverticulitis/other GI conditions (HR 3.25 [95% CI 1.62-6.50]), and prednisone use at >7.5 mg/day (HR 2.29 [95% CI 1.39-3.78]) were associated with lower GI tract perforation. The incidence of upper GI tract perforation was similar among all drug exposures. The risk of lower GI tract perforation associated with tocilizumab treatment, and possibly tofacitinib treatment, is elevated compared to that associated with TNF blockade. © 2016, American College of Rheumatology.

Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials.

PubMed

Mabilleau, Guillaume; Mieczkowska, Aleksandra; Chappard, Daniel

2014-05-01

Patients with type 2 diabetes mellitus (T2DM) are at a higher risk of bone fractures independent of the use of antidiabetic medications. Furthermore, antidiabetic medications could directly affect bone metabolism. Recently, the use of dipeptidyl peptidase-4 inhibitors has been associated with a lower rate of bone fracture. The aim of the present meta-analysis was to assess whether patients with T2DM treated with glucagon-like peptide-1 receptor agonists (GLP-1Ra) present a lower incidence of bone fracture compared with patients using other antidiabetic drugs. A search on Medline, Embase, and http://www.clinicaltrials.gov, as well as a manual search for randomized clinical trials of T2DM treated with either a GLP-1Ra or another antidiabetic drug for a duration of ≥24 weeks was conducted by two authors (GM, AM) independently. Although 28 eligible studies were identified, only seven trials reported the occurrence of at least a bone fracture in one arm of the trial. The total number of fractures was 19 (13 and six with GLP-1Ra and comparator, respectively). The pooled Mantel-Haenszel odds ratio for GLP-1Ra was 0.75 (95% confidence interval 0.28-2.02, P = 0.569) in trials versus other antidiabetic agents. Although preliminary, our study highlighted that the use of GLP-1Ra does not modify the risk of bone fracture in T2DM compared with the use of other antidiabetic medications. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Underestimation of the efficacy, effectiveness, tolerability, and safety of weekly low-dose methotrexate in information presented to physicians and patients.

PubMed

Pincus, T; Furer, V; Sokka, T

2010-01-01

Ten specific examples of the underestimation of the efficacy, effectiveness and tolerability, and overestimation of adverse events of weekly, low-dose methotrexate, administered with folic acid, in treatment of rheumatic diseases are summarised. These examples include: 1) meta-analyses of clinical trials suggest that methotrexate has an efficacy similar to other disease-modifying anti-rheumatic drugs (DMARDs); 2) information in textbooks and websites may overstate adverse events and drug interactions associated with weekly low-dose methotrexate; 3) information presented to patients when filling a prescription for methotrexate understates 'side effects' of RA and overstates those of methotrexate; 4) an admonition to patients to refrain entirely from consumption of alcohol while taking methotrexate may be unnecessary; 5) frequent blood testing in patients who take methotrexate may be overused; 6) eligibility of only a small minority of patients for clinical trials to compare biologic agents and methotrexate; 7) Step-up design in most comparisons of biologic agents with methotrexate includes only patients who had experienced an incomplete response to methotrexate; 8) in parallel design trials, the efficacy of biologic agents is not substantially greater than that of methotrexate; 9) low, inflexible dosage schedules of methotrexate and requirement for withdrawal with minimal liver function abnormalities in many clinical trials may underestimate efficacy, effectiveness, tolerability and safety; 10) interpretation of clinical trial results may overstate the clinical significance of lower radiographic progression in patients treated with biologic agents versus patients treated with methotrexate. More accurate interpretation of information for physicians and other health professionals, as well as patients, concerning use of weekly low-dose methotrexate in contemporary care could improve care and outcomes for patients with RA and other rheumatic diseases.

Medical therapy is best for atherosclerotic renal artery stenosis: Arguments for.

PubMed

Annigeri, R A

2012-01-01

Atherosclerotic renal artery stenosis (ARAS) is a common condition that causes hypertension and reduction in the glomerular filtration rate and is an independent risk factor for death. Despite high technical success, the clinical benefit of renal artery (RA) angioplasty with stenting in ARAS remains doubtful. The published randomized clinical trials provide no support for the notion that renal angioplasty with stenting significantly improves blood pressure, preserves renal function, or reduces episodes of congestive heart failure in patients with ARAS. RA stenting is associated with procedure-related morbidity and mortality. Agents to block the renin-angiotensin-aldosterone system improve outcome and should be a part of a multifaceted medical regimen in ARAS. Medical therapy effectively controls atherosclerotic renovascular disease at all levels of vasculature and hence is the best therapy for ARAS.

[The reentrant binomial model of nuclear anomalies growth in rhabdomyosarcoma RA-23 cell populations under increasing doze of rare ionizing radiation].

PubMed

Alekseeva, N P; Alekseev, A O; Vakhtin, Iu B; Kravtsov, V Iu; Kuzovatov, S N; Skorikova, T I

2008-01-01

Distributions of nuclear morphology anomalies in transplantable rabdomiosarcoma RA-23 cell populations were investigated under effect of ionizing radiation from 0 to 45 Gy. Internuclear bridges, nuclear protrusions and dumbbell-shaped nuclei were accepted for morphological anomalies. Empirical distributions of the number of anomalies per 100 nuclei were used. The adequate model of reentrant binomial distribution has been found. The sum of binomial random variables with binomial number of summands has such distribution. Averages of these random variables were named, accordingly, internal and external average reentrant components. Their maximum likelihood estimations were received. Statistical properties of these estimations were investigated by means of statistical modeling. It has been received that at equally significant correlation between the radiation dose and the average of nuclear anomalies in cell populations after two-three cellular cycles from the moment of irradiation in vivo the irradiation doze significantly correlates with internal average reentrant component, and in remote descendants of cell transplants irradiated in vitro - with external one.

Remote sensing and GIS techniques for assessment of the soil water content in order to improve agricultural practice and reduce the negative impact on groundwater: case study, agricultural area Ştefan cel Mare, Călăraşi County.

PubMed

Tevi, Giuliano; Tevi, Anca

2012-01-01

Traditional agricultural practices based on non-customized irrigation and soil fertilization are harmful for the environment, and may pose a risk for human health. By continuing the use of these practices, it is not possible to ensure effective land management, which might be acquired by using advanced satellite technology configured for modern agricultural development. The paper presents a methodology based on the correlation between remote sensing data and field observations, aiming to identify the key features and to establish an interpretation pattern for the inhomogeneity highlighted by the remote sensing data. Instead of using classical methods for the evaluation of land features (field analysis, measurements and mapping), the approach is to use high resolution multispectral and hyperspectral methods, in correlation with data processing and geographic information systems (GIS), in order to improve the agricultural practices and mitigate their environmental impact (soil and shallow aquifer).

Penile angioedema developing after 3 years of ACEI therapy.

PubMed

Miller, Daniel G; Sweis, Rolla T; Toerne, Theodore S

2012-08-01

Angiotensin-converting enzyme inhibitor-related angioedema (ACEI-RA) is a well-described condition, yet isolated genital ACEI-RA is a little-known entity. A case of isolated genital angioedema is presented with photographic documentation. Possible complications and therapeutic options are discussed. A 71-year-old man presented with painless, nonpruritic genital swelling of 4 h duration. Medical history included peptic ulcer disease, hypertension, and benign prostatic hypertrophy. His medications included pantoprazole, hydrochlorothiazide, and lisinopril, which he had been taking for 3 years without any recent change in dosing. He was otherwise asymptomatic and previously had been in good health generally. The physical examination was positive only for diffuse, soft, nonpitting edema isolated to the scrotum and uncircumcised penis. The foreskin was only partially retractable. Urinalysis was normal. All symptoms resolved without complications within 48 h of discontinuing lisinopril and had not recurred at follow-up 4 months later. All cases of ACEI-RA isolated to the genitals that have been reported in the literature resolved without complications. ACEI-RA can present as isolated swelling of the genitals and is a potential cause of genital swelling. Patients who have no evidence of airway compromise, paraphimosis, or urinary retention from complications such as phimosis can be safely discharged with instructions to discontinue the offending agent and to return in case of development of the aforementioned conditions. Published by Elsevier Inc.

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma

PubMed Central

Mir, Muhammad A.; Maurer, Matthew J.; Ziesmer, Steven C.; Slager, Susan L.; Habermann, Thomas; Macon, William R.; Link, Brian K.; Syrbu, Sergei; Witzig, Thomas; Friedberg, Jonathan W.; Press, Oliver; LeBlanc, Michael; Cerhan, James R.; Novak, Anne

2015-01-01

Serum cytokines and chemokines may reflect tumor biology and host response in follicular lymphoma (FL). To determine whether the addition of these biological factors may further refine prognostication, 30 cytokines and chemokines were measured in pretreatment serum specimens from newly diagnosed FL patients (n = 209) and from 400 matched controls. Cytokine levels were correlated with clinical outcome in patients who were observed or received single agent rituximab, or those who received chemotherapy. Correlations with outcome in chemotherapy treated patients were further examined in a separate cohort of 183 South West Oncology Group (SWOG) patients and all patients were then included in a meta-analysis. Six cytokines were associated with outcome in the Molecular Epidemiology Resource (MER) after adjusting for the FL international prognostic index. In patients who were observed or treated with rituximab alone, increased serum IL-12 and interleukin 1 receptor antagonist (IL-1RA) (P = .005 and .02) were associated with a shorter event-free survival. In patients receiving chemotherapy, hepatocyte growth factor, IL-8, IL-1RA, and CXCL9 (P = .015, .048, .004, and .0005) predicted a shorter EFS. When the MER chemotherapy treated patients and SWOG patients were combined in a meta-analysis, IL-2R, IL-1RA, and CXCL9 (P = .013, .042, and .0012) were associated with a poor EFS. PMID:25422100

PML–RARA-RXR Oligomers Mediate Retinoid and Rexinoid/cAMP Cross-Talk in Acute Promyelocytic Leukemia Cell Differentiation

PubMed Central

Kamashev, Dmitrii; Vitoux, Dominique; de Thé, Hugues

2004-01-01

PML–RARA was proposed to initiate acute promyelocytic leukemia (APL) through PML–RARA homodimer–triggered repression. Here, we examined the nature of the PML–RARA protein complex and of its DNA targets in APL cells. Using a selection/amplification approach, we demonstrate that PML–RARA targets consist of two AGGTCA elements in an astonishing variety of orientations and spacings, pointing to highly relaxed structural constrains for DNA binding and identifying a major gain of function of this oncogene. PML–RARA-specific response elements were identified, which all conveyed a major transcriptional response to RA only in APL cells. In these cells, we demonstrate that PML–RARA oligomers are complexed to RXR. Directly probing PML–RARA function in APL cells, we found that the differentiation enhancer cyclic AMP (cAMP) boosted transcriptional activation by RA. cAMP also reversed the normal silencing (subordination) of the transactivating function of RXR when bound to RARA or PML–RARA, demonstrating that the alternate rexinoid/cAMP-triggered APL differentiation pathway also activates PML–RARA targets. Finally, cAMP restored both RA-triggered differentiation and PML–RARA transcriptional activation in mutant RA-resistant APL cells. Collectively, our findings directly demonstrate that APL cell differentiation parallels transcriptional activation through PML–RARA-RXR oligomers and that those are functionally targeted by cAMP, identifying this agent as another oncogene-targeted therapy. PMID:15096541

MRA_1571 is required for isoleucine biosynthesis and improves Mycobacterium tuberculosis H37Ra survival under stress

PubMed Central

Sharma, Rishabh; Keshari, Deepa; Singh, Kumar Sachin; Yadav, Shailendra; Singh, Sudheer Kumar

2016-01-01

Threonine dehydratase is a pyridoxal 5-phosphate dependent enzyme required for isoleucine biosynthesis. Threonine dehydratase (IlvA) participates in conversion of threonine to 2-oxobutanoate and ammonia is released as a by-product. MRA_1571 is annotated to be coding for IlvA in Mycobacterium tuberculosis H37Ra (Mtb-Ra). We developed a recombinant (KD) Mtb-Ra strain by down-regulating IlvA. The growth studies on different carbon sources suggested reduced growth of KD compared to wild-type (WT), also, isoleucine concentration dependent KD growth restoration was observed. The expression profiling of IlvA suggested increased expression of IlvA during oxygen, acid and oxidative stress. In addition, KD showed reduced survival under pH, starvation, nitric oxide and peroxide stresses. KD was more susceptible to antimycobacterial agents such as streptomycin (STR), rifampicin (RIF) and levofloxacin (LVF), while, no such effect was noticeable when exposed to isoniazid. Also, an increase in expression of IlvA was observed when exposed to STR, RIF and LVF. The dye accumulation studies suggested increased permeability of KD to ethidium bromide and Nile Red as compared to WT. TLC and Mass studies confirmed altered lipid profile of KD. In summary down-regulation of IlvA affects Mtb growth, increases its susceptibility to stress and leads to altered cell wall lipid profile. PMID:27353854

[Current concepts of pharmacotherapy in rheumatoid arthritis].

PubMed

Balabanova, R M

2003-01-01

Although there were essential achievements in understanding the pathogenesis of rheumatoid arthritis (RA), the mentioned pathologies still remain one of the most complicated problems in practical medicine. Rheumatologists arrived, during the last decade, at a conclusion on a need in an early aggressive therapy, because the destructive changes develop in joints yet during the first 4 months starting from the onset of initial RA clinical signs. The approach towards treatment by non-steroid anti-inflammatory drugs changed with respect to the risk factors related with the onset of potential complications and to choosing the safest drugs, which became possible owing to the development of drugs, whose action is aimed at suppression of cyclo-oxygenase-2 (COG-2). The group of "disease-modifying antirheumatic drugs" (DMARD) was added two new cytotoxic drugs, i.e. cyclosporin A and leflunomid. A concept of combined therapy by 2 or 3 DMARD was elaborated to ensure an effect in case of tolerance to monotherapy. The feasibility and safety of therapy by glucocorticosteroids both with small daily doses and with pulse therapy in extra aggressive RA variations were proven. The use of biological agents, i.e. of monoclonal antibodies to TNF alpha and IL-4 or of their receptors antagonists, is an absolutely new trend in RA treatment. Treatment safety is in the focus of attention; monitoring methods were designed to ensure such safety.

Portuguese guidelines for the use of biological agents in rheumatoid arthritis - March 2010 update.

PubMed

Fonseca, João Eurico; Canhão, Helena; Reis, Paulo; Santos, Maria José; Branco, Jaime; Quintal, Alberto; Malcata, Armando; Araújo, Domingos; Ventura, Francisco; Figueiredo, Guilherme; da Silva, José Canas; Patto, José Vaz; de Queiroz, Mário Viana; Santos, Rui André; Neto, Adriano José; de Matos, Alves de; Rodrigues, Ana; Mourão, Ana Filipa; Ribeiro, Ana Sofia; Cravo, Ana Rita; Barcelos, Anabela; Cardoso, Anabela; Vilar, António; Braña, Arecili; Faustino, Augusto; Silva, Candida; Godinho, Fátima; Cunha, Inês; Costa, José António; Gomes, José António Melo; Pinto, José António Araújo; da Silva, J A Pereira; Miranda, Luís Cunha; Inês, Luís; Santos, Luís Maurício; Cruz, Margarida; Salvador, Maria João; Ferreira, Maria Júlia; Rial, Maria; Bernardes, Miguel; Bogas, Mónica; Araújo, Paula; Machado, Pedro; Pinto, Patrícia; de Melo, Rui Gomes; Cortes, Sara; Alcino, Sérgio; Capela, Susana

2010-01-01

The authors present the revised version of the Portuguese Society of Rheumatology (SPR) guidelines for the treatment of rheumatoid arthritis (RA) with biological therapies. In these guidelines the criteria for introduction and maintenance of biological agents are discussed as well as the contraindications and procedures in the case of non-responders. Biological treatment should be considered in RA patients with a disease activity score 28 (DAS 28) superior to 3.2 despite treatment with 20mg/week of methotrexate (MTX) for at least 3 months or, if such treatment is not possible, after 6 months of other conventional disease modifying drug or combination therapy. A DAS 28 score between 2.6 and 3.2 with a significant functional or radiological deterioration under treatment with conventional regimens could also constitute an indication for biological treatment. The treatment goal should be remission or, if that is not achievable, at least a low disease activity, characterized by a DAS28 lower than 3.2, without significative functional or radiological worsening. The response criteria, at the end of the first 3 months of treatment, are a decrease of 0.6 in the DAS28 score. After 6 months of treatment response criteria is defined as a decrease of more than 1.2 in the DAS28 score. Non-responders, in accordance to the Rheumatologist's clinical opinion, should try a switch to another biological agent (tumour necrosis factor antagonist, abatacept, rituximab or tocilizumab).

Efficacy and Safety of Induction Therapy in Kidney Transplantation: A Network Meta-Analysis.

PubMed

Hwang, S D; Lee, J H; Lee, S W; Park, K-M; Kim, J K; Kim, M-J; Song, J H

2018-05-01

Rejection and infection can occur after kidney transplantation and are important factors in preserving graft kidney function. The use of immunosuppressant agents in transplantation is therefore important, and the question of which induction therapy should be used as an immunosuppressant is controversial. The goal of this study was to assess the comparative benefits and harms of various maintenance immunosuppressive induction agents in adults undergoing kidney transplantation by using a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy. CENTRAL, MEDLINE, EMBASE, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers were searched until May 2017 to identify randomized controlled trials on immunosuppression for kidney transplantation. Twenty-seven studies involving 4484 participants were eligible for analysis. Induction and maintenance treatments were administered for 12 months. There was no evidence of differences in outcomes between therapies on all-cause mortality, graft loss, cytomegalovirus, BK virus, neutropenia, thrombocytopenia, and biopsy-proven acute rejection. However, compared with intravenous basiliximab (an interleukin-2 receptor antagonist [IL-2RA]), the most effective treatments to decrease biopsy-proven acute rejection were intravenous alemtuzumab and rabbit antithymocyte globulin (rATG). The odds ratios were 0.45 (95% confidence interval [CI], 0.29-40.78) and 0.63 (95% CI, 0.42-0.95), respectively. As a side effect, rATG was accompanied by more bacterial infection than the IL-2RA (OR, 1.8 [95% CI, 1.01-2.8]). The determination of induction in kidney transplantation is important for future prognosis of the graft kidney. Alemtuzumab and rATG exhibited lower biopsy-proven acute rejection than the IL-2RA. As a side effect, rATG produced frequent bacterial infections. Copyright © 2018 Elsevier Inc. All rights reserved.

Impact of biologic agents with and without concomitant methotrexate and at reduced doses in older rheumatoid arthritis patients.

PubMed

Zhang, Jie; Xie, Fenglong; Delzell, Elizabeth; Yun, Huifeng; Lewis, James D; Haynes, Kevin; Chen, Lang; Beukelman, Timothy; Saag, Kenneth G; Curtis, Jeffrey R

2015-05-01

To examine whether concomitant methotrexate (MTX) use is associated with better biologic persistence and whether self-administered anti-tumor necrosis factor (anti-TNF) therapies are used at reduced doses in real-world clinical care settings, not just clinical trials. We conducted a retrospective cohort study among rheumatoid arthritis (RA) patients using Medicare claims data from 2006 to 2012. Subjects were new initiators of etanercept, infliximab, adalimumab, abatacept, and tocilizumab with at least 12 months of continuous medical and pharmacy coverage after treatment initiation. We examined the association between concomitant MTX use and persistence on biologic agents using Cox proportional hazards regression, adjusting for demographics and baseline comorbidities. We further identified a subgroup of patients who initiated and were adherent on etanercept or adalimumab for at least 12 months and examined the proportion of patients who subsequently used these therapies at reduced doses continuously for an additional 12, 18, and 24 months. Of 26,510 eligible RA patients, 10,511 initiated biologic monotherapy. Overall, patients who initiated biologic monotherapy were 1.4 (95% confidence interval [95% CI] 1.3-1.5) times more likely to discontinue at 1 year compared to those who initiated combination therapy, and 1.8 (95% CI 1.7-2.0) times more likely if starting infliximab monotherapy. Approximately 10-20% of patients who initiated and adhered to etanercept and adalimumab for ≥12 months subsequently received reduced-dose therapy for an 12 additional months and beyond. In real-world practice, concomitant MTX was associated with improved persistence on biologic therapy, especially for infliximab users; reduced-dose injectable anti-TNF therapy was used by a substantial proportion of RA patients. © 2015, American College of Rheumatology.

Combination Therapy With and Without Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis: A Meta-Analysis of Randomized Trials.

PubMed

Graudal, Niels; Hubeck-Graudal, Thorbjørn; Faurschou, Mikkel; Baslund, Bo; Jürgens, Gesche

2015-11-01

The costs of biologic treatment per patient with rheumatoid arthritis (RA) are approximately 100 times the costs of treatment with a combination of conventional disease-modifying antirheumatic drugs (DMARDs). Despite this, biologic agents have not been proven superior. We compared the effects of combination DMARD therapies with and without biologic agents as therapy for patients with RA. Eight randomized controlled trials published in 10 articles were selected from a systematic literature search of 1,674 identified studies and integrated in a meta-analysis. These trials compared combinations of DMARDs versus a tumor necrosis factor (TNF) inhibitor plus methotrexate. Two reviewers independently entered data into standardized extraction forms. The combined effect measures were compared by means of the inverse variance method (continuous data) and the Mantel-Haenszel method (dichotomous data) using a random-effects model. The primary outcome, radiographic progression score, did not differ between the combination DMARD group and the TNF inhibitor group, neither during the second year (-0.09 units [-0.61, 0.44]) of treatment or during the first 2 years (0.66 units [-0.12, 1.43]). There were significant differences in the radiographic progression score, the American College of Rheumatology criteria for 50% improvement (ACR50), and the ACR70 response criteria at 6 months in favor of TNF inhibitor treatment, but these differences were not present in patients treated with an initial steroid course and disappeared at 24 months, irrespective of the use of steroids. The difference between DMARD combination treatments, including or excluding TNF inhibitors, is small. Due to the enormous cost differences, RA guidelines should recommend combination DMARD treatment before initiation of TNF inhibitors. © 2015, American College of Rheumatology.

Gene expression profile predicting the response to anti-TNF treatment in patients with rheumatoid arthritis; analysis of GEO datasets.

PubMed

Kim, Tae-Hwan; Choi, Sung Jae; Lee, Young Ho; Song, Gwan Gyu; Ji, Jong Dae

2014-07-01

Anti-tumor necrosis factor (TNF) therapy is the treatment of choice for rheumatoid arthritis (RA) patients in whom standard disease-modifying anti-rheumatic drugs are ineffective. However, a substantial proportion of RA patients treated with anti-TNF agents do not show a significant clinical response. Therefore, biomarkers predicting response to anti-TNF agents are needed. Recently, gene expression profiling has been applied in research for developing such biomarkers. We compared gene expression profiles reported by previous studies dealing with the responsiveness of anti-TNF therapy in RA patients and attempted to identify differentially expressed genes (DEGs) that discriminated between responders and non-responders to anti-TNF therapy. We used microarray datasets available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO). This analysis included 6 studies and 5 sets of microarray data that used peripheral blood samples for identification of DEGs predicting response to anti-TNF therapy. We found little overlap in the DEGs that were highly ranked in each study. Three DEGs including IL2RB, SH2D2A and G0S2 appeared in more than 1 study. In addition, a meta-analysis designed to increase statistical power found one DEG, G0S2 by the Fisher's method. Our finding suggests the possibility that G0S2 plays as a biomarker to predict response to anti-TNF therapy in patients with rheumatoid arthritis. Further investigations based on larger studies are therefore needed to confirm the significance of G0S2 in predicting response to anti-TNF therapy. Copyright © 2014 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations.

PubMed

Koay, Debbie C; Zerillo, Cynthia; Narayan, Murli; Harris, Lyndsay N; DiGiovanna, Michael P

2010-01-01

HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects. The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed. In HER2-overexpressing/ER-positive BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid, 13-cis-retinoic acid, or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, the single retinoid agents did cause apoptosis in SKBR3 cells; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells. Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients.

Nacelle Aerodynamic and Inertial Loads (NAIL) project. Appendix B

NASA Technical Reports Server (NTRS)

1981-01-01

The testing was conducted on the Boeing-owned 747 RA001 test bed airplane during the concurrent 767/JT9D-7R4 engine development program. Following a functional check flight conducted from Boeing Field International (BFI) on 3 October 1980, the airplane and test personnel were ferried to Valley Industrial Park (GSG) near Glasgow, Montana, on 7 October 1980. The combined NAL and 7670JT9D-7R4 test flights were conducted at the Glasgow remote test site, and the airplane was returned to Seattle on 26 October 1980.

Blaptica dubia as sentinels for exposure to chemical warfare agents - a pilot study.

PubMed

Worek, Franz; Seeger, Thomas; Neumaier, Katharina; Wille, Timo; Thiermann, Horst

2016-11-16

The increased interest of terrorist groups in toxic chemicals and chemical warfare agents presents a continuing threat to our societies. Early warning and detection is a key component for effective countermeasures against such deadly agents. Presently available and near term solutions have a number of major drawbacks, e.g. lack of automated, remote warning and detection of primarily low volatile chemical warfare agents. An alternative approach is the use of animals as sentinels for exposure to toxic chemicals. To overcome disadvantages of vertebrates the present pilot study was initiated to investigate the suitability of South American cockroaches (Blaptica dubia) as warning system for exposure to chemical warfare nerve and blister agents. Initial in vitro experiments with nerve agents showed an increasing inhibitory potency in the order tabun - cyclosarin - sarin - soman - VX of cockroach cholinesterase. Exposure of cockroaches to chemical warfare agents resulted in clearly visible and reproducible reactions, the onset being dependent on the agent and dose. With nerve agents the onset was related to the volatility of the agents. The blister agent lewisite induced signs largely comparable to those of nerve agents while sulfur mustard exposed animals exhibited a different sequence of events. In conclusion, this first pilot study indicates that Blaptica dubia could serve as a warning system to exposure of chemical warfare agents. A cockroach-based system will not detect or identify a particular chemical warfare agent but could trigger further actions, e.g. specific detection and increased protective status. By designing appropriate boxes with (IR) motion sensors and remote control (IR) camera automated off-site warning systems could be realized. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Automation of [(18) F]fluoroacetaldehyde synthesis: application to a recombinant human interleukin-1 receptor antagonist (rhIL-1RA).

PubMed

Morris, Olivia; McMahon, Adam; Boutin, Herve; Grigg, Julian; Prenant, Christian

2016-06-15

[(18) F]Fluoroacetaldehyde is a biocompatible prosthetic group that has been implemented pre-clinically using a semi-automated remotely controlled system. Automation of radiosyntheses permits use of higher levels of [(18) F]fluoride whilst minimising radiochemist exposure and enhancing reproducibility. In order to achieve full-automation of [(18) F]fluoroacetaldehyde peptide radiolabelling, a customised GE Tracerlab FX-FN with fully programmed automated synthesis was developed. The automated synthesis of [(18) F]fluoroacetaldehyde is carried out using a commercially available precursor, with reproducible yields of 26% ± 3 (decay-corrected, n = 10) within 45 min. Fully automated radiolabelling of a protein, recombinant human interleukin-1 receptor antagonist (rhIL-1RA), with [(18) F]fluoroacetaldehyde was achieved within 2 h. Radiolabelling efficiency of rhIL-1RA with [(18) F]fluoroacetaldehyde was confirmed using HPLC and reached 20% ± 10 (n = 5). Overall RCY of [(18) F]rhIL-1RA was 5% ± 2 (decay-corrected, n = 5) within 2 h starting from 35 to 40 GBq of [(18) F]fluoride. Specific activity measurements of 8.11-13.5 GBq/µmol were attained (n = 5), a near three-fold improvement of those achieved using the semi-automated approach. The strategy can be applied to radiolabelling a range of peptides and proteins with [(18) F]fluoroacetaldehyde analogous to other aldehyde-bearing prosthetic groups, yet automation of the method provides reproducibility thereby aiding translation to Good Manufacturing Practice manufacture and the transformation from pre-clinical to clinical production. Copyright © 2016 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons, Ltd.

Operation and Hydrodynamic Evaluations of a Controlled-Depth Towed Depressor Designed to House a Conductivity, Temperature, Depth (CTD) Instrument System

DTIC Science & Technology

1981-03-01

ljIi 0 10 20 30 40 50 60 70 80 LENGTH (W) Figure 2 - Predicted Tension in Remote Sensor Cable at 10 Knots as a Function of Cable Length for Two Remote...10.0 -8.0 -10 4.11 0.68 40 5.0 -8.0 -15 0.66 0.44 41 8.0 -8.0 -15 1.57 0.41 42 10.0 -8.0 -15 2.63 0.44 43 5.0 -8.0 -20 0.48 0.32 44 8.0 -8.0 -20 0.89...HH fIH 1 IH r-4 H r- rIH rIH 4 i HHH.-4H H -4 rIH HHHHH r Cfr- 40 00 0 0q - zI - ri-4- oi 0 -A- \\.o. m M- r-. A- - rA- r-c r(0 P4 r

Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study

PubMed Central

Naranjo, Antonio; Sokka, Tuulikki; Descalzo, Miguel A; Calvo-Alén, Jaime; Hørslev-Petersen, Kim; Luukkainen, Reijo K; Combe, Bernard; Burmester, Gerd R; Devlin, Joe; Ferraccioli, Gianfranco; Morelli, Alessia; Hoekstra, Monique; Majdan, Maria; Sadkiewicz, Stefan; Belmonte, Miguel; Holmqvist, Ann-Carin; Choy, Ernest; Tunc, Recep; Dimic, Aleksander; Bergman, Martin; Toloza, Sergio; Pincus, Theodore

2008-01-01

Introduction We analyzed the prevalence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA) and its association with traditional CV risk factors, clinical features of RA, and the use of disease-modifying antirheumatic drugs (DMARDs) in a multinational cross-sectional cohort of nonselected consecutive outpatients with RA (The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis Program, or QUEST-RA) who were receiving regular clinical care. Methods The study involved a clinical assessment by a rheumatologist and a self-report questionnaire by patients. The clinical assessment included a review of clinical features of RA and exposure to DMARDs over the course of RA. Comorbidities were recorded; CV morbidity included myocardial infarction, angina, coronary disease, coronary bypass surgery, and stroke. Traditional risk factors recorded were hypertension, hyperlipidemia, diabetes mellitus, smoking, physical inactivity, and body mass index. Unadjusted and adjusted hazard ratios (HRs) (95% confidence interval [CI]) for CV morbidity were calculated using Cox proportional hazard regression models. Results Between January 2005 and October 2006, the QUEST-RA project included 4,363 patients from 48 sites in 15 countries; 78% were female, more than 90% were Caucasian, and the mean age was 57 years. The prevalence for lifetime CV events in the entire sample was 3.2% for myocardial infarction, 1.9% for stroke, and 9.3% for any CV event. The prevalence for CV risk factors was 32% for hypertension, 14% for hyperlipidemia, 8% for diabetes, 43% for ever-smoking, 73% for physical inactivity, and 18% for obesity. Traditional risk factors except obesity and physical inactivity were significantly associated with CV morbidity. There was an association between any CV event and age and male gender and between extra-articular disease and myocardial infarction. Prolonged exposure to methotrexate (HR 0.85; 95% CI 0.81 to 0.89), leflunomide (HR 0.59; 95% CI 0.43 to 0.79), sulfasalazine (HR 0.92; 95% CI 0.87 to 0.98), glucocorticoids (HR 0.95; 95% CI 0.92 to 0.98), and biologic agents (HR 0.42; 95% CI 0.21 to 0.81; P < 0.05) was associated with a reduction of the risk of CV morbidity; analyses were adjusted for traditional risk factors and countries. Conclusion In conclusion, prolonged use of treatments such as methotrexate, sulfasalazine, leflunomide, glucocorticoids, and tumor necrosis factor-alpha blockers appears to be associated with a reduced risk of CV disease. In addition to traditional risk factors, extra-articular disease was associated with the occurrence of myocardial infarction in patients with RA. PMID:18325087

Periodontal treatment decreases levels of antibodies to Porphyromonas gingivalis and citrulline in patients with rheumatoid arthritis and periodontitis.

PubMed

Okada, Moe; Kobayashi, Tetsuo; Ito, Satoshi; Yokoyama, Tomoko; Abe, Asami; Murasawa, Akira; Yoshie, Hiromasa

2013-12-01

Porphyromonas gingivalis has been implicated as an etiologic agent of rheumatoid arthritis (RA) because of the expression of peptidylarginine deiminase. The present study evaluates whether periodontal treatment may affect serum antibodies to P. gingivalis and citrulline levels in relation to disease activity of RA. Fifty-five patients with RA were randomly assigned to receive oral hygiene instruction and supragingival scaling (treatment group, n = 26) or no periodontal treatment (control group, n = 29). Periodontal and rheumatologic parameters and serum levels of cytokine and inflammatory markers citrulline and immunoglobulin (Ig)G to P. gingivalis were examined at baseline and 8 weeks later. Both groups did not differ statistically in any parameters except percentage of sites with probing depth and clinical attachment level ≥ 4 mm at baseline. The treatment group exhibited a significantly greater decrease in disease activity score including 28 joints using C-reactive protein (DAS28-CRP) (P = 0.02), serum levels of IgG to P. gingivalis hemin binding protein (HBP)35 (P = 0.04), and citrulline (P = 0.02) than the control group. Serum levels of IgG to P. gingivalis HBP35 were significantly correlated positively with those of anti-cyclic citrullinated peptide antibodies (P = 0.0002). The same correlation was obtained between serum levels of IgG to P. gingivalis-sonicated extracts and those of rheumatoid factor (P = 0.02). These results suggest that supragingival scaling decreases DAS28-CRP and serum levels of IgG to P. gingivalis HBP35 and citrulline in patients with RA. These observations may reflect a role of P. gingivalis in the protein citrullination, which is related to the pathogenesis of RA.

A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid.

PubMed

Zhou, Ru; Horai, Reiko; Mattapallil, Mary J; Caspi, Rachel R

2011-10-15

The eye is an immunologically privileged and profoundly immunosuppressive environment. Early studies reported inhibition of T cell proliferation, IFN-γ production, and generation of regulatory T cells (Tregs) by aqueous humor (AH) and identified TGF-β as a critical factor. However, T cell subsets including Foxp3(+) Treg and Th17 were unknown at that time, as was the role of retinoic acid (RA) in Treg induction. Consequently, the effect of the ocular microenvironment on T cell lineage commitment and function, and the role of RA in this process, had not been explored. We now use gene-manipulated mice and highly purified T cell populations to demonstrate that AH suppresses lineage commitment and acquisition of Th1 and Th17 effector function of naive T cells, manifested as reduction of lineage-specific transcription factors and cytokines. Instead, AH promoted its massive conversion to Foxp3(+) Tregs that expressed CD25, GITR, CTLA-4, and CD103 and were functionally suppressive. TGF-β and RA were both needed and synergized for Treg conversion by AH, with TGF-β-enhancing T cell expression of RA receptor α. Newly converted Foxp3(+) Tregs were unstable, but were stabilized upon continued exposure to AH or by the DNA demethylating agent 5-aza-2'-deoxycytidine. In contrast, T cells already committed to effector function were resistant to the suppressive and Treg-inducing effects of AH. We conclude that RA in the eye plays a dual role: in vision and in immune privilege. Nevertheless, primed effector T cells are relatively insensitive to AH, helping to explain their ability to induce uveitis despite an inhibitory ocular microenvironment.

Disease Activity in Rheumatoid Arthritis and the Risk of Cardiovascular Events

PubMed Central

Solomon, DH; Reed, G; Kremer, JM; Curtis, JR; Farkouh, ME; Harrold, LR; Hochberg, MC; Tsao, P; Greenberg, J

2015-01-01

Background Use of several immunomodulatory agents has been associated with reduced cardiovascular (CV) events in epidemiologic studies of rheumatoid arthritis (RA). However, it is unknown whether time-averaged disease activity in RA correlates with CV events. Methods We studied patients with RA followed in a longitudinal US-based registry. Time-averaged disease activity was assessed using the area under the curve of the Clinical Disease Activity Index, a validated measure of rheumatoid arthritis disease activity, assessed during follow-up. Age, gender, diabetes, hypertension, hyperlipidemia, body mass index, family history of myocardial infarction (MI), aspirin use, NSAID use presence of CV disease, and baseline immunomodulator use were assessed at baseline. Cox proportional hazards regression models were examined to determine the risk of a composite CV endpoint that included MI, stroke, and CV death. Results 24,989 subjects followed for a median of 2.7 years were included in these analyses. During follow-up, we observed 422 confirmed CV endpoints for an incidence rate of 9.08 (95% confidence interval, CI, 7.90 – 10.26) per 1,000 person-years. In models adjusting for variables noted above, a 10-point reduction in time-averaged Clinical Disease Activity Index was associated with a 26% reduction in CV risk (95% confidence interval 17-34%). These results were robust in subgroup analyses stratified by presence of CV disease, use of corticosteroids, use of non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors, change in RA treatment, and also when restricted to events adjudicated as definite or probable. Conclusions Reduced time-averaged disease activity in RA is associated with fewer CV events. PMID:25776112

Predictors of failure of awake regional anesthesia for neonatal hernia repair: data from the General Anesthesia compared to Spinal anesthesia (GAS) study: comparing apnoea and neurodevelopmental outcomes

PubMed Central

Frawley, Geoff; Bell, Graham; Disma, Nicola; Withington, Davinia E.; de Graaff, Jurgen C.; Morton, Neil S.; McCann, Mary Ellen; Arnup, Sarah J.; Bagshaw, Oliver; Wolfler, Andrea; Bellinger, David; Davidson, Andrew J.

2015-01-01

Background Awake regional anesthesia (RA) is a viable alternative to general anesthesia (GA) for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes. The General Anesthesia compared to Spinal anesthesia (GAS) study compares neurodevelopmental outcomes following awake RA or GA in otherwise healthy infants. Our aim was to describe success and failure rates of RA in this study and report factors associated with failure. Methods This was a nested cohort study within a prospective randomized, controlled, observer blind, equivalence trial. Seven hundred twenty two infants ≤ 60 weeks postmenstrual age, scheduled for herniorrhaphy under anesthesia were randomly assigned to receive RA (spinal, caudal epidural or combined spinal caudal anesthetic) or GA with sevoflurane. The data of 339 infants, where spinal or combined spinal caudal anesthetic was attempted, was analyzed. Possible predictors of failure were assessed including: patient factors, technique, experience of site and anesthetist and type of local anesthetic. Results RA was sufficient for the completion of surgery in 83.2% of patients. Spinal anesthesia was successful in 86.9% of cases and combined spinal caudal anesthetic in 76.1%. Thirty four patients required conversion to GA and an additional 23 (6.8%) required brief sedation. Bloody tap on the first attempt at lumbar puncture was the only risk factor significantly associated with block failure (OR = 2.46). Conclusions The failure rate of spinal anesthesia was low. Variability in application of combined spinal caudal anesthetic limited attempts to compare the success of this technique to spinal alone. PMID:26001028

Security Measures to Protect Mobile Agents

NASA Astrophysics Data System (ADS)

Dadhich, Piyanka; Govil, M. C.; Dutta, Kamlesh

2010-11-01

The security issues of mobile agent systems have embarrassed its widespread implementation. Mobile agents that move around the network are not safe because the remote hosts that accommodate the agents initiates all kinds of attacks. These hosts try to analyze the agent's decision logic and their accumulated data. So, mobile agent security is the most challenging unsolved problems. The paper analyzes various security measures deeply. Security especially the attacks performed by hosts to the visiting mobile agent (the malicious hosts problem) is a major obstacle that prevents mobile agent technology from being widely adopted. Being the running environment for mobile agent, the host has full control over them and could easily perform many kinds of attacks against them.

Regional universities and rural clinical schools contribute to rural medical workforce, a cohort study of 2002 to 2013 graduates.

PubMed

Shires, Lizzi; Allen, Penny; Cheek, Colleen; Deb, Wilson

2015-01-01

Rural clinical schools and regionally based medical schools have a major role in expanding the rural medical workforce. The aim of this cohort study was to compare location of practice of graduates from the University of Tasmania School of Medicine's clinical schools based in the larger cities of Hobart and Launceston (UTAS SoM), with those graduates who spent at least 1 year at the University of Tasmania School of Medicine's Rural Clinical School based in the smaller regional city of Burnie (UTAS RCS) in Australia. Specifically, the aim was to quantify the proportion who worked in an Australian regional or remote location, or in the regional cities and smaller towns within Tasmania. The 2014 locations of practice of all graduates from the UTAS SoM and UTAS RCS between 2002 and 2013 were determined using the postcode listed in the Australian Health Practitioners Authority database. These postcodes were mapped against the Australian Bureau of Statistics Australian Standard Geographic Classification - Remoteness Areas (ASGC-RA) and the 2011 Census population data for Tasmania to define Modified Monash Model classifications. The study tracked 974 UTAS SoM graduates; 202 (21%) spent at least 1 year at the Rural Clinical School (UTAS RCS graduates). Students who had spent a year at the UTAS RCS were five times more likely to be working in RA3 to RA5 than those who hadn't spent a clinical year there (28% vs 7%, χ2(1)=59.5, p<0.0001) (odds ratio (OR) 4.9, 95% confidence interval (CI) 3.2-7.6). Using the Modified Monash Model, it was found that UTAS RCS graduates were nine times more likely (OR 9.0, 95%CI 4.7-17.2) to be working in the regional cities and smaller towns of Tasmania. This study adds to the growing evidence that training medical students in rural areas delivers graduates that work rurally. The additional year spent in a rural area, even when their medical school is in a regional city, significantly affects their workplace choices over the first 3 years post-graduation.

Model Checking the Remote Agent Planner

NASA Technical Reports Server (NTRS)

Khatib, Lina; Muscettola, Nicola; Havelund, Klaus; Norvig, Peter (Technical Monitor)

2001-01-01

This work tackles the problem of using Model Checking for the purpose of verifying the HSTS (Scheduling Testbed System) planning system. HSTS is the planner and scheduler of the remote agent autonomous control system deployed in Deep Space One (DS1). Model Checking allows for the verification of domain models as well as planning entries. We have chosen the real-time model checker UPPAAL for this work. We start by motivating our work in the introduction. Then we give a brief description of HSTS and UPPAAL. After that, we give a sketch for the mapping of HSTS models into UPPAAL and we present samples of plan model properties one may want to verify.

Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials.

PubMed

Strand, Vibeke; Ahadieh, Sima; French, Jonathan; Geier, Jamie; Krishnaswami, Sriram; Menon, Sujatha; Checchio, Tina; Tensfeldt, Thomas G; Hoffman, Elaine; Riese, Richard; Boy, Mary; Gómez-Reino, Juan J

2015-12-15

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib modulates the signaling of cytokines that are integral to lymphocyte activation, proliferation, and function. Thus, tofacitinib therapy may result in suppression of multiple elements of the immune response. Serious infections have been reported in tofacitinib RA trials. However, limited head-to-head comparator data were available within the tofacitinib RA development program to directly compare rates of serious infections with tofacitinib relative to biologic agents, and specifically adalimumab (employed as an active control agent in two randomized controlled trials of tofacitinib). A systematic literature search of data from interventional randomized controlled trials and long-term extension studies with biologics in RA was carried out. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results of the review and meta-analysis. Incidence rates (unique patients with events/100 patient-years) for each therapy were estimated based on data from randomized controlled trials and long-term extension studies using a random-effects model. Relative and absolute risk comparisons versus placebo used Mantel-Haenszel methods. The search produced 657 hits. In total, 66 randomized controlled trials and 22 long-term extension studies met the selection criteria. Estimated incidence rates (95% confidence intervals [CIs]) for abatacept, rituximab, tocilizumab, and tumor necrosis factor inhibitors were 3.04 (2.49, 3.72), 3.72 (2.99, 4.62), 5.45 (4.26, 6.96), and 4.90 (4.41, 5.44), respectively. Incidence rates (95% CIs) for tofacitinib 5 and 10 mg twice daily (BID) in phase 3 trials were 3.02 (2.25, 4.05) and 3.00 (2.24, 4.02), respectively. Corresponding incidence rates in long-term extension studies were 2.50 (2.05, 3.04) and 3.19 (2.74, 3.72). The risk ratios (95% CIs) versus placebo for tofacitinib 5 and 10 mg BID were 2.21 (0.60, 8.14) and 2.02 (0.56, 7.28), respectively. Risk differences (95% CIs) versus placebo for tofacitinib 5 and 10 mg BID were 0.38% (-0.24%, 0.99%) and 0.40% (-0.22%, 1.02%), respectively. In interventional studies, the risk of serious infections with tofacitinib is comparable to published rates for biologic disease-modifying antirheumatic drugs in patients with moderate to severely active RA.

Indian Herbal Medicines: Possible Potent Therapeutic Agents for Rheumatoid Arthritis

PubMed Central

Rathore, Brijesh; Ali Mahdi, Abbas; Nath Paul, Bhola; Narayan Saxena, Prabhu; Kumar Das, Siddharth

2007-01-01

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology and is mainly characterized by the progressive erosion of cartilage leading to chronic polyarthritis and joint distortion. Although the exact pathogenesis of the disease has yet not been elucidated, however, studies suggest that cellular proliferation of synoviocytes result in pannus formation which damages the cartilage and bone. Recent reports also support the role of free radicals in its pathogenesis. Apart from the conventional treatment strategies using nonsteroidal anti-inflammatory drugs, disease modifying antirheumatic drugs and glucocorticoids, newer and safer drugs are continuously being searched, as long term usage of these drugs have resulted in adverse effects. Alternative medicine provides another approach for treatment of RA and currently a number of medicinal plants are under scientific evaluation to develop a novel drug. There is a dire need to investigate the complete therapeutic potential and adverse effects, if any, of these herbals for providing newer and safer treatment options with minimum side effects. In this review we have tried to explore various Indian ancient Ayurvedic, Unani and Tibbi, as also some Chinese and Korean, herbals for their potential to treat RA. PMID:18392103

The clinical development of p53-reactivating drugs in sarcomas - charting future therapeutic approaches and understanding the clinical molecular toxicology of Nutlins.

PubMed

Biswas, Swethajit; Killick, Emma; Jochemsen, Aart G; Lunec, John

2014-05-01

The majority of human sarcomas, particularly soft tissue sarcomas, are relatively resistant to traditional cytotoxic therapies. The proof-of-concept study by Ray-Coquard et al., using the Nutlin human double minute (HDM)2-binding antagonist RG7112, has recently opened a new chapter in the molecular targeting of human sarcomas. In this review, the authors discuss the challenges and prospective remedies for minimizing the significant haematological toxicities of the cis-imidazole Nutlin HDM2-binding antagonists. Furthermore, they also chart the future direction of the development of p53-reactivating (p53-RA) drugs in 12q13-15 amplicon sarcomas and as potential chemopreventative therapies against sarcomagenesis in germ line mutated TP53 carriers. Drawing lessons from the therapeutic use of Imatinib in gastrointestinal tumours, the authors predict the potential pitfalls, which may lie in ahead for the future clinical development of p53-RA agents, as well as discussing potential non-invasive methods to identify the development of drug resistance. Medicinal chemistry strategies, based on structure-based drug design, are required to re-engineer cis-imidazoline Nutlin HDM2-binding antagonists into less haematologically toxic drugs. In silico modelling is also required to predict toxicities of other p53-RA drugs at a much earlier stage in drug development. Whether p53-RA drugs will be therapeutically effective as a monotherapy remains to be determined.

Arsenic-induced PML targeting onto nuclear bodies: Implications for the treatment of acute promyelocytic leukemia

PubMed Central

Zhu, Jun; Koken, Marcel H. M.; Quignon, Frédérique; Chelbi-Alix, Mounira K.; Degos, Laurent; Wang, Zhen Yi; Chen, Zhu; de Thé, Hugues

1997-01-01

Acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RARα fusion protein between PML, a growth suppressor localized on nuclear matrix-associated bodies, and RARα, a nuclear receptor for retinoic acid (RA). PML/RARα was proposed to block myeloid differentiation through inhibition of nuclear receptor response, as does a dominant negative RARα mutant. In addition, in APL cells, PML/RARα displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respective contributions of RARα (or PML/RARα) activation, PML/RARα degradation, and restoration of NB antigens localization are poorly determined. Arsenic trioxide also leads to remissions in APL patients, presumably through induction of apoptosis. We demonstrate that in non-APL cells, arsenic recruits the nucleoplasmic form of several NB antigens onto NB, but induces the degradation of PML only, identifying a powerful tool to approach NB function. In APL cells, arsenic targets PML and PML/RARα onto NB and induces their degradation. Thus, RA and arsenic target RARα and PML, respectively, but both induce the degradation of the PML/RARα fusion protein, which should contribute to their therapeutic effects. The difference in the cellular events triggered by these two agents likely stems from RA-induced transcriptional activation and arsenic effects on NB proteins. PMID:9108090

Correlation of bond strength with surface roughness using a new roughness measurement technique.

PubMed

Winkler, M M; Moore, B K

1994-07-01

The correlation between shear bond strength and surface roughness was investigated using new surface measurement methods. Bonding agents and associated resin composites were applied to set amalgam after mechanically roughening its surface. Surface treatments were noe (as set against glass), 80 grit, and 600 grit abrasive paper. Surface roughness (R(a) as measured parallel and perpendicular (+) to the direction of the polishing scratches and true profile length were measured. A knife-edge was applied (rate = 2.54 mm/min) at the bonding agent/amalgam interface of each sample until failure. Coefficients of determination for mean bond strength vs either roughness (R(a), of profile length were significantly higher for measurements in parallel directions than for those measurements in (+) directions. The shear bond strength to set amalgam for a PENTA-containing adhesives system (L.D. Caulk Division) was not significantly different from that of a PENTA-free adhesive (3M Dental Products Division), even though PENTA has been reported to increase bond strength to nonprecious metals. The shear bond strength of resin composite to amalgam is correlated to surface roughness when it is measured parallel to the polishing scratches. This correlation is significantly lower when surface roughness is measured in the typical manner, perpendicular to the polishing scratches.

Remote sensing of forest insect disturbances: Current state and future directions

NASA Astrophysics Data System (ADS)

Senf, Cornelius; Seidl, Rupert; Hostert, Patrick

2017-08-01

Insect disturbance are important agents of change in forest ecosystems around the globe, yet their spatial and temporal distribution and dynamics are not well understood. Remote sensing has gained much attention in mapping and understanding insect outbreak dynamics. Consequently, we here review the current literature on the remote sensing of insect disturbances. We suggest to group studies into three insect types: bark beetles, broadleaved defoliators, and coniferous defoliators. By so doing, we systematically compare the sensors and methods used for mapping insect disturbances within and across insect types. Results suggest that there are substantial differences between methods used for mapping bark beetles and defoliators, and between methods used for mapping broadleaved and coniferous defoliators. Following from this, we highlight approaches that are particularly suited for each insect type. Finally, we conclude by highlighting future research directions for remote sensing of insect disturbances. In particular, we suggest to: 1) Separate insect disturbances from other agents; 2) Extend the spatial and temporal domain of analysis; 3) Make use of dense time series; 4) Operationalize near-real time monitoring of insect disturbances; 5) Identify insect disturbances in the context of coupled human-natural systems; and 6) Improve reference data for assessing insect disturbances. Since the remote sensing of insect disturbances has gained much interest beyond the remote sensing community recently, the future developments identified here will help integrating remote sensing products into operational forest management. Furthermore, an improved spatiotemporal quantification of insect disturbances will support an inclusion of these processes into regional to global ecosystem models.

Remote sensing of forest insect disturbances: Current state and future directions.

PubMed

Senf, Cornelius; Seidl, Rupert; Hostert, Patrick

2017-08-01

Insect disturbance are important agents of change in forest ecosystems around the globe, yet their spatial and temporal distribution and dynamics are not well understood. Remote sensing has gained much attention in mapping and understanding insect outbreak dynamics. Consequently, we here review the current literature on the remote sensing of insect disturbances. We suggest to group studies into three insect types: bark beetles, broadleaved defoliators, and coniferous defoliators. By so doing, we systematically compare the sensors and methods used for mapping insect disturbances within and across insect types. Results suggest that there are substantial differences between methods used for mapping bark beetles and defoliators, and between methods used for mapping broadleaved and coniferous defoliators. Following from this, we highlight approaches that are particularly suited for each insect type. Finally, we conclude by highlighting future research directions for remote sensing of insect disturbances. In particular, we suggest to: 1) Separate insect disturbances from other agents; 2) Extend the spatial and temporal domain of analysis; 3) Make use of dense time series; 4) Operationalize near-real time monitoring of insect disturbances; 5) Identify insect disturbances in the context of coupled human-natural systems; and 6) Improve reference data for assessing insect disturbances. Since the remote sensing of insect disturbances has gained much interest beyond the remote sensing community recently, the future developments identified here will help integrating remote sensing products into operational forest management. Furthermore, an improved spatiotemporal quantification of insect disturbances will support an inclusion of these processes into regional to global ecosystem models.

Portuguese guidelines for the use of biological agents in rheumatoid arthritis - October 2011 update.

PubMed

Fonseca, João Eurico; Bernardes, Miguel; Canhão, Helena; Santos, Maria José; Quintal, Alberto; Malcata, Armando; Neto, Adriano; Cordeiro, Ana; Rodrigues, Ana; Mourão, Ana Filipa; Ribeiro, Ana Sofia; Cravo, Ana Rita; Barcelos, Anabela; Cardoso, Anabela; Vilar, António; Braña, Arecili; Faustino, Augusto; Silva, Candida; Duarte, Cátia; Araújo, Domingos; Nour, Dolores; Sousa, Elsa; Simões, Eugénia; Godinho, Fátima; Brandão, Filipe; Ventura, Francisco; Sequeira, Graça; Figueiredo, Guilherme; Cunha, Inês; Matos, J Alves; Branco, Jaime; Ramos, João; Costa, José António; Gomes, José António; Pinto, José; Silva, José Canas; Silva, J A; Patto, José Vaz; Costa, Lúcia; Miranda, Luís Cunha; Inês, Luís; Santos, Luís Maurício; Cruz, Margarida; Salvador, Maria João; Ferreira, Maria Júlia; Rial, Maria; Queiroz, Mário Viana; Bogas, Mónica; Araújo, Paula; Reis, Paulo; Abreu, Pedro; Machado, Pedro; Pinto, Patrícia; André, Rui; Melo, Rui; Garcês, Sandra; Cortes, Sara; Alcino, Sérgio; Ramiro, Sofia; Capela, Susana

2011-01-01

The authors present the revised version of the Portuguese Society of Rheumatology (SPR) guidelines for the treatment of Rheumatoid Arthritis (RA) with biological therapies. In these guidelines the criteria for introduction and maintenance of biological agents are discussed as well as the contraindications and procedures in the case of nonresponders. Biological treatment (with a tumour necrosis factor antagonist, abatacept or tocilizumab) should be considered in RA patients with a disease activity score 28 (DAS 28) equal to or greater than 3.2 despite treatment with at least 20mg-weekly-dose of methotrexate (MTX) for at least 3 months or, if such treatment is not possible, after 3 months of other conventional disease modifying drug or combination therapy. A DAS 28 score between 2.6 and 3.2 with a significant functional or radiological deterioration under treatment with conventional regimens could also constitute an indication for biological treatment. The treatment goal should be remission or, if that is not achievable, at least a low disease activity, defined by a DAS28 lower than 3.2, without significative functional or radiological worsening. The response criteria, at the end of the first 3 months of treatment, are a decrease of at least 0.6 in the DAS28 score. After 6 months of treatment res­ponse criteria is defined as a decrease greater than 1.2 in the DAS28 score. Non-responders, in accordance to the Rheumatologist’s clinical opinion, should try a switch to another biological agent (tumour necrosis factor antagonist, abatacept, rituximab or tocilizumab).

VARIAR Study: Assessment of short-term efficacy and safety of rituximab compared to an tumor necrosis factor alpha antagonists as second-line drug therapy in patients with rheumatoid arthritis refractory to a first tumor necrosis factor alpha antagonist.

PubMed

Torrente-Segarra, Vicenç; Acosta Pereira, Asunción; Morla, Rosa; Ruiz, José Miguel; Clavaguera, Teresa; Figuls, Ramon; Corominas, Hector; Geli, Carme; Roselló, Rosa; de Agustín, Juan José; Alegre, Cayetano; Pérez, Carolina; García, Angel; Rodríguez de la Serna, Arturo

to compare the short-term efficacy and safety of rituximab (RTX) therapy versus anti-TNF in rheumatoid arthritis (RA) patients after discontinuation of a first anti-TNF agent. prospective observational multicenter study in the clinical practice setting, involving patients with severe RA refractory to a first anti-TNF agent, who received either RTX or a second anti-TNF (2TNF), comparing the efficacy endpoints, EULAR response (Good/Moderate) and safety at 6 months. 103 patients enrolled, 82 completed 6-month follow-up, 73.7% women. Baseline data for RTX and 2TNF groups, respectively: TJC, 8.6 and 6.6; SJC, 8.8 and 7.5; DAS28 score, 5.45 (±1.28) and 5.18 (±1.21) (p=0.048), ESR, 41 and 38.7mmHg; and HAQ, 1.2 and 1.0. Improvement was observed in all parameters, with no significant differences (except for a more marked reduction in ESR with RTX). There were no serious adverse events. RTX use as second-line therapy after anti-TNF failure led to improvements in the efficacy and functional variables at 6 months, with no serious adverse events. These results were comparable to those observed in patients who used a second anti-TNF agent in the same clinical scenario. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Remote diagnosis server

NASA Technical Reports Server (NTRS)

Deb, Somnath (Inventor); Ghoshal, Sudipto (Inventor); Malepati, Venkata N. (Inventor); Kleinman, David L. (Inventor); Cavanaugh, Kevin F. (Inventor)

2004-01-01

A network-based diagnosis server for monitoring and diagnosing a system, the server being remote from the system it is observing, comprises a sensor for generating signals indicative of a characteristic of a component of the system, a network-interfaced sensor agent coupled to the sensor for receiving signals therefrom, a broker module coupled to the network for sending signals to and receiving signals from the sensor agent, a handler application connected to the broker module for transmitting signals to and receiving signals therefrom, a reasoner application in communication with the handler application for processing, and responding to signals received from the handler application, wherein the sensor agent, broker module, handler application, and reasoner applications operate simultaneously relative to each other, such that the present invention diagnosis server performs continuous monitoring and diagnosing of said components of the system in real time. The diagnosis server is readily adaptable to various different systems.

Remote-handled/special case TRU waste characterization summary

DOE Office of Scientific and Technical Information (OSTI.GOV)

Detamore, J.A.

1984-03-30

TRU wastes are those (other than high level waste) contaminated with specified quantities of certain alpha-emitting radionuclides of long half-life and high specific radiotoxicity. TRU waste is defined as /sup 226/Ra isotopic sources and those other materials that, without regard to source or form, are contaminated with transuranic elements with half-lives greater than 20 years, and have TRU alpha contamination greater than 100 nCi/g. RH TRU waste has high beta and gamma radiation levels, up to 30,000 R/hr, and thermal output may be a few hundred watts per container. The radiation levels in most of this remotely handled (RH) TRUmore » waste, however, are below 100 R/hr. Remote-handled wastes are stored at Los Alamos, Hanford, Oak Ridge, and the Idaho National Engineering Laboratory. This report presents a site by site discussion of RH waste handling, placement, and container data. This is followed by a series of data tables that were compiled in the TRU Waste Systems Office. These tables are a compendium of data that are the most up to date and accurate data available today. 10 tables.« less

Effect of solubilizing agents on mupirocin loading into and release from PEGylated nanoliposomes.

PubMed

Cern, Ahuva; Nativ-Roth, Einat; Goldblum, Amiram; Barenholz, Yechezkel

2014-07-01

Mupirocin was identified by quantitative structure property relationship models as a good candidate for remote liposomal loading. Mupirocin is an antibiotic that is currently restricted to topical administration because of rapid hydrolysis in vivo to its inactive metabolite. Formulating mupirocin in PEGylated nanoliposomes may potentially expand its use to parenteral administration by protecting it from degradation in the circulation and target it (by the enhanced permeability effect) to the infected tissue. Mupirocin is slightly soluble in aqueous medium and its solubility can be increased using solubilizing agents. The effect of the solubilizing agents on mupirocin remote loading was studied when the solubilizing agents were added to the drug loading solution. Propylene glycol was found to increase mupirocin loading, whereas polyethylene glycol 400 showed no effect. Hydroxypropyl-β-cyclodextrin (HPCD) showed a concentration-dependent effect on mupirocin loading; using the optimal HPCD concentration increased loading, but higher concentrations inhibited it. The inclusion of HPCD in the liposome aqueous phase while forming the liposomes resulted in increased drug loading and substantially inhibited drug release in serum. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Construction of a smart medication dispenser with high degree of scalability and remote manageability.

PubMed

Pak, JuGeon; Park, KeeHyun

2012-01-01

We propose a smart medication dispenser having a high degree of scalability and remote manageability. We construct the dispenser to have extensible hardware architecture for achieving scalability, and we install an agent program in it for achieving remote manageability. The dispenser operates as follows: when the real-time clock reaches the predetermined medication time and the user presses the dispense button at that time, the predetermined medication is dispensed from the medication dispensing tray (MDT). In the proposed dispenser, the medication for each patient is stored in an MDT. One smart medication dispenser contains mainly one MDT; however, the dispenser can be extended to include more MDTs in order to support multiple users using one dispenser. For remote management, the proposed dispenser transmits the medication status and the system configurations to the monitoring server. In the case of a specific event such as a shortage of medication, memory overload, software error, or non-adherence, the event is transmitted immediately. All these operations are performed automatically without the intervention of patients, through the agent program installed in the dispenser. Results of implementation and verification show that the proposed dispenser operates normally and performs the management operations from the medication monitoring server suitably.

Anti-inflammatory agents from plants: progress and potential.

PubMed

Recio, M C; Andujar, I; Rios, J L

2012-01-01

The identification of substances that can promote the resolution of inflammation in a way that is homeostatic, modulatory, efficient, and well-tolerated by the body is of fundamental importance. Traditional medicines have long provided front-line pharmacotherapy for many millions of people worldwide. Medicinal extracts are a rich source of therapeutic leads for the pharmaceutical industry. The use of medicinal plant therapies to treat chronic illness, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), is thus widespread and on the rise.The aim of this review is to present recent progress in clinical anti-inflammatory studies of plant extracts and compound leads such as green tea polyphenols, curcumin, resveratrol, boswellic acid, and cucurbitacins, among others, against chronic inflammatory diseases, mainly RA and IBD. In this context, the present paper also highlights the most promising experimental data on those plant extracts and pure compounds active in animal models of the aforementioned diseases.

Polyamine Analogues as Novel Anti-HER Family Agents in Human Breast Cancer

DTIC Science & Technology

2007-09-01

Davidson NE, & Casero RA Jr. Spermine oxidase SMO(PAOh1), not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Elevated levels of all three naturally occurring polyamines, spermine , spermidine and...protein in multiple human breast cancer cell lines. This suppression is both time and dose dependent. A relationship between oligoamine structure , growth

Modulation of TIP60 by Human Papilloma Virus in Breast Cancer

DTIC Science & Technology

2013-04-01

infection caused by adenovirus make us hypothesize that adenovirus can also be a etiological agent or can augment the breast epithelial cells...cells. These cells were cultured in selective HAT medium to select for fused cells called Hybridoma cells. These hybridoma cells were cultured and...KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA et al. Association between an oncogenes and an anti -oncogene: the adenovirus EIA protein binds to

Management of patients with rheumatoid arthritis in Latin America: a consensus position paper from Pan-American League of Associations of Rheumatology and Grupo Latino Americano De Estudio De Artritis Reumatoide.

PubMed

Massardo, Loreto; Suárez-Almazor, María E; Cardiel, Mario H; Nava, Arnulfo; Levy, Roger A; Laurindo, Ieda; Soriano, Enrique R; Acevedo-Vázquez, Eduardo; Millán, Alberto; Pineda-Villaseñor, Carlos; Galarza-Maldonado, Claudio; Caballero-Uribe, Carlo V; Espinosa-Morales, Rolando; Pons-Estel, Bernardo A

2009-06-01

A consensus meeting of representatives of 18 Latin-American and Caribbean countries gathered in Reñaca, Chile, for 2 days to identify problems and provide recommendations for the care of patients with rheumatoid arthritis (RA) in Latin America, a region where poverty and other health priorities make the efforts to provide effective and high quality care difficult. This report includes recommendations for health professionals, patients, and health authorities in Latin America, with an emphasis on education and therapeutic issues. Fifty-one rheumatologists (list available only online on the JCR website) from 18 Latin-American and Caribbean countries with a special interest in RA participated in the consensus meeting. Participants were experts identified and appointed by the National Societies of Rheumatology affiliated with the Pan-American League of Associations for Rheumatology (PANLAR) and by the Grupo Latino Americano De Estudio de Artritis Reumatoide (GLADAR)-an independent group of Latin American rheumatologist researchers were also invited to the meeting. Eight topics were identified as priorities: patient, community and allied health professional education, health policy and decision making, programs for early detection and appropriate treatment of RA, role of classic disease modifying antirheumatic drugs (DMARDs), role of biologic therapy, and drug safety surveillance. To reach consensus, a survey with questions relevant to the topic of interest was sent to all participants before the meeting. During a 2 day meeting, the answers of the survey were reviewed and discussed by each group, with final recommendations on action items. The specific topic of the survey was answered by 86% of the participants and 68% of them answered the entire survey. It was agreed that RA and rheumatic diseases which are currently not but should be public health priorities in Latin America, because of their prevalence and impact on quality of life. Strategic areas identified as priorities for our region included: early diagnosis and access to care by multidisciplinary teams, creation of databases to identify infections with the use of biologic agents in RA which are relevant to Latin America, and overall efforts to improve the care of RA patients in accordance with international standards. Implementation of educational programs aimed to improve self-management for patients with RA was also considered crucial.

Flexible Wing Base Micro Aerial Vehicles: Micro Air Vehicles (MAVs) for Surveillance and Remote Sensor Delivery

NASA Technical Reports Server (NTRS)

Ifju, Peter

2002-01-01

Micro Air Vehicles (MAVs) will be developed for tracking individuals, locating terrorist threats, and delivering remote sensors, for surveillance and chemical/biological agent detection. The tasks are: (1) Develop robust MAV platform capable of carrying sensor payload. (2) Develop fully autonomous capabilities for delivery of sensors to remote and distant locations. The current capabilities and accomplishments are: (1) Operational electric (inaudible) 6-inch MAVs with novel flexible wing, providing superior aerodynamic efficiency and control. (2) Vision-based flight stability and control (from on-board cameras).

Retrograde Amnesia for Episodic and Semantic Memories in Amnestic Mild Cognitive Impairment.

PubMed

De Simone, Maria Stefania; Fadda, Lucia; Perri, Roberta; De Tollis, Massimo; Aloisi, Marta; Caltagirone, Carlo; Carlesimo, Giovanni Augusto

2017-01-01

Retrograde amnesia (RA), which includes loss of memory for past personal events (autobiographical RA) and for acquired knowledge (semantic RA), has been largely documented in patients with amnestic mild cognitive impairment (aMCI). However, previous studies have produced controversial results particularly concerning the temporal extent of memory impairment. Here we investigated whether, with the onset of hippocampal pathology, age of memory acquisition and retrieval frequency play different roles in modulating the progressive loss of semantic and episodic contents of retrograde memory respectively. For this purpose, aMCI patients and healthy controls were tested for the ability to recall semantic and autobiographical information related to famous public events as a function of both age of acquisition and retrieval frequency. In aMCI patients, we found that the impairment in recollecting past personal incidents was modulated by the combined action of memory age and retrieval frequency, because older and more frequently retrieved episodes are less susceptible to loss than more recent and less frequently retrieved ones. On the other side, we found that the loss of semantic information depended only on memory age, because the remoteness of the trace allows for better preservation of the memory. Our results provide evidence that the loss of the two components of retrograde memory is regulated by different mechanisms. This supports the view that diverse neural mechanisms are involved in episodic and semantic memory trace storage and retrieval, as postulated by the Multiple Trace Theory.

Contemporaneous disequilibrium of bio-optical properties in the Southern Ocean

NASA Astrophysics Data System (ADS)

Kahru, Mati; Lee, Zhongping; Mitchell, B. Greg

2017-03-01

Significant changes in satellite-detected net primary production (NPP, mg C m-2 d-1) were observed in the Southern Ocean during 2011-2016: an increase in the Pacific sector and a decrease in the Atlantic sector. While no clear physical forcing was identified, we hypothesize that the changes in NPP were associated with changes in the phytoplankton community and reflected in the concomitant bio-optical properties. Satellite algorithms for chlorophyll a concentration (Chl a, mg m-3) use a combination of estimates of the remote sensing reflectance Rrs(λ) that are statistically fitted to a global reference data set. In any particular region or point in space/time the estimate produced by the global "mean" algorithm can deviate from the true value. Reflectance anomaly (RA) is supposed to remove the first-order variability in Rrs(λ) associated with Chl a and reveal bio-optical properties that are due to the composition of phytoplankton and associated materials. Time series of RA showed variability at multiple scales, including the life span of the sensor, multiyear and annual. Models of plankton functional types using estimated Chl a as input cannot be expected to correctly resolve regional and seasonal anomalies due to biases in the Chl a estimate that they are based on. While a statistical model using RA(λ) time series can predict the times series of NPP with high accuracy (R2 = 0.82) in both Pacific and Atlantic regions, the underlying mechanisms in terms of phytoplankton groups and the associated materials remain elusive.

Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models.

PubMed

Lee, Jae-Dong; Huh, Jeong-Eun; Jeon, GeumSeon; Yang, Ha-Ru; Woo, Hyun-Su; Choi, Do-Young; Park, Dong-Suk

2009-03-01

Rheumatoid arthritis (RA) is an aggressive inflammatory disease in which cytokines/chemokines are thought to recruit leukocytes and induce angiogenesis. The aim of this study is to investigate the effect of flavonol-rich residual layer of hexane fraction from Rhus verniciflua Stokes (RVHxR) and its major compound fisetin on inflammatory cytokine/chemokine production and angiogenic factor in IL-1beta-stimulated RA fibroblast-like synovial cells (FLS) and inflammatory in vivo models. Flavonol-rich RVHxR and its major compound fisetin significantly inhibited IL-1beta-induced FLS proliferation in a dose-dependent manner. Flavonol-rich RVHxR and fisetin significantly decreased IL-1beta-induced inflammatory cytokines (TNF-alpha, interleukin (IL)-6)/chemokines (IL-8, monocyte chemoattractant protein (MCP)-1), and vascular endothelial growth factor (VEGF) of RA FLS. Flavonol-rich RVHxR dose dependently diminished the phophorylation of extracellular signal regulated kinase (ERK) and phospho-Jun NH((2))-terminal kinase (JNK), and its down regulation induced by RVHxR at nontoxic concentrations, while activated the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS. The p38 specific inhibitor SB203580 cotreatment with RVHxR effectively increased the expression of VEGF and blocked the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS, confirming a critical role of p38 MAPK pathway in angiogenesis inhibition. In experimental inflammation-related models, flavonol-rich RVHxR and fisetin have shown significant anti-inflammatory activities on vascular permeability, leukocyte migration and cellular immunity. Also, flavonol-rich RVHxR and fisetin treatments significantly reduced the incidence and severity of collagen-induced arthritis model. These results suggest that RVHxR and its major compound fisetin have shown potent suppressive effects on some inflammatory cytokines/chemokines and angiogenic factor in IL-1beta-stimulated RA FLS and inflammatory in vivo models. We believe that flavonol-rich RVHxR is a potential therapeutic agent in the treatment of inflammatory and angiogenesis related diseases.

Military Role in Countering Terrorist Use of Weapons of Mass Destruction

DTIC Science & Technology

1999-04-01

chemical and biological mobile point detection. “The M21 Remote Sensing Chemical Agent Alarm (RSCAAL) is an automatic scanning, passive infrared sensor...The M21 detects nerve and blister agent clouds based on changes in the background infrared spectra caused by the presence of the agent vapor.”15...required if greater than 3 years since last vaccine. VEE Yes Multiple vaccines required. VHF No Botulism Yes SEB No Ricin No Mycotoxin s No Source

Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis.

PubMed

Finckh, Axel; Bansback, Nick; Marra, Carlo A; Anis, Aslam H; Michaud, Kaleb; Lubin, Stanley; White, Marc; Sizto, Sonia; Liang, Matthew H

2009-11-03

Long-term control or remission of rheumatoid arthritis (RA) may be possible with very early treatment. However, no optimal first therapeutic strategy has been determined. To assess the potential cost-effectiveness of major therapeutic strategies for very early RA. Decision analytic model with probabilistic sensitivity analyses. Published data, the National Data Bank for Rheumatic Diseases, and actual 2007 hospital costs. U.S. adults with very early RA (symptom duration

Aerial sketchmapping for monitoring forest conditions in Southern Brazil

Treesearch

Y. M. Malheiros de Oliveira; M. A. Doetzer Rosot; N. B. da Luz; W. M. Ciesla; E.W. Johnson; R. Rhea; J.F. Jr. Penteado

2006-01-01

Aerial sketchmapping is a simple, low cost remote sensing method used for detection and mapping of forest damage caused by biotic agents (insects, pathogens and other pests) and abiotic agents (wind, fire, storms, hurricane, ice storms) in North America. This method was introduced to Brazil in 2001/2002 via a USDA Forest Service/EMBRAPA technical exchange program,...

Survival of the Human Granulocytic Ehrlichiosis Agent under Refrigeration Conditions

PubMed Central

Kalantarpour, Fatemeh; Chowdhury, Ishraq; Wormser, Gary P.; Aguero-Rosenfeld, Maria E.

2000-01-01

The human granulocytic ehrlichiosis (HGE) agent in infected blood specimens remained viable during refrigeration at 4°C for up to 18 days. These findings suggest that blood specimens submitted for culture may withstand transportation to a remote laboratory. HGE should be added to the list of infections potentially transmitted by blood transfusion. PMID:10835014

Morphological Differentiation Towards Neuronal Phenotype of SH-SY5Y Neuroblastoma Cells by Estradiol, Retinoic Acid and Cholesterol.

PubMed

Teppola, Heidi; Sarkanen, Jertta-Riina; Jalonen, Tuula O; Linne, Marja-Leena

2016-04-01

Human SH-SY5Y neuroblastoma cells maintain their potential for differentiation and regression in culture conditions. The induction of differentiation could serve as a strategy to inhibit cell proliferation and tumor growth. Previous studies have shown that differentiation of SH-SY5Y cells can be induced by all-trans-retinoic-acid (RA) and cholesterol (CHOL). However, signaling pathways that lead to terminal differentiation of SH-SY5Y cells are still largely unknown. The goal of this study was to examine in the RA and CHOL treated SH-SY5Y cells the additive impacts of estradiol (E2) and brain-derived neurotrophic factor (BDNF) on cell morphology, cell population growth, synaptic vesicle recycling and presence of neurofilaments. The above features indicate a higher level of neuronal differentiation. Our data show that treatment for 10 days in vitro (DIV) with RA alone or when combined with E2 (RE) or CHOL (RC), but not when combined with BDNF (RB), significantly (p < 0.01) inhibited the cell population growth. Synaptic vesicle recycling, induced by high-K(+) depolarization, was significantly increased in all treatments where RA was included (RE, RC, RB, RCB), and when all agents were added together (RCBE). Specifically, our results show for the first time that E2 treatment can alone increase synaptic vesicle recycling in SH-SY5Y cells. This work contributes to the understanding of the ways to improve suppression of neuroblastoma cells' population growth by inducing maturation and differentiation.

Sustained clinical remission in rheumatoid arthritis: prevalence and prognostic factors in an inception cohort of patients treated with conventional DMARDS.

PubMed

Jayakumar, Keeranur; Norton, Sam; Dixey, Josh; James, David; Gough, Andrew; Williams, Peter; Prouse, Peter; Young, Adam

2012-01-01

Clinical remission is now a realistic goal in managing RA following the introduction of biologic agents. As there are limited data on sustained remission in conventionally treated RA, this study examines prevalence and predictive factors of sustained remission in a pre-biologic inception cohort of RA. Patients with recent onset RA and before use of DMARDs were recruited from nine centres. Standard clinical and radiological assessments were recorded at baseline and yearly. Point remission was defined by DAS of <1.6, and sustained remission if DAS was <1.6 at all 3-, 4- and 5-year follow-ups. Sustained remission was compared with baseline features, with mortality and with radiological and functional progression in 704 patients. Point remission at 3, 4 and 5 years was 25, 26 and 22%, respectively. Eleven per cent (n = 78) had sustained remission. Male sex, short duration of symptoms and less tender joints at baseline were independent predictors of sustained remission. These patients had fewer DMARD therapies and less radiographic progression by 5 years. Mean HAQ decreased from 0.79 to 0.13 (P < 0.001) in sustained remission, compared with an increase from 0.92 to 1.1 (P < 0.001) in the non-remission group. Sustained clinical remission by 5 years with conventional DMARDs was 11%, half as likely as point remission. Prognostic factors were similar to comparable studies and simple to measure. Patients in sustained clinical remission showed less structural damage and better functional outcomes.

A Community-Based IoT Personalized Wireless Healthcare Solution Trial.

PubMed

Catherwood, Philip A; Steele, David; Little, Mike; Mccomb, Stephen; Mclaughlin, James

2018-01-01

This paper presents an advanced Internet of Things point-of-care bio-fluid analyzer; a LoRa/Bluetooth-enabled electronic reader for biomedical strip-based diagnostics system for personalized monitoring. We undertake test simulations (technology trial without patient subjects) to demonstrate potential of long-range analysis, using a disposable test 'key' and companion Android app to form a diagnostic platform suitable for remote point-of-care screening for urinary tract infection (UTI). The 868 MHz LoRaWAN-enabled personalized monitor demonstrated sound potential with UTI test results being correctly diagnosed and transmitted to a remote secure cloud server in every case. Tests ranged over distances of 1.1-6.0 Km with radio path losses from 119-141 dB. All tests conducted were correctly and robustly received at the base station and relayed to the secure server for inspection. The UTI test strips were visually inspected for correct diagnosis based on color change and verified as 100% accurate. Results from testing across a number of regions indicate that such an Internet of Things medical solution is a robust and simple way to deliver next generation community-based smart diagnostics and disease management to best benefit patients and clinical staff alike. This significant step can be applied to any type of home or region, particularly those lacking suitable mobile signals, broadband connections, or even landlines. It brings subscription-free long-range bio-telemetry to healthcare providers and offers savings on regular clinician home visits or frequent clinic visits by the chronically ill. This paper highlights practical hurdles in establishing an Internet of Medical Things network, assisting informed deployment of similar future systems.

A Community-Based IoT Personalized Wireless Healthcare Solution Trial

PubMed Central

Steele, David; Little, Mike; Mccomb, Stephen; Mclaughlin, James

2018-01-01

This paper presents an advanced Internet of Things point-of-care bio-fluid analyzer; a LoRa/Bluetooth-enabled electronic reader for biomedical strip-based diagnostics system for personalized monitoring. We undertake test simulations (technology trial without patient subjects) to demonstrate potential of long-range analysis, using a disposable test ‘key’ and companion Android app to form a diagnostic platform suitable for remote point-of-care screening for urinary tract infection (UTI). The 868 MHz LoRaWAN-enabled personalized monitor demonstrated sound potential with UTI test results being correctly diagnosed and transmitted to a remote secure cloud server in every case. Tests ranged over distances of 1.1–6.0 Km with radio path losses from 119–141 dB. All tests conducted were correctly and robustly received at the base station and relayed to the secure server for inspection. The UTI test strips were visually inspected for correct diagnosis based on color change and verified as 100% accurate. Results from testing across a number of regions indicate that such an Internet of Things medical solution is a robust and simple way to deliver next generation community-based smart diagnostics and disease management to best benefit patients and clinical staff alike. This significant step can be applied to any type of home or region, particularly those lacking suitable mobile signals, broadband connections, or even landlines. It brings subscription-free long-range bio-telemetry to healthcare providers and offers savings on regular clinician home visits or frequent clinic visits by the chronically ill. This paper highlights practical hurdles in establishing an Internet of Medical Things network, assisting informed deployment of similar future systems. PMID:29888145

A Phase IIb Study of ABT‐494, a Selective JAK‐1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor Therapy

PubMed Central

Emery, Paul; Camp, Heidi S.; Friedman, Alan; Wang, Li; Othman, Ahmed A.; Khan, Nasser; Pangan, Aileen L.; Jungerwirth, Steven; Keystone, Edward C.

2016-01-01

Objective To compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti–tumor necrosis factor (anti‐TNF) agent. Methods In this 12‐week, double‐blind, placebo‐controlled, dose‐ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti‐TNF agent were randomized equally to receive immediate‐release ABT‐494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12. Results At week 12, significantly more patients receiving ABT‐494 (53–71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose‐response relationship among all ABT‐494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT‐494 (36–42% and 22–26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) were significantly greater for all doses of ABT‐494 than for placebo (P ≤ 0.01). Onset of action of ABT‐494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28‐CRP (P < 0.001 for 6–18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT‐494, but no infections were serious. No deaths were reported among those receiving ABT‐494. Conclusion In patients with an inadequate response or intolerance to anti‐TNF agents, ABT‐494 added to MTX showed rapid, dose‐dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class. No new AEs were identified. PMID:27389975

Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cells.

PubMed

Ferrari-Toninelli, Giulia; Bonini, Sara Anna; Uberti, Daniela; Buizza, Laura; Bettinsoli, Paola; Poliani, Pietro Luigi; Facchetti, Fabio; Memo, Maurizio

2010-12-01

High-risk neuroblastoma is a severe pediatric tumor characterized by poor prognosis. Understanding the molecular mechanisms involved in tumor development and progression is strategic for the improvement of pharmacological therapies. Notch was recently proposed as a pharmacological target for the therapy of several cancers and is emerging as a new neuroblastoma-related molecular pathway. However, the precise role played by Notch in this cancer remains to be studied extensively. Here, we show that Notch activation by the Jagged1 ligand enhances the proliferation of neuroblastoma cells, and we propose the possible use of Notch-blocking γ-secretase inhibitors (GSIs) in neuroblastoma therapy. Two different GSIs, Compound E and DAPT, were tested alone or in combination with 13-cis retinoic acid (RA) on neuroblastoma cell lines. SH-SY5Y and IMR-32 cells were chosen as paradigms of lower and higher malignancy, respectively. Used alone, GSIs induced complete cell growth arrest, promoted neuronal differentiation, and significantly reduced cell motility. The combination of GSIs and 13-cis RA resulted in the enhanced growth inhibition, differentiation, and migration of neuroblastoma cells. In summary, our data suggest that a combination of GSIs with 13-cis RA offers a therapeutic advantage over a single agent, indicating a potential novel therapy for neuroblastoma.

Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis

PubMed Central

Migita, K; Izumi, Y; Jiuchi, Y; Kozuru, H; Kawahara, C; Izumi, M; Sakai, T; Nakamura, M; Motokawa, S; Nakamura, T; Kawakami, A

2014-01-01

The Janus kinase inhibitor tofacitinib is currently being investigated as a disease-modifying agent in rheumatoid arthritis (RA). We investigated the in-vivo effects of tofacitinib treatment for 4 weeks on elevated circulating acute-phase serum amyloid (SAA) levels in 14 Japanese patients with RA. SAA levels fell from 110·5 ± 118·5 μg/ml (mean ± standard deviation) at treatment initiation to 15·3 ± 13·3 μg/ml after 4 weeks treatment with tofacitinib. The reduction in SAA levels was greater in patients receiving tofacitinib plus methotrexate compared with those receiving tofacitinib monotherapy. Tofacitinib was also associated with reduced serum interleukin (IL)-6, but had no effect on serum levels of soluble IL-6 receptor. Patients were divided into groups with adequate (normalization) and inadequate SAA responses (without normalization). Serum IL-6 levels were reduced more in the group with adequate SAA response compared with those with inadequate SAA response. These results suggest that tofacitinib down-regulates the proinflammatory cytokine, IL-6, accompanied by reduced serum SAA levels in patients with active RA. The ability to regulate elevated serum IL-6 and SAA levels may explain the anti-inflammatory activity of tofacitinib. PMID:24665995

[Impact of a PACS/RIS-integrated speech recognition system on radiology reporting time and report availability].

PubMed

Trumm, C G; Glaser, C; Paasche, V; Crispin, A; Popp, P; Küttner, B; Francke, M; Nissen-Meyer, S; Reiser, M

2006-04-01

Quantification of the impact of a PACS/RIS-integrated speech recognition system (SRS) on the time expenditure for radiology reporting and on hospital-wide report availability (RA) in a university institution. In a prospective pilot study, the following parameters were assessed for 669 radiographic examinations (CR): 1. time requirement per report dictation (TED: dictation time (s)/number of images [examination] x number of words [report]) with either a combination of PACS/tape-based dictation (TD: analog dictation device/mini-cassette/transcription) or PACS/RIS/speech recognition system (RR: remote recognition/transcription and OR: online recognition/self-correction by radiologist), respectively, and 2. the Report Turnaround Time (RTT) as the time interval from the entry of the first image into the PACS to the available RIS/HIS report. Two equal time periods were chosen retrospectively from the RIS database: 11/2002 - 2/2003 (only TD) and 11/2003 - 2/2004 (only RR or OR with speech recognition system [SRS]). The mid-term (> or = 24 h, 24 h intervals) and short-term (< 24 h, 1 h intervals) RA after examination completion were calculated for all modalities and for CR, CT, MR and XA/DS separately. The relative increase in the mid-term RA (RIMRA: related to total number of examinations in each time period) and increase in the short-term RA (ISRA: ratio of available reports during the 1st to 24th hour) were calculated. Prospectively, there was a significant difference between TD/RR/OR (n = 151/257/261) regarding mean TED (0.44/0.54/0.62 s [per word and image]) and mean RTT (10.47/6.65/1.27 h), respectively. Retrospectively, 37 898/39 680 reports were computed from the RIS database for the time periods of 11/2002 - 2/2003 and 11/2003 - 2/2004. For CR/CT there was a shift of the short-term RA to the first 6 hours after examination completion (mean cumulative RA 20 % higher) with a more than three-fold increase in the total number of available reports within 24 hours (all modalities). The RIMRA for CR/CT/MR was 3.1/5.8/4.0 in the first 24 hours, and 2.0 for XA/DS in the second 24-hour interval. In comparison to tape-based dictation, an SRS results in a significantly higher primary time expenditure and a modified report dictation workflow. In a university institution, a PACS/RIS-integrated SRS achieves a marked improvement in both short- and mid-term RA which eventually results in an improvement in patient care.

Pattern and predictors of the initiation of biologic agents for the treatment of rheumatoid arthritis in the United States: an analysis using a large observational data bank.

PubMed

DeWitt, Esi Morgan; Lin, Li; Glick, Henry A; Anstrom, Kevin J; Schulman, Kevin A; Reed, Shelby D

2009-08-01

The aim of this study was to identify factors associated with the initiation of biologic agents for the treatment of rheumatoid arthritis (RA) in a large US observational cohort. Semiannual patient-reported data in the ARAMIS (Arthritis, Rheumatism and Aging Medical Information System) data bank from January 1998 to January 2006 were analyzed retrospectively using pooled logistic regression (with adjustment for center-level and temporal effects) to identify patient-, disease-, and treatment-related characteristics associated with the initiation of biologics for the treatment of RA. The analysis included 1545 patients from 7 US centers. By 2006, 41.4% of 679 patients remaining in the sample had received biologics. Initiation of biologics was significantly associated with greater disability in the previous 6-month period (per 1-unit increase in Health Assessment Questionnaire score: odds ratio [OR] = 1.45; 95% CI, 1.22-1.72; P < 0.01) and treatment in the previous period with steroids (OR = 2.24; 95% CI, 1.76-2.85; P < 0.01) or nonbiologic disease-modifying antirheumatic drugs (OR = 2.43; 95% CI, 1.71-3.46; P < 0.01). Two sociodemographic factors were significant predictors of decreased use of biologics: older age (per 10 years: OR = 0.74; 95% CI, 0.660.82; P < 0.01) and lower annual income (per $10,000 reduction: OR = 0.95; 95% CI, 0.91-1.00; P = 0.04). There were no significant differences with respect to sex, race, employment status, comorbidity, previous NSAID use, or treatment center. Disease- and treatment-related factors were significant predictors of the initiation of biologics for RA. Independent of these factors, however, biologics were less often used in patients who were older and those with lower incomes. Use of biologics increased steadily over the period studied.

Objects and mappings: incompatible principles of display design - a critique of Marino and Mahan.

PubMed

Bennett, Kevin B

2005-01-01

Representation aiding (and similar approaches that share the general orientation) has a great deal of utility, predictive ability, and explanatory power. Marino and Mahan (2005) discuss principles that are critical to the RA approach (configurality, emergent features, and mappings) in a reasonable fashion. However, the application of these principles is far from reasonable. The authors explicitly realize the potential for interactions between nutrients: "The nutritional quality of a food product is a multidimensional concept, and higher order interactions between nutrients may exist" (p. 126). However, they made no effort to discover the nature of these interactions: "No attempt was made to identify contingent interactions between nutrients" (p. 126). Despite not knowing the nature of the interactions between nutrients, they purposely chose a highly configural display that produced numerous emergent features dependent upon these interactions: "A radial spoke display was selected because of the strong configural properties of such display formats (Bennett & Flach, 1992)" (p. 124). Finally, the authors show apparent disdain for the specific mappings among domain, agent, and display that are fundamental to the RA approach: "[O]ther configural display formats could have been used" (p. 124). It is impossible to reconcile these statements and the RA approach to display design. However, these statements make perfect sense if a perceptual object is a guiding principle in one's approach to display design. Marino and Mahan (2005) draw heavily upon the principle of a perceptual object in their design justifications, experimental predictions, and interpretations of results. As we have indicated here and elsewhere (Bennett & Flach, 1992), we believe that these two sets of organizing principles for display design (i.e., objects and mappings) are incompatible. Display design will never be an exact science; there will always be elements of art and creativity. However, the guiding principles have moved well beyond the simple strategy of throwing variables into a geometric object format and relying upon the human agent's powerful perceptual systems to carry the design.

Effect of enamel etching time on roughness and bond strength.

PubMed

Barkmeier, Wayne W; Erickson, Robert L; Kimmes, Nicole S; Latta, Mark A; Wilwerding, Terry M

2009-01-01

The current study examined the effect of different enamel conditioning times on surface roughness and bond strength using an etch-and-rinse system and four self-etch adhesives. Surface roughness (Ra) and composite to enamel shear bond strengths (SBS) were determined following the treatment of flat ground human enamel (4000 grit) with five adhesive systems: (1) Adper Single Bond Plus (SBP), (2) Adper Prompt L-Pop (PLP), (3) Clearfil SE Bond (CSE), (4) Clearfil S3 Bond (CS3) and (5) Xeno IV (X4), using recommended treatment times and an extended treatment time of 60 seconds (n = 10/group). Control groups were also included for Ra (4000 grit surface) and SBS (no enamel treatment and Adper Scotchbond Multi-Purpose Adhesive). For surface roughness measurements, the phosphoric acid conditioner of the SBP etch-and-rinse system was rinsed from the surface with an air-water spray, and the other four self-etch adhesive agents were removed with alternating rinses of water and acetone. A Proscan 2000 non-contact profilometer was used to determine Ra values. Composite (Z100) to enamel bond strengths (24 hours) were determined using Ultradent fixtures and they were debonded with a crosshead speed of 1 mm/minute. The data were analyzed with ANOVA and Fisher's LSD post-hoc test. The etch-and- rinse system (SBP) produced the highest Ra (microm) and SBS (MPa) using both the recommended treatment time (0.352 +/- 0.028 microm and 40.5 +/- 6.1 MPa) and the extended treatment time (0.733 +/- 0.122 microm and 44.2 +/- 8.2 MPa). The Ra and SBS of the etch-and-rinse system were significantly greater (p < 0.05) than all the self-etch systems and controls. Increasing the treatment time with phosphoric acid (SBP) and PLP produced greater surface roughness (p < 0.05) but did not result in significantly higher bond strengths (p > 0.05).

Internalization of rituximab and the efficiency of B Cell depletion in rheumatoid arthritis and systemic lupus erythematosus.

PubMed

Reddy, Venkat; Cambridge, Geraldine; Isenberg, David A; Glennie, Martin J; Cragg, Mark S; Leandro, Maria

2015-05-01

Rituximab, a type I anti-CD20 monoclonal antibody (mAb), induces incomplete B cell depletion in some patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), thus contributing to a poor clinical response. The mechanisms of this resistance remain elusive. The purpose of this study was to determine whether type II mAb are more efficient than type I mAb at depleting B cells from RA and SLE patients, whether internalization influences the efficiency of depletion, and whether Fcγ receptor type IIb (FcγRIIb) and the B cell receptor regulate this internalization process. We used an in vitro whole blood B cell-depletion assay to assess the efficiency of depletion, flow cytometry to study cell surface protein expression, and surface fluorescence-quenching assays to assess rituximab internalization, in samples from patients with RA and patients with SLE. Paired t-test or Mann-Whitney U test was used to compare groups, and Spearman's rank correlation test was used to assess correlation. We found that type II mAb internalized significantly less rituximab than type I mAb and depleted B cells from patients with RA and SLE at least 2-fold more efficiently than type I mAb. Internalization of rituximab was highly variable between patients, was regulated by FcγRIIb, and inversely correlated with cytotoxicity in whole blood B cell-depletion assays. The lowest levels of internalization were seen in IgD- B cells, including postswitched (IgD-CD27+) memory cells. Internalization of type I anti-CD20 mAb was also partially inhibited by anti-IgM stimulation. Variability in internalization of rituximab was observed and was correlated with impaired B cell depletion. Therefore, slower-internalizing type II mAb should be considered as alternative B cell-depleting agents for the treatment of RA and SLE. © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Combination of 13 cis-retinoic acid and tolfenamic acid induces apoptosis and effectively inhibits high-risk neuroblastoma cell proliferation.

PubMed

Shelake, Sagar; Eslin, Don; Sutphin, Robert M; Sankpal, Umesh T; Wadwani, Anmol; Kenyon, Laura E; Tabor-Simecka, Leslie; Bowman, W Paul; Vishwanatha, Jamboor K; Basha, Riyaz

2015-11-01

Chemotherapeutic regimens used for the treatment of Neuroblastoma (NB) cause long-term side effects in pediatric patients. NB arises in immature sympathetic nerve cells and primarily affects infants and children. A high rate of relapse in high-risk neuroblastoma (HRNB) necessitates the development of alternative strategies for effective treatment. This study investigated the efficacy of a small molecule, tolfenamic acid (TA), for enhancing the anti-proliferative effect of 13 cis-retinoic acid (RA) in HRNB cell lines. LA1-55n and SH-SY5Y cells were treated with TA (30μM) or RA (20μM) or both (optimized doses, derived from dose curves) for 48h and tested the effect on cell viability, apoptosis and selected molecular markers (Sp1, survivin, AKT and ERK1/2). Cell viability and caspase activity were measured using the CellTiter-Glo and Caspase-Glo kits. The apoptotic cell population was determined by flow cytometry with Annexin-V staining. The expression of Sp1, survivin, AKT, ERK1/2 and c-PARP was evaluated by Western blots. The combination therapy of TA and RA resulted in significant inhibition of cell viability (p<0.0001) when compared to individual agents. The anti-proliferative effect is accompanied by a decrease in Sp1 and survivin expression and an increase in apoptotic markers, Annexin-V positive cells, caspase 3/7 activity and c-PARP levels. Notably, TA+RA combination also caused down regulation of AKT and ERK1/2 suggesting a distinct impact on survival and proliferation pathways via signaling cascades. This study demonstrates that the TA mediated inhibition of Sp1 in combination with RA provides a novel therapeutic strategy for the effective treatment of HRNB in children. Copyright © 2015 Elsevier Ltd. All rights reserved.

Internalization of Rituximab and the Efficiency of B Cell Depletion in Rheumatoid Arthritis and Systemic Lupus Erythematosus

PubMed Central

Cambridge, Geraldine; Isenberg, David A.; Glennie, Martin J.; Cragg, Mark S.; Leandro, Maria

2015-01-01

Objective Rituximab, a type I anti‐CD20 monoclonal antibody (mAb), induces incomplete B cell depletion in some patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), thus contributing to a poor clinical response. The mechanisms of this resistance remain elusive. The purpose of this study was to determine whether type II mAb are more efficient than type I mAb at depleting B cells from RA and SLE patients, whether internalization influences the efficiency of depletion, and whether Fcγ receptor type IIb (FcγRIIb) and the B cell receptor regulate this internalization process. Methods We used an in vitro whole blood B cell–depletion assay to assess the efficiency of depletion, flow cytometry to study cell surface protein expression, and surface fluorescence–quenching assays to assess rituximab internalization, in samples from patients with RA and patients with SLE. Paired t‐test or Mann‐Whitney U test was used to compare groups, and Spearman's rank correlation test was used to assess correlation. Results We found that type II mAb internalized significantly less rituximab than type I mAb and depleted B cells from patients with RA and SLE at least 2‐fold more efficiently than type I mAb. Internalization of rituximab was highly variable between patients, was regulated by FcγRIIb, and inversely correlated with cytotoxicity in whole blood B cell–depletion assays. The lowest levels of internalization were seen in IgD– B cells, including postswitched (IgD–CD27+) memory cells. Internalization of type I anti‐CD20 mAb was also partially inhibited by anti‐IgM stimulation. Conclusion Variability in internalization of rituximab was observed and was correlated with impaired B cell depletion. Therefore, slower‐internalizing type II mAb should be considered as alternative B cell–depleting agents for the treatment of RA and SLE. PMID:25916583

Rosmarinic acid, a new snake venom phospholipase A2 inhibitor from Cordia verbenacea (Boraginaceae): antiserum action potentiation and molecular interaction.

PubMed

Ticli, Fábio K; Hage, Lorane I S; Cambraia, Rafael S; Pereira, Paulo S; Magro, Angelo J; Fontes, Marcos R M; Stábeli, Rodrigo G; Giglio, José R; França, Suzelei C; Soares, Andreimar M; Sampaio, Suely V

2005-09-01

Many plants are used in traditional medicine as active agents against various effects induced by snakebite. The methanolic extract from Cordia verbenacea (Cv) significantly inhibited paw edema induced by Bothrops jararacussu snake venom and by its main basic phospholipase A2 homologs, namely bothropstoxins I and II (BthTXs). The active component was isolated by chromatography on Sephadex LH-20 and by RP-HPLC on a C18 column and identified as rosmarinic acid (Cv-RA). Rosmarinic acid is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid [2-O-cafeoil-3-(3,4-di-hydroxy-phenyl)-R-lactic acid]. This is the first report of RA in the species C. verbenacea ('baleeira', 'whaler') and of its anti-inflammatory and antimyotoxic properties against snake venoms and isolated toxins. RA inhibited the edema and myotoxic activity induced by the basic PLA2s BthTX-I and BthTX-II. It was, however, less efficient to inhibit the PLA2 activity of BthTX-II and, still less, the PLA2 and edema-inducing activities of the acidic isoform BthA-I-PLA2 from the same venom, showing therefore a higher inhibitory activity upon basic PLA2s. RA also inhibited most of the myotoxic and partially the edema-inducing effects of both basic PLA2s, thus reinforcing the idea of dissociation between the catalytic and pharmacological domains. The pure compound potentiated the ability of the commercial equine polyvalent antivenom in neutralizing lethal and myotoxic effects of the crude venom and of isolated PLA2s in experimental models. CD data presented here suggest that, after binding, no significant conformation changes occur either in the Cv-RA or in the target PLA2. A possible model for the interaction of rosmarinic acid with Lys49-PLA2 BthTX-I is proposed.

Systemic blockade of TNF-α does not improve insulin resistance in humans.

PubMed

Ferraz-Amaro, I; Arce-Franco, M; Muñiz, J; López-Fernández, J; Hernández-Hernández, V; Franco, A; Quevedo, J; Martínez-Martín, J; Díaz-González, F

2011-10-01

The purpose of this study was to determine whether long-term modulation of inflammatory activity by tumor necrosis factor (TNF)-α inhibitors has some influence on insulin resistance (IR). 16 active rheumatoid arthritis (RA) patients without CV risk factors treated with anti-TNF-α agents were included in this study. RA activity by disease activity score 28, IR by HOMA2-IR, body composition by impedance analysis, physical activity by accelerometry, abdominal fat distribution by magnetic resonance imaging, and serum level of key adipokines by ELISA were measured at baseline and during a 1-year follow-up period. Patient body mass index increased significantly (26.94 ± 3.88 vs. 28.06 ± 4.57 kg/m2, p=0.02) after 1 year of treatment. Body composition, in terms of fat and fat-free mass, remained unchanged except for a significant elevation in body cell mass (25.50 ± 4.60 vs. 26.60 ± 3.17 kg, p=0.02). Basal levels of IR in the RA patients included in this study were significantly higher than healthy controls (1.6 ± 0.8 vs. 1.11 ± 0.56, p=0.011) but did not change during the follow-up. Nor did basal concentrations of adiponectin, visfatin, leptin, ghrelin, resistin, and apelin in response to anti-TNF-α treatment; only retinol-binding protein 4, showed a significant increase (51.7 ± 32.7 vs. 64.9 ± 28.4 μg/ml, p=0.03) at the end of the study. IR, adiposity distribution, and serum levels of most adipokines are not significantly affected by long-term inhibition of TNF-α in RA patients. Our data suggest that although systemic blockade of TNF-α exerts an anticachectic effect in RA patients, it does not seem to play a major role in IR. © Georg Thieme Verlag KG Stuttgart · New York.

Long-term survival of subcutaneous anti-tumor necrosis factor biological drugs administered between 2008 and 2012 in a cohort of rheumatoid arthritis patients.

PubMed

Alvarez Rivas, Noelia; Vazquez Rodriguez, Tomas R; Miranda Filloy, Jose A; Garcia-Porrua, Carlos; Sanchez-Andrade Fernández, Amalia

2017-05-25

To compare the survival of subcutaneous anti-tumor necrosis factor (TNF) drugs used between 2008 and 2012 prescribed in accordance with clinical practice. Retrospective, observational study of the patients in our center diagnosed with rheumatoid arthritis (RA). We included patients who had received a subcutaneous anti-TNF agent for at least 6 months. The data were analyzed using the SPSS V17.0 statistical package. Forty-nine RA patients started subcutaneous biological treatment with an anti-TNF agent (32 with etanercept and 17 with adalimumab). The mean age was 45.94 years (75.5% female). The mean disease duration prior to starting anti-TNF administration was 2.67 years. The mean age at the start of treatment was 51.84 years, and the average Disease Activity Score 28 was 4.93. The median survival of the anti-TNF treatment was 8.40 years; the survival of etanercept was the longer of the two. The main reason for discontinuation was secondary failure (90.9%). In routine clinical practice, the survival of subcutaneous anti-TNF treatment was extensive and was independent of whether or not the patients received concomitant immunosuppressive therapy. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Genetic effects of ELISA-based segregation for control of bacterial kidney disease in Chinook salmon (Oncorhynchus tshawytscha)

USGS Publications Warehouse

Hard, J.J.; Elliott, D.G.; Pascho, R.J.; Chase, D.M.; Park, L.K.; Winton, J.R.; Campton, D.E.

2006-01-01

We evaluated genetic variation in ability of Chinook salmon (Oncorhynchus tshawytscha) to resist two bacterial pathogens: Renibacterium salmoninarum, the agent of bacterial kidney disease (BKD), and Listonella anguillarum, an agent of vibriosis. After measuring R. salmoninarum antigen in 499 adults by enzyme-linked immunosorbent assay (ELISA), we mated each of 12 males with high or low antigen levels to two females with low to moderate levels and exposed subsets of their progeny to each pathogen separately. We found no correlation between R. salmoninarum antigen level in parents and survival of their progeny following pathogen exposure. We estimated high heritability for resistance to R. salmoninarum (survival h2 = 0.890 ?? 0.256 (mean ?? standard error)) independent of parental antigen level, but low heritability for resistance to L. anguillarum (h2 = 0.128 ?? 0.078). The genetic correlation between these survivals (rA = -0.204 ?? 0.309) was near zero. The genetic and phenotypic correlations between survival and antigen levels among surviving progeny exposed to R. salmoninarum were both negative (rA = -0.716 ?? 0.140; rP = -0.378 ?? 0.041), indicating that variation in antigen level is linked to survival. These results suggest that selective culling of female broodstock with high antigen titers, which is effective in controlling BKD in salmon hatcheries, will not affect resistance of their progeny. ?? 2006 NRC.

Overview of the joint services lightweight standoff chemical agent detector (JSLSCAD)

NASA Astrophysics Data System (ADS)

Hammond, Barney; Popa, Mirela

2005-05-01

This paper presents a system-level description of the Joint Services Lightweight Standoff Chemical Agent Detector (JSLSCAD). JSLSCAD is a passive Fourier Transform InfraRed (FTIR) based remote sensing system for detecting chemical warfare agents. Unlike predecessor systems, JSLSCAD is capable of operating while on the move to accomplish reconnaissance, surveillance, and contamination avoidance missions. Additionally, the system is designed to meet the needs for application on air and sea as well as ground mobile and fixed site platforms. The core of the system is a rugged Michelson interferometer with a flexure spring bearing mechanism and bi-directional data acquisition capability. The sensor is interfaced to a small, high performance spatial scanner that provides high-speed, two-axis area coverage. Command, control, and processing electronics have been coupled with real time control software and robust detection/discrimination algorithms. Operator interfaces include local and remote options in addition to interfaces to external communications networks. The modular system design facilitates interfacing to the many platforms targeted for JSLSCAD.

An Agent Based Collaborative Simplification of 3D Mesh Model

NASA Astrophysics Data System (ADS)

Wang, Li-Rong; Yu, Bo; Hagiwara, Ichiro

Large-volume mesh model faces the challenge in fast rendering and transmission by Internet. The current mesh models obtained by using three-dimensional (3D) scanning technology are usually very large in data volume. This paper develops a mobile agent based collaborative environment on the development platform of mobile-C. Communication among distributed agents includes grasping image of visualized mesh model, annotation to grasped image and instant message. Remote and collaborative simplification can be efficiently conducted by Internet.

Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans.

PubMed

Jiang, Lei; Yin, Jian; Ye, Lingying; Yang, Jian; Hemani, Gibran; Liu, Ai-Jun; Zou, Hejian; He, Dongyi; Sun, Lingyun; Zeng, Xiaofeng; Li, Zhanguo; Zheng, Yi; Lin, Yiping; Liu, Yi; Fang, Yongfei; Xu, Jianhua; Li, Yinong; Dai, Shengming; Guan, Jianlong; Jiang, Lindi; Wei, Qianghua; Wang, Yi; Li, Yang; Huang, Cibo; Zuo, Xiaoxia; Liu, Yu; Wu, Xin; Zhang, Libin; Zhou, Ling; Zhang, Qing; Li, Ting; Chen, Ling; Xu, Zhen; Yang, Xiaoping; Qian, Feng; Xie, Weilin; Liu, Wei; Guo, Qian; Huang, Shaolan; Zhao, Jing; Li, Mengmeng; Jin, Yanhua; Gao, Jie; Lv, Ying; Wang, Yiwen; Lin, Li; Guo, Aihua; Danoy, Patrick; Willner, Dana; Cremin, Catherine; Hadler, Johanna; Zhang, Fengchun; Zhao, Yan; Li, Mengtao; Yue, Tao; Fan, Xiaolei; Guo, Jianping; Mu, Rong; Li, Jingyi; Wu, Chao; Zeng, Ming; Wang, Jiucun; Li, Shilin; Jin, Li; Wang, Binbin; Wang, Jing; Ma, Xu; Sun, Liangdan; Zhang, Xuejun; Brown, Matthew A; Visscher, Peter M; Su, Ding-Feng; Xu, Huji

2014-05-01

To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans. A genome-wide association study was conducted in China with 952 patients and 943 controls, and 32 variants were followed up in 2,132 patients and 2,553 controls. A transpopulation meta-analysis with results from a large European RA study was also performed to compare the genetic architecture across the 2 ethnic remote populations. Three non-major histocompatibility complex (non-MHC) loci were identified at the genome-wide significance level, the effect sizes of which were larger in anti-citrullinated protein antibody (ACPA)-positive patients than in ACPA-negative patients. These included 2 novel variants, rs12617656, located in an intron of DPP4 (odds ratio [OR] 1.56, P = 1.6 × 10(-21) ), and rs12379034, located in the coding region of CDK5RAP2 (OR 1.49, P = 1.1 × 10(-16) ), as well as a variant at the known CCR6 locus, rs1854853 (OR 0.71, P = 6.5 × 10(-15) ). The analysis of ACPA-positive patients versus ACPA-negative patients revealed that rs12617656 at the DPP4 locus showed a strong interaction effect with ACPAs (P = 5.3 × 10(-18) ), and such an interaction was also observed for rs7748270 at the MHC locus (P = 5.9 × 10(-8) ). The transpopulation meta-analysis showed genome-wide overlap and enrichment in association signals across the 2 populations, as confirmed by prediction analysis. This study has expanded the list of alleles that confer risk of RA, provided new insight into the pathogenesis of RA, and added empirical evidence to the emerging polygenic nature of complex trait variation driven by common genetic variants. Copyright © 2014 by the American College of Rheumatology.

Boyfriends, Babies and Basketball: Present Lives and Future Aspirations of Young Women in a Remote Australian Aboriginal Community

ERIC Educational Resources Information Center

Senior, Kate A.; Chenhall, Richard D.

2012-01-01

This paper explores the aspirations of a group of young women in a remote Aboriginal community in the Northern Territory of Australia. It examines how their hopes and expectations are influenced by the reality of their everyday lives and the extent to which they are able to influence the course of their lives and become agents for change in their…

Towards a framework for agent-based image analysis of remote-sensing data

PubMed Central

Hofmann, Peter; Lettmayer, Paul; Blaschke, Thomas; Belgiu, Mariana; Wegenkittl, Stefan; Graf, Roland; Lampoltshammer, Thomas Josef; Andrejchenko, Vera

2015-01-01

Object-based image analysis (OBIA) as a paradigm for analysing remotely sensed image data has in many cases led to spatially and thematically improved classification results in comparison to pixel-based approaches. Nevertheless, robust and transferable object-based solutions for automated image analysis capable of analysing sets of images or even large image archives without any human interaction are still rare. A major reason for this lack of robustness and transferability is the high complexity of image contents: Especially in very high resolution (VHR) remote-sensing data with varying imaging conditions or sensor characteristics, the variability of the objects’ properties in these varying images is hardly predictable. The work described in this article builds on so-called rule sets. While earlier work has demonstrated that OBIA rule sets bear a high potential of transferability, they need to be adapted manually, or classification results need to be adjusted manually in a post-processing step. In order to automate these adaptation and adjustment procedures, we investigate the coupling, extension and integration of OBIA with the agent-based paradigm, which is exhaustively investigated in software engineering. The aims of such integration are (a) autonomously adapting rule sets and (b) image objects that can adopt and adjust themselves according to different imaging conditions and sensor characteristics. This article focuses on self-adapting image objects and therefore introduces a framework for agent-based image analysis (ABIA). PMID:27721916

Automatic and remote controlled ictal SPECT injection for seizure focus localization by use of a commercial contrast agent application pump.

PubMed

Feichtinger, Michael; Eder, Hans; Holl, Alexander; Körner, Eva; Zmugg, Gerda; Aigner, Reingard; Fazekas, Franz; Ott, Erwin

2007-07-01

In the presurgical evaluation of patients with partial epilepsy, the ictal single photon emission computed tomography (SPECT) is a useful noninvasive diagnostic tool for seizure focus localization. To achieve optimal SPECT scan quality, ictal tracer injection should be carried out as quickly as possible after the seizure onset and under highest safety conditions possible. Compared to the commonly used manual injection, an automatic administration of the radioactive tracer may provide higher quality standards for this procedure. In this study, therefore, we retrospectively analyzed efficiency and safety of an automatic injection system for ictal SPECT tracer application. Over a 31-month period, 26 patients underwent ictal SPECT by use of an automatic remote-controlled injection pump originally designed for CT-contrast agent application. Various factors were reviewed, including latency of ictal injection, radiation safety parameters, and ictal seizure onset localizing value. Times between seizure onset and tracer injection ranged between 3 and 48 s. In 21 of 26 patients ictal SPECT supported the localization of the epileptogenic focus in the course of the presurgical evaluation. In all cases ictal SPECT tracer injection was performed with a high degree of safety to patients and staff. Ictal SPECT by use of a remote-controlled CT-contrast agent injection system provides a high scan quality and is a safe and confirmatory presurgical evaluation technique in the epilepsy-monitoring unit.

Towards a framework for agent-based image analysis of remote-sensing data.

PubMed

Hofmann, Peter; Lettmayer, Paul; Blaschke, Thomas; Belgiu, Mariana; Wegenkittl, Stefan; Graf, Roland; Lampoltshammer, Thomas Josef; Andrejchenko, Vera

2015-04-03

Object-based image analysis (OBIA) as a paradigm for analysing remotely sensed image data has in many cases led to spatially and thematically improved classification results in comparison to pixel-based approaches. Nevertheless, robust and transferable object-based solutions for automated image analysis capable of analysing sets of images or even large image archives without any human interaction are still rare. A major reason for this lack of robustness and transferability is the high complexity of image contents: Especially in very high resolution (VHR) remote-sensing data with varying imaging conditions or sensor characteristics, the variability of the objects' properties in these varying images is hardly predictable. The work described in this article builds on so-called rule sets. While earlier work has demonstrated that OBIA rule sets bear a high potential of transferability, they need to be adapted manually, or classification results need to be adjusted manually in a post-processing step. In order to automate these adaptation and adjustment procedures, we investigate the coupling, extension and integration of OBIA with the agent-based paradigm, which is exhaustively investigated in software engineering. The aims of such integration are (a) autonomously adapting rule sets and (b) image objects that can adopt and adjust themselves according to different imaging conditions and sensor characteristics. This article focuses on self-adapting image objects and therefore introduces a framework for agent-based image analysis (ABIA).

HBA1C CONTROL AND COST-EFFECTIVENESS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS INITIATED ON CANAGLIFLOZIN OR A GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONIST IN A REAL-WORLD SETTING.

PubMed

Wysham, Carol H; Pilon, Dominic; Ingham, Mike; Lafeuille, Marie-Hélène; Emond, Bruno; Kamstra, Rhiannon; Pfeifer, Michael; Lefebvre, Patrick

2018-03-01

To compare glycated hemoglobin (HbA1c) control and medication costs between patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin 300 mg (CANA) or a glucagon-like peptide 1 receptor agonist (GLP-1 RA) in a real-world setting. Adults with T2DM newly initiated on CANA or a GLP-1 RA (index date) were identified from IQVIA ™ Real-World Data Electronic Medical Records U.S. database (March 29, 2012-April 30, 2016). Inverse probability of treatment weighting accounted for differences in baseline characteristics. HbA1c levels at 3-month intervals were compared using generalized estimating equations. Medication costs used wholesale acquisition costs. For both cohorts (CANA: n = 11,435; GLP-1 RA: n = 11,582), HbA1c levels decreased at 3 months postindex and remained lower through 30 months. Absolute changes in mean HbA1c from index to 3 months postindex for CANA and GLP-1 RA were -1.16% and -1.21% (patients with baseline HbA1c ≥7% [53 mmol/mol]); -1.54% and -1.51% (patients with baseline HbA1c ≥8% [64 mmol/mol]); and -2.13% and -1.99% (patients with baseline HbA1c ≥9% [75 mmol/mol]), respectively. Postindex, CANA patients with baseline HbA1c ≥7% had similar HbA1c levels at each interval versus GLP-1 RA patients, except 9 months (mean HbA1c, 7.75% [61 mmol/mol] vs. 7.86% [62 mmol/mol]; P = .0305). CANA patients with baseline HbA1c ≥8% and ≥9% had consistently lower HbA1c numerically versus GLP-1 RA patients and statistically lower HbA1c at 9 (baseline HbA1c ≥8% or ≥9%), 27, and 30 months (baseline HbA1c ≥9%). Continuous 12-month medication cost $3,326 less for CANA versus GLP-1 RA. This retrospective study demonstrated a similar evolution of HbA1c levels among CANA and GLP-1 RA patients in a real-world setting. Lower medication costs suggest CANA is economically dominant over GLP-1 RA (similar effectiveness, lower cost). AHA = antihyperglycemic agent BMI = body mass index CANA = canagliflozin 300 mg DCSI = diabetes complications severity index eGFR = estimated glomerular filtration rate EMR = electronic medical record GLP-1 RA = glucagon-like peptide 1 receptor agonist HbA1c = glycated hemoglobin ICD-9-CM = International Classification of Diseases-Ninth Revision-Clinical Modification ICD-10-CM = International Classification of Diseases-Tenth Revision-Clinical Modification IPTW = inverse probability of treatment weighting ITT = intent-to-treat MPR = medication possession ratio PDC = proportion of days covered PS = propensity score PSM = propensity score matching Quan-CCI = Quan-Charlson comorbidity index SGLT2 = sodium-glucose cotransporter 2 T2DM = type 2 diabetes mellitus WAC = wholesale acquisition cost.

Progressive loss of sensitivity to growth control by retinoic acid and transforming growth factor-beta at late stages of human papillomavirus type 16-initiated transformation of human keratinocytes.

PubMed

Creek, K E; Geslani, G; Batova, A; Pirisi, L

1995-01-01

Retinoids (vitamin A and its natural and synthetic derivatives) have shown potential as chemopreventive agents, and diets poor in vitamin A and/or its precursor beta-carotene have been linked to an increased risk of cancer at several sites including the cervix. Human papillomavirus (HPV) plays an important role in the etiology of cervical cancer. We have developed an in vitro model of cancer progression using human keratinocytes (HKc) immortalized by HPV16 DNA (HKc/HPV16). Although immortal, early passage HKc/HPV16, like normal HKc, require epidermal growth factor (EGF) and bovine pituitary extract (BPE) for proliferation and undergo terminal differentiation in response to serum and calcium. However, following prolonged culture, growth factor independent HKc/HPV16 lines that no longer require EGF and BPE can be selected (HKc/GFI). Further selection of HKc/GFI produces lines that are resistant to serum- and calcium- induced terminal differentiation (HKc/DR). HKc/DR, but not early passage HKc/HPV16, are susceptible to malignant conversion following transfection with viral Harvey ras or Herpes simplex virus type II DNA. We have investigated the sensitivity of low to high passage HKc/HPV16 and HKc/GFI to growth control by all-trans-retinoic acid (RA, an active metabolite of vitamin A). Early passage HKc/HPV16 are very sensitive to growth inhibition by RA, and in these cells RA decreases the expression of the HPV16 oncogenes E6 and E7. However, as the cells progress in culture they lose their sensitivity to RA. Growth inhibition by RA may be mediated through the cytokine transforming growth factor-beta (TGF-beta), a potent inhibitor of epithelial cell proliferation. RA treatment of HKc/HPV16 and HKc/GFI results in a dose-and time-dependent induction (maximal of 3-fold) in secreted levels of TGF-beta. Also, Northern blot analysis of mRNA isolated from HKc/HPV16 demonstrated that RA treatment induced TGF-beta 1 and TGF-beta 2 expression about 3- and 50-fold, respectively. We next studied the effect of TGF-beta 1 and TGF-beta 2 on the proliferation of early to late passage HKc/HPVa6, HKc/GFI and HKc/DR. While early passage HKc/HPV16 were as sensitive as normal HKc to growth inhibition by TGF-beta 1 and TGF-beta 2, the cells became increasingly resistant to TGF-beta during in vitro progression, with the proliferation of HKc/DR being virtually unaffected by TGF-beta 1 or TGF-beta 2 treatment. Overall, loss of growth inhibition by RA parallels loss of TGF-beta sensitivity.(ABSTRACT TRUNCATED AT 400 WORDS)

50 CFR 665.626 - Notifications.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., DEPARTMENT OF COMMERCE (CONTINUED) FISHERIES IN THE WESTERN PACIFIC Pacific Remote Island Area Fisheries... contact the appropriate NMFS enforcement agent in American Samoa, Guam, or Hawaii at least 24 hours before...

Adaptive Sensing of Time Series with Application to Remote Exploration

NASA Technical Reports Server (NTRS)

Thompson, David R.; Cabrol, Nathalie A.; Furlong, Michael; Hardgrove, Craig; Low, Bryan K. H.; Moersch, Jeffrey; Wettergreen, David

2013-01-01

We address the problem of adaptive informationoptimal data collection in time series. Here a remote sensor or explorer agent throttles its sampling rate in order to track anomalous events while obeying constraints on time and power. This problem is challenging because the agent has limited visibility -- all collected datapoints lie in the past, but its resource allocation decisions require predicting far into the future. Our solution is to continually fit a Gaussian process model to the latest data and optimize the sampling plan on line to maximize information gain. We compare the performance characteristics of stationary and nonstationary Gaussian process models. We also describe an application based on geologic analysis during planetary rover exploration. Here adaptive sampling can improve coverage of localized anomalies and potentially benefit mission science yield of long autonomous traverses.

An Imaging System to Monitor Efficacy of Adenovirus-Based Virotherapy Agents

DTIC Science & Technology

2006-02-01

The essence of oncolytic ARTICLE IN PRESS J. Li et al. / Virology xx (2005) – 9virus function is to infect and kill target cells, a concept...protein– protein interactions in living animals. Methods 29 (1), 110–122 (Jan.) Meulenbroek, R.A., Sargent, K.L., Lunde, J., Jasmin , B.J., Parks, R.J...associated with nucleoli. J Gen Virol 79 ( Pt 7), 1671-1675. Meulenbroek, R. A., Sargent, K. L., Lunde, J., Jasmin , B. J., and Parks, R. J. (2004). Use

Potential for Terahertz/Optical, Two Color Non-linear Sensing of Liquid Biochemical Agents

DTIC Science & Technology

2011-05-18

through the geometry and phase matching dependencies in the setup using enantiomeric and racemic limonene as a me- dium. In completely identical...around the 532 nm 18 795.2 cm−1 YAG line generated in S- limonene by 0.61 THz 20.3 cm−1. The rotation angle was 27°. At each point, 500 mixing events...In the following, signals are extracted as the integral of the total sideband line. Sum frequency sidebands for both S- limonene and a ra- cemic

Bioenvironmental Engineer’s Guide to Ionizing Radiation

DTIC Science & Technology

2005-10-01

mercury x-rays 186 (4 % ) - y Ra -226 radon x-rays Luminous Products, Neutron (tl/2: 1600 y) Alpha photons from daughters: Sources (w/ Be ) Rn-222, Po...Radioisotope Thermoelectric (t1,2: 88 y) Generators Pu-239 Alpha uranium x-rays Nuclear Weapons, Neutron (t1 /2: 2.4 x 104 y) Sources (w/ Be ...Calibration Am-241 .60 (36 %) - Static Eliminators, Chemical (h2: 432 y) Alpha n Agent Detectors, Neutron neptunium x-rays Sources (w/ Be ) 11 October 2005

A Study of the Interactive Effects of Stresses from Respirator Wear and Simultaneous Exposure to Toxic Anticholinesterase Agents

DTIC Science & Technology

1983-06-01

Pressure (PAO) 5. Left Atrial Pressure ( P LA) 6. Right Atrial Pressure ( P RA) 7. Pulmonary Artery Pressure ( P P ) b. Respiration 1. Respiratory Frequency...the respiration of monkeys. Porton Technical Paper, p . 316, 1953a. Homstedt, B. Synthesis and pharmacology of tabun. Acta. Physiol. Scand. 25:suppl...and P . Lynne-Davies. Functional importance of the Breuer-Hering reflex. Respir . Physiol. 15:125-139, 1972. McGregor, M. and M.R. Becklake. The

Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer.

PubMed

Scott, Frank I; Mamtani, Ronac; Brensinger, Colleen M; Haynes, Kevin; Chiesa-Fuxench, Zelma C; Zhang, Jie; Chen, Lang; Xie, Fenglong; Yun, Huifeng; Osterman, Mark T; Beukelman, Timothy; Margolis, David J; Curtis, Jeffrey R; Lewis, James D

2016-02-01

Immune dysfunction underlies the pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Immunosuppressive therapy is the standard of care for these diseases. Both immune dysfunction and therapy-related immunosuppression can inhibit cancer-related immune surveillance in this population. Drug-induced immunosuppression is a risk factor for nonmelanoma skin cancer (NMSC), particularly squamous cell tumors. For patients with a history of NMSC, data are limited on the effect of these drugs on the risk of additional NMSCs. To determine the relative hazard of a second NMSC in patients with RA or IBD who use methotrexate, anti-tumor necrosis factor (anti-TNF) therapy, or thiopurines after an initial NMSC. In this retrospective cohort study, we studied 9460 individuals with RA or IBD enrolled in Medicare from January 1, 2006, through December 31, 2012. Exposure to methotrexate, thiopurines, anti-TNFs, sulfasalazine, hydroxychloroquine, abatacept, or rituximab after the incident NMSC surgery. A second NMSC occurring 1 year or more after the incident NMSC using Cox proportional hazards regression models. Among 9460 individuals (6841 with RA and 2788 with IBD), the incidence rate of a second NMSC per 1000 person-years was 58.2 (95% CI, 54.5-62.1) and 58.9 (95% CI, 53.2-65.2) in patients with RA and IBD, respectively. Among patients with RA, methotrexate used in conjunction with other medications was associated with an increased risk of a second NMSC (hazard ratio [HR], 1.60; 95% CI, 1.08-2.37). Adjusted for other medications, the risk of NMSC increased with 1 year or more of methotrexate use (HR, 1.24; 95% CI, 1.04-1.48). Compared with methotrexate alone, the addition of anti-TNF drugs was significantly associated with risk of NMSC (HR, 1.49; 95% CI, 1.03-2.16). Abatacept and rituximab were not associated with increased NMSC risk. The nonsignificant HRs for 1 year or more of thiopurine and anti-TNF use for IBD were 1.49 (95% CI, 0.98-2.27) and 1.36 (95% CI, 0.76-2.44), respectively. Methotrexate use is associated with an increased risk of a second NMSC. Anti-TNF use may increase the risk of a second NMSC when used with methotrexate for RA. Further long-term studies are required before one can conclude that thiopurine and/or anti-TNF do not increase the risk of a second NMSC in patients with IBD.

[Biologics and mycobacterial diseases].

PubMed

Tsuyuguchi, Kazunari; Matsumoto, Tomoshige

2013-03-01

Various biologics such as TNF-alpha inhibitor or IL-6 inhibitor are now widely used for treatment of rheumatoid arthritis. Many reports suggested that one of the major issues is high risk of developing tuberculosis (TB) associated with using these agents, which is especially important in Japan where tuberculosis still remains endemic. Another concern is the risk of development of nontuberculous mycobacterial (NTM) diseases and we have only scanty information about it. The purpose of this symposium is to elucidate the role of biologics in the development of mycobacterial diseases and to establish the strategy to control them. First, Dr. Tohma showed the epidemiologic data of TB risks associated with using biologics calculated from the clinical database on National Database of Rheumatic Diseases by iR-net in Japan. He estimated TB risks in rheumatoid arthritis (RA) patients to be about four times higher compared with general populations and to become even higher by using biologics. He also pointed out a low rate of implementation of QuantiFERON test (QFT) as screening test for TB infection. Next, Dr. Tokuda discussed the issue of NTM disease associated with using biologics. He suggested the airway disease in RA patients might play some role in the development of NTM disease, which may conversely lead to overdiagnosis of NTM disease in RA patients. He suggested that NTM disease should not be uniformly considered a contraindication to treatment with biologics, considering from the results of recent multicenter study showing relatively favorable outcome of NTM patients receiving biologics. Patients with latent tuberculosis infection (LTBI) should receive LTBI treatment before starting biologics. Dr. Kato, a chairperson of the Prevention Committee of the Japanese Society for Tuberculosis, proposed a new LTBI guideline including active implementation of LTBI treatment, introducing interferon gamma release assay, and appropriate selection of persons at high risk for developing TB. Lastly, Dr. Matsumoto stressed the risk of discontinuing TNF-alpha inhibitor during treatment for tuberculosis. He showed from his clinical experience that TNF-alpha inhibitor can be safely used in active TB patient receiving effective antituberculosis chemotherapy and it is even more effective for prevention of paradoxical response. Active discussion was done about the four topics, including the matter beyond present guidelines. We hope these discussions will form the basis for the establishment of new guideline for the management of mycobacterial disease when using immunosuppressive agents including biologics. 1. The risk of developing tuberculosis (TB) and situations of screening for TB risk at administration of biologics-the case of rheumatoid arthritis: Shigeto TOHMA (Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital) We calculated the standardized incidence ratio (SIR) of TB from the clinical data on National Database of Rheumatic Diseases by iR-net in Japan (NinJa) and compared with the SIR of TB from the data of the post-marketing surveillances of five biologics. Among 43584 patient-years, forty patients developed TB. The SIR of TB in NinJa was 4.34 (95%CI: 3.00-5.69). According to the post-marketing surveillances of 5 biologics, the SIR of TB were 3.62-34.4. The incidence of TB in patients with RA was higher than general population in Japan, and was increased more by some biologics. We have to recognize the risk of TB when we start biologics therapy to patients with RA. Although the frequency of implementation of QuantiFERON test (QFT) had gradually increased, it was still limited to 41%. In order to predict the risk of developing TB and to prevent TB, it might be better to check all RA patients by QFT at time time of biologics administration. 2. Biologics and nontuberculous mycobacterial diseases: Hitoshi TOKUDA (Social Insurance Central General Hospital) Several topics about the relationship between RA and nontuberculous mycobacterial (NTM) diseases were discussed, which is still poorly understood. It is well known that airway diseases often accompany RA, which may be considered as a possible etiology for development of NTM diseases, but conversely it may lead to overdiagnosis of NTM disease. Next, we evaluated justification for the contraindication of biologics in patients with NTM diseases. Recent multicenter study showed that prognosis of patients developing NTM diseases during treatment with biologics were not always poor, which throws doubt on uniform prohibition of biologics in NTM diseases. 3. Future guideline for treating latent tuberculosis infection: Seiya KATO (Research Institute of Tuberculosis, Japan AntiTuberculosis Association) The Japanese Society for Tuberculosis issued a joint statement on chemoprophylaxis with the Japan College of Rheumatology in 2004. However, issues and challenges due to changing circumstance indicate application of interferon gamma release assay (IGRA), increased variety and indication of biologics, dissemination of knowledge on strategy and system for latent tuberculosis infection (LTBI), etc. Future guideline should include 1) promoting LTBI treatment to achieve low incidence, 2) updated information on IGRAs, 3) treatment strategy and target: contact to infectious cases, immunosuppressive cases (especially HIV and patients treated with biologics), high risk groups, etc. 4) fundamental information on tuberculosis control strategies, especially DOTS. 4. Therapy for RA and tuberculosis in patients with RA and TB activated by anti-TNF treatment: Tomoshige MATSUMOTO (Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) Biologics targeting TNF, including infliximab, have brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). In 2001, tuberculosis, an ancient and also modem scourge, became spotlighted again, because Keane reported in the New England Journal of Medicine that infliximab administration induced reactivation of tuberculosis. How should we treat RA after we successfully treated tuberculosis? Decisions regarding the treatment of patients with refractory RA in the setting of active tuberculosis remain difficult. We successfully treated RA in patients with tuberculosis by anti-TNF therapy. These demonstrate that anti-TNF therapy can be considered for patients with refractory RA who have tuberculosis and in whom antituberculosis therapy can be maintained.

Factors associated with use of disease modifying agents for rheumatoid arthritis in the National Hospital and Ambulatory Medical Care Survey.

PubMed

Gaitonde, Priyanka; Bozzi, Laura M; Shaya, Fadia T

2018-04-01

We examined the treatment patterns among adults with rheumatoid arthritis (RA) and identified factors influencing access to traditional and biological disease modifying antirheumatic drugs (DMARDs). We analyzed visits recorded in the National Ambulatory Medical Care Survey from 2005 to 2014 with a RA diagnosis. The primary outcome was DMARD use (traditional and/or biological). We included prescriptions of all RA-related treatments such as traditional and biological DMARDs, glucocorticoids, gold preparations, immunosuppressants, and non-steroidal anti-inflammatory drugs. Covariates in the logistic regression models included age, gender, race/ethnicity, type of health care coverage, provider type, geographic region, and number of comorbidities. Among 1405 visits with a RA diagnosis, 60.4% (n = 807) were prescribed DMARDs and 23.8% (n = 334) biological DMARDs. In fully adjusted models, females have 1.57 times higher odds of any DMARD use (95% confidence interval (CI): 1.02-2.46). Also, Medicare beneficiaries as compared to privately insured have 2.31 times higher odds of receiving any DMARDs (95% CI: 1.40-3.82), while visits with specialist vs. general physician are 2.38 times more associated with any DMARD use (95% CI: 1.37-4.14). For biological DMARDs, Medicare beneficiaries were at 2.58 times higher odds (95% CI: 1.42-4.70) than privately insured, while visits with specialist are at 3.37 times higher odds than general physician (95% CI: 1.40-8.23). Visits with a specialist and Medicare beneficiaries were significantly associated with any DMARD or biological DMARD use. Additionally, contrary to prior evidence, race/ethnicity was not associated with any DMARD or biological DMARD use, which may indicate reduction in disparity of treatment access. Copyright © 2018 Elsevier Inc. All rights reserved.

Development of the Digital Arthritis Index, a Novel Metric to Measure Disease Parameters in a Rat Model of Rheumatoid Arthritis.

PubMed

Lim, Maria A; Louie, Brenton; Ford, Daniel; Heath, Kyle; Cha, Paulyn; Betts-Lacroix, Joe; Lum, Pek Yee; Robertson, Timothy L; Schaevitz, Laura

2017-01-01

Despite a broad spectrum of anti-arthritic drugs currently on the market, there is a constant demand to develop improved therapeutic agents. Efficient compound screening and rapid evaluation of treatment efficacy in animal models of rheumatoid arthritis (RA) can accelerate the development of clinical candidates. Compound screening by evaluation of disease phenotypes in animal models facilitates preclinical research by enhancing understanding of human pathophysiology; however, there is still a continuous need to improve methods for evaluating disease. Current clinical assessment methods are challenged by the subjective nature of scoring-based methods, time-consuming longitudinal experiments, and the requirement for better functional readouts with relevance to human disease. To address these needs, we developed a low-touch, digital platform for phenotyping preclinical rodent models of disease. As a proof-of-concept, we utilized the rat collagen-induced arthritis (CIA) model of RA and developed the Digital Arthritis Index (DAI), an objective and automated behavioral metric that does not require human-animal interaction during the measurement and calculation of disease parameters. The DAI detected the development of arthritis similar to standard in vivo methods, including ankle joint measurements and arthritis scores, as well as demonstrated a positive correlation to ankle joint histopathology. The DAI also determined responses to multiple standard-of-care (SOC) treatments and nine repurposed compounds predicted by the SMarTR TM Engine to have varying degrees of impact on RA. The disease profiles generated by the DAI complemented those generated by standard methods. The DAI is a highly reproducible and automated approach that can be used in-conjunction with standard methods for detecting RA disease progression and conducting phenotypic drug screens.

Hepatitis B virus-related mortality in rheumatoid arthritis patients undergoing long-term low-dose glucocorticoid treatment: A population-based study.

PubMed

Yang, Sheng-Shun; Hung, Chin-Tun; Li, Shu-Fen; Lee, Horng-Mo; Chung, Yueh-Chin; Chen, Hsin-Hua; Chang, Shu-Chuan

2017-09-04

Glucocorticoids (GC) are commonly used in rheumatoid arthritis (RA) patients which bears a risk of hepatitis B virus (HBV) reactivation. The purpose of this study was to investigate the risk of HBV-related mortality under long-term low-dose GCs in Taiwanese RA patients. We retrospectively analyzed 45,423 RA patients using National Health Insurance Research Database from January 1999 to December 2011. Of them, 2204 patients had the diagnosis of HBV and were classified into four groups according to GCs regimens. Outcome comparison by Cox model analysis for liver-related mortality was performed. In this cohort, 90.5% were older than 40. One hundred and five patients had been treated with short-term large-dose GCs (Group A); 862 patients received GCs ≥20 mg/day for ≥3 days or a variable dose but did not meet Group C criteria (Group B); 689 patients were continuously treated with low-dose (<20 mg/day) GCs for ≥3 months for at least one session (Group C); and 548 patients had never been exposed to GCs (Group D). Two hundred and sixty-one patients had been exposed to antiviral agents, which was significantly higher in Group C. Fifty-eight patients (2.63%) died of acute hepatic failure, while no statistically significant difference between each groups (p = 0.074). Groups C and D comparison by two-sample test showed that long-term low-dose GC treatment was not associated with liver-related death after adjusting for malignancy. Long-term low-dose GC treatment was not associated with liver-related mortality in RA with concomitant HBV patients probably due to commonly applied antiviral therapy by rheumatologists. Copyright © 2017. Published by Elsevier B.V.

Tacrolimus potently inhibits human osteoclastogenesis induced by IL-17 from human monocytes alone and suppresses human Th17 differentiation.

PubMed

Yago, Toru; Nanke, Yuki; Kawamoto, Manabu; Yamanaka, Hisashi; Kotake, Shigeru

2012-08-01

Tacrolimus (FK506, Prograf®) is an orally available, T cell specific and anti-inflammatory agent that has been proposed as a therapeutic drug in rheumatoid arthritis (RA) patients. It has been known that T cells have a critical role in the pathogenesis of RA. Recent studies suggest that Th17 cells, which mainly produce IL-17, are involved in many autoimmune inflammatory disease including RA. The present study was undertaken to assess the effect of tacrolimus on IL-17-induced human osteoclastogenesis and human Th17 differentiation. Human CD14(+) monocytes were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and IL-17. From day 4, tacrolimus was added to these cultures. Osteoclasts were immunohistologically stained for vitronectin receptor 10days later. IL-17 production from activated T cells stimulated with IL-23 was measured by enzyme-linked immunosorbent assay (ELISA). Th17 differentiation from naïve T cells was assayed by flow cytometry. Tacrolimus potently inhibited IL-17-induced osteoclastogenesis from human monocytes and osteoclast activation. Addition of tacrolimus also reduced production of IL-17 in human activated T cells stimulated with IL-23. Interestingly, the population of human IL-17(+)IFN-γ(-) CD4 T cells or IL-17(+)TNF-α(+) CD4 T cells were decreased by adding of tacrolimus. The present study demonstrates that the inhibitory effect of tacrolimus on IL-17-induced osteoclastogenesis from human monocytes. Tacrolimus also inhibited expression of IL-17 or TNF-α by reducing the proportion of Th17, suggesting that therapeutic effect on Th17-associated disease such as RA, inflammatory bowel disease, multiple sclerosis, psoriasis, or allograft rejection. Copyright © 2012 Elsevier Ltd. All rights reserved.

Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production

PubMed Central

Ahmed, Salahuddin; Marotte, Hubert; Kwan, Kevin; Ruth, Jeffrey H.; Campbell, Phillip L.; Rabquer, Bradley J.; Pakozdi, Angela; Koch, Alisa E.

2008-01-01

Regulation of IL-6 transsignaling by the administration of soluble gp130 (sgp130) receptor to capture the IL-6/soluble IL-6R complex has shown promise for the treatment of rheumatoid arthritis (RA). However, enhancing endogenous sgp130 via alternative splicing of the gp130 gene has not yet been tested. We found that epigallocatechin-3-gallate (EGCG), an anti-inflammatory compound found in green tea, inhibits IL-1β–induced IL-6 production and transsignaling in RA synovial fibroblasts by inducing alternative splicing of gp130 mRNA, resulting in enhanced sgp130 production. Results from in vivo studies using a rat adjuvant-induced arthritis model showed specific inhibition of IL-6 levels in the serum and joints of EGCG-treated rats by 28% and 40%, respectively, with concomitant amelioration of rat adjuvant-induced arthritis. We also observed a marked decrease in membrane-bound gp130 protein expression in the joint homogenates of the EGCG-treated group. In contrast, quantitative RT-PCR showed that the gp130/IL-6Rα mRNA ratio increased by ∼2-fold, suggesting a possible mechanism of sgp130 activation by EGCG. Gelatin zymography results showed EGCG inhibits IL-6/soluble IL-6R–induced matrix metalloproteinase-2 activity in RA synovial fibroblasts and in joint homogenates, possibly via up-regulation of sgp130 synthesis. The results of these studies provide previously undescribed evidence of IL-6 synthesis and transsignaling inhibition by EGCG with a unique mechanism of sgp130 up-regulation, and thus hold promise as a potential therapeutic agent for RA. PMID:18796608

Early medication use in new-onset rheumatoid arthritis may delay joint replacement: results of a large population-based study.

PubMed

Moura, Cristiano S; Abrahamowicz, Michal; Beauchamp, Marie-Eve; Lacaille, Diane; Wang, Yishu; Boire, Gilles; Fortin, Paul R; Bessette, Louis; Bombardier, Claire; Widdifield, Jessica; Hanly, John G; Feldman, Debbie; Maksymowych, Walter; Peschken, Christine; Barnabe, Cheryl; Edworthy, Steve; Bernatsky, Sasha

2015-08-03

Use of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) may prevent joint damage and potentially reduce joint replacement surgeries. We assessed the association between RA drug use and joint replacement in Quebec, Canada. A cohort of new-onset RA patients was identified from Quebec's physician billing and hospitalization databases from 2002-2011. The outcome was defined using procedure codes submitted by orthopedic surgeons. Medication use was obtained from pharmacy databases. We used alternative Cox regression models with time-dependent variables measuring the cumulative effects of past use during different time windows (one model focussing on the first year after cohort entry) for methotrexate (MTX), and other DMARDs. Models were adjusted for baseline sociodemographics, co-morbidity and prior health service use, time-dependent cumulative use of other drugs (anti-tumor necrosis factor [anti-TNF] agents, other biologics, cyclooxygenase-2 inhibitors [COXIBs], nonselective nonsteroidal antiinflammatory drugs [NSAIDs], and systemic steroids), and markers of disease severity. During follow-up, 608 joint replacements occurred among 11,333 patients (median follow-up: 4.6 years). The best-fitting model relied on the cumulative early use (within the first year after cohort entry) of MTX and of other DMARDs, with an interaction between MTX and other DMARDs. In this model, greater exposure within the first year, to either MTX (adjusted hazard ratio, HR = 0.95 per 1 month, 95% confidence interval, 95% CI 0.93-0.97) or other DMARDs (HR = 0.97, 95% CI 0.95-0.99) was associated with longer time to joint replacement. Our results suggest that longer exposure to either methotrexate (MTX) or other DMARDs within the first year after RA diagnosis is associated with longer time to joint replacement surgery.

The Annexin a2 Promotes Development in Arthritis through Neovascularization by Amplification Hedgehog Pathway.

PubMed

Yi, Jun; Zhu, Yan; Jia, Yin; Jiang, Hongdie; Zheng, Xin; Liu, Dejing; Gao, Shunxiang; Sun, Mingjuan; Hu, Bo; Jiao, Binghua; Wang, Lianghua; Wang, Kaihui

2016-01-01

The neovascularization network of pannus formation plays a crucial role in the development of rheumatoid arthritis (RA). Annexin a2 (Axna2) is an important mediating agent that induces angiogenesis in vascular diseases. The correlation between Axna2 and pannus formation has not been studied. Here, we provided evidence that compared to osteoarthritis (OA) patients and healthy people, the expression of Axna2 and Axna2 receptor (Axna2R) were up-regulated in patients with RA. Joint swelling, inflammation and neovascularization were increased significantly in mice with collagen-induced arthritis (CIA) that were exogenously added Axna2. Cell experiments showed that Axna2 promoted HUVEC proliferation by binding Axna2R, and could activate Hedgehog (HH) signaling and up-regulate the expression of Ihh and Gli. Besides, expression of Ihh, Patched (Ptc), Smoothened (Smo) and Gli and matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), angiogenic growth factor of HH signaling downstream, were down-regulated after inhibition of expression Axna2R on HUVEC. Together, our research definitely observed that over-expression of Axna2 could promote the development of CIA, especially during the process of pannus formation for the first time. Meanwhile, Axna2 depended on combining Axna2R to activate and enlarge HH signaling and the expression of its downstream VEGF, Ang-2 and MMP-2 to promote HUVEC proliferation, and eventually caused to angiogenesis. Therefore, the role of Axna2 is instructive for understanding the development of RA, suppress the effect of Axna2 might provide a new potential measure for treatment of RA.

Evaluation of surface roughness of enamel after various bonding and clean-up procedures on enamel bonded with three different bonding agents: An in-vitro study

PubMed Central

Goel, Amit; Singh, Atul; Gupta, Tarun

2017-01-01

Background The purpose of this study was to analyze and compare the enamel surface roughness before bonding and after debonding, to find correlation between the adhesive remnant index and its effect on enamel surface roughness and to evaluate which clean-up method is most efficient to provide a smoother enamel surface. Material and Methods 135 premolars were divided into 3 groups containing 45 premolars in each group. Group I was bonded by using moisture insensitive primer, Group II by using conventional orthodontic adhesive and Group III by using self-etching primer. Each group was divided into 3 sub-groups on the basis of type of clean-up method applied i,e scaling followed by polishing, tungsten carbide bur and Sof-Lex disc. Enamel surface roughness was measured and compared before bonding and after clean-up. Results Evaluation of pre bonding and post clean-up enamel surface roughness (Ra value) with the t test showed that Post clean-up Ra values were greater than Pre bonding Ra values in all the groups except in teeth bonded with self-etching primer cleaned with Sof-Lex disc. Reliability of ARI score taken at different time interval tested with Kruskal Wallis test suggested that all the readings were reliable. Conclusions No clean-up procedure was able to restore the enamel to its original smoothness. Self-etching primer and Sof-Lex disc clean-up method combination restored the enamel surface roughness (Ra value) closest to its pre-treatment value. Key words:Enamel surface roughness, clean-up method, adhesive remnant index. PMID:28512535

Dietary Phytochemicals: Natural Swords Combating Inflammation and Oxidation-Mediated Degenerative Diseases.

PubMed

Islam, Md Asiful; Alam, Fahmida; Solayman, Md; Khalil, Md Ibrahim; Kamal, Mohammad Amjad; Gan, Siew Hua

2016-01-01

Cumulatively, degenerative disease is one of the most fatal groups of diseases, and it contributes to the mortality and poor quality of life in the world while increasing the economic burden of the sufferers. Oxidative stress and inflammation are the major pathogenic causes of degenerative diseases such as rheumatoid arthritis (RA), diabetes mellitus (DM), and cardiovascular disease (CVD). Although a number of synthetic medications are used to treat these diseases, none of the current regimens are completely safe. Phytochemicals (polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes) from natural products such as dietary fruits, vegetables, and spices are potential sources of alternative medications to attenuate the oxidative stress and inflammation associated with degenerative diseases. Based on in vitro , in vivo , and clinical trials, some of these active compounds have shown good promise for development into novel agents for treating RA, DM, and CVD by targeting oxidative stress and inflammation. In this review, phytochemicals from natural products with the potential of ameliorating degenerative disease involving the bone, metabolism, and the heart are described.

The cholinomimetic agent carbachol induces headache in healthy subjects.

PubMed

Schytz, H W; Wienecke, T; Oturai, P S; Olesen, J; Ashina, M

2009-02-01

The parasympathetic nervous system is likely to be involved in migraine pathogenesis. We hypothesized that the cholinomimetic agonist carbachol would induce headache and vasodilation of cephalic and radial arteries. Carbachol (3 microg/kg) or placebo was randomly infused into 12 healthy subjects in a double-blind crossover study. Headache was scored on a verbal rating scale from 0-10. Velocity in the middle cerebral artery (V(MCA)) and diameter of the superficial temporal artery (STA) and radial artery (RA) were recorded. Nine participants developed headache after carbachol compared with three after placebo. The area under the curve for headache was increased after carbachol compared with placebo both during infusion (0-30 min) (P = 0.042) and in the postinfusion period (30-90 min) (P = 0.027). Carbachol infusion caused a drop in V(MCA) (P = 0.003) and an increase in STA diameter (P = 0.006), but no increase in the RA diameter (P = 0.200). In conclusion, the study demonstrated that carbachol caused headache and dilation of cephalic arteries in healthy subjects.

Preparation and participation of undergraduate students to inform culturally sensitive research.

PubMed

Wells, Jo Nell; Cagle, Carolyn Spence

2009-07-01

Most student work as research assistants occurs at the graduate level of nursing education, and little is known about the role of undergraduate students as research assistants (RAs) in major research projects. Based on our desire to study Mexican American (MA) cancer caregivers, we needed bilingual and bicultural RAs to serve as data collectors with women who spoke Spanish and possessed cultural beliefs that influenced their caregiving. Following successful recruitment, orientation, and mentoring based on Bandura's social learning theory [Bandura, A., 2001. Social learning theory: an agentic perspective. Annual Review of Psychology 52, 1-26] and accepted teaching-learning principles, RAs engaged in various behaviors that facilitated study outcomes. Faculty researchers, RAs, and study participants benefitted greatly from the undergraduate student involvement in this project. This article describes successful student inclusion approaches, ongoing faculty-RA interactions, and lessons learned from the research team experience. Guidelines discussed support the potential for making the undergraduate RA role a useful and unique learning experience.

The potential and prospects of proximal remote sensing of arthropod pests.

PubMed

Nansen, Christian

2016-04-01

Bench-top or proximal remote sensing applications are widely used as part of quality control and machine vision systems in commercial operations. In addition, these technologies are becoming increasingly important in insect systematics and studies of insect physiology and pest management. This paper provides a review and discussion of how proximal remote sensing may contribute valuable quantitative information regarding identification of species, assessment of insect responses to insecticides, insect host responses to parasitoids and performance of biological control agents. The future role of proximal remote sensing is discussed as an exciting path for novel paths of multidisciplinary research among entomologists and scientists from a wide range of other disciplines, including image processing engineers, medical engineers, research pharmacists and computer scientists. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

Molindone: effects in pigeons responding under conditional discrimination tasks.

PubMed

Picker, M J; Cleary, J P; Berens, K; Oliveto, A H; Dykstra, L A

1989-02-01

Pigeons were trained to respond under three conditional discrimination procedures; 1) a fixed-consecutive-number procedure with (FCN 8-SD) and without (FCN 8) an added external discriminative stimulus, 2) a delayed matching-to-sample (DMTS) procedure using 0-sec, 2-sec and 8-sec delay intervals, and 3) a repeated acquisition of behavioral chains (RA) procedure using a four-link response chain with three stimulus keys. The atypical neuroleptic agent molindone decreased accuracy under the FCN 8 at doses that had no effect on accuracy under the FCN 8-SD. Under the DMTS procedure, molindone-induced decreases in accuracy were directly related to the delay interval, with the largest relative decrements obtained at the 8-sec delay and the smallest at the 0-sec delay. Under the RA procedure, molindone decreased accuracy at doses that had little or no effect on the number of correct responses emitted. Relative to control values, molindone-induced decreases in accuracy were smallest under the DMTS and FCN 8-SD procedures and largest under the FCN 8 and RA procedures. The differential effects obtained with molindone under each of these procedures illustrate the need to employ a variety of assays when determining the behavioral actions of neuroleptics. In addition, this battery of behavioral tests may provide a useful tool for assessing the different neurochemical actions of neuroleptic compounds.

Non-invasive In Vivo Fluorescence Optical Imaging of Inflammatory MMP Activity Using an Activatable Fluorescent Imaging Agent.

PubMed

Schwenck, Johannes; Maier, Florian C; Kneilling, Manfred; Wiehr, Stefan; Fuchs, Kerstin

2017-05-08

This paper describes a non-invasive method for imaging matrix metalloproteinases (MMP)-activity by an activatable fluorescent probe, via in vivo fluorescence optical imaging (OI), in two different mouse models of inflammation: a rheumatoid arthritis (RA) and a contact hypersensitivity reaction (CHR) model. Light with a wavelength in the near infrared (NIR) window (650 - 950 nm) allows a deeper tissue penetration and minimal signal absorption compared to wavelengths below 650 nm. The major advantages using fluorescence OI is that it is cheap, fast and easy to implement in different animal models. Activatable fluorescent probes are optically silent in their inactivated states, but become highly fluorescent when activated by a protease. Activated MMPs lead to tissue destruction and play an important role for disease progression in delayed-type hypersensitivity reactions (DTHRs) such as RA and CHR. Furthermore, MMPs are the key proteases for cartilage and bone degradation and are induced by macrophages, fibroblasts and chondrocytes in response to pro-inflammatory cytokines. Here we use a probe that is activated by the key MMPs like MMP-2, -3, -9 and -13 and describe an imaging protocol for near infrared fluorescence OI of MMP activity in RA and control mice 6 days after disease induction as well as in mice with acute (1x challenge) and chronic (5x challenge) CHR on the right ear compared to healthy ears.

Predictive factors for structural remission using abatacept: results from the ABROAD study.

PubMed

Murakami, Kosaku; Sekiguchi, Masahiro; Hirata, Shintaro; Fujii, Takao; Matsui, Kiyoshi; Morita, Satoshi; Ohmura, Koichiro; Kawahito, Yutaka; Nishimoto, Norihiro; Mimori, Tsuneyo; Sano, Hajime

2018-05-29

To investigate the effect of abatacept (ABA) on preventing joint destruction in biological disease-modifying anti-rheumatic drug (bDMARD)-naïve rheumatoid arthritis (RA) patients in real-world clinical practice. RA patients were collected from the ABROAD (ABatacept Research Outcomes as a First-line Biological Agent in the Real WorlD) study cohort. They had moderate or high disease activity and were treated with ABA as a first-line bDMARD. Radiographic change between baseline and 1 year after ABA treatment was assessed with the van der Heijde's modified total Sharp score (mTSS). Predictive factors for structural remission (St-REM), defined as ΔmTSS ≤0.5/year, were determined. Among 118 patients, 81 (67.5%) achieved St-REM. Disease duration <3 years (odds ratio (OR) = 3.152, p = 0.007) and slower radiographic progression (shown as "baseline mTSS/year <3", OR = 3.727, p = 0.004) were independently significant baseline predictive factors for St-REM irrespective of age and sex. St-REM prevalence increased significantly if clinical remission based on the Simplified Disease Activity Index was achieved at least once until 24 weeks after ABA treatment. Shorter disease duration, smaller radiographic progression at baseline, and rapid clinical response were predictive factors for sustained St-REM after ABA therapy in bDMARD-naïve RA patients.

Impact of Managed Care Health Insurance System for Indigent Patients with Rheumatoid Arthritis in Puerto Rico

PubMed Central

Santiago-Casas, Yesenia; González-Rivera, Tania; Castro-Santana, Lesliane; Ríos, Grissel; Martínez, David; Rodríguez, Vanessa; González-Alcover, Rafael; Mayor, Ángel M.; Vilá, Luis M.

2013-01-01

The aim of this study was to determine the clinical outcome among indigent patients with rheumatoid arthritis (RA) in Puerto Rico receiving their healthcare in a managed care system, as compared to non-indigent patients treated in fee-for-service settings. A cross-sectional study was conducted in 214 Puerto Ricans with RA (per American College of Rheumatology classification criteria). Demographic features, health-related behaviors, cumulative clinical manifestations, disease activity (per Disease Activity Score 28), comorbid conditions, functional status (per Health Assessment Questionnaire, HAQ), and pharmacologic profile were determined. Data were examined using univariable and multivariable (logistic regression) analyses. The mean (standard deviation [SD]) age of the study population was 56.6 (13.5) years; 180 (84.1%) were women. The mean (SD) disease duration was 10.8 (9.6) years. Sixty-seven patients were treated in the managed care setting and 147 patients received their healthcare in fee-for-service settings. In the multivariable analyses RA patients treated in the managed care setting had more joint deformities, extra-articular manifestations, arterial hypertension, type 2 diabetes mellitus, cardiovascular events, fibromyalgia syndrome, and poorer functional status, while having a lower exposure to biologic agents than those treated in fee-for-service settings. Efforts should be undertaken to curtail the gap of health disparities among these Hispanic patients in order to improve their long term outcomes. PMID:23314687

Impact of managed care health insurance system for indigent patients with rheumatoid arthritis in Puerto Rico.

PubMed

Santiago-Casas, Yesenia; González-Rivera, Tania; Castro-Santana, Lesliane; Ríos, Grissel; Martínez, David; Rodríguez, Vanessa; González-Alcover, Rafael; Mayor, Angel M; Vilá, Luis M

2013-06-01

The aim of this study was to determine the clinical outcome among indigent patients with rheumatoid arthritis (RA) in Puerto Rico receiving their healthcare in a managed care system, as compared with non-indigent patients treated in fee-for-service settings. A cross-sectional study was conducted in 214 Puerto Ricans with RA (per American College of Rheumatology classification criteria). Demographic features, health-related behaviors, cumulative clinical manifestations, disease activity (per disease activity score 28), comorbid conditions, functional status (per Health Assessment Questionnaire), and pharmacologic profile were determined. Data were examined using uni- and multivariable (logistic regression) analyses. The mean (standard deviation (SD)) age of the study population was 56.6 (13.5) years; 180 (84.1 %) were women. The mean (SD) disease duration was 10.8 (9.6) years. Sixty-seven patients were treated in the managed care setting, and 147 patients received their healthcare in fee-for-service settings. In the multivariable analyses, RA patients treated in the managed care setting had more joint deformities, extra-articular manifestations, arterial hypertension, type 2 diabetes mellitus, cardiovascular events, fibromyalgia syndrome, and poorer functional status while having a lower exposure to biological agents than those treated in fee-for-service settings. Efforts should be undertaken to curtail the gap of health disparities among these Hispanic patients in order to improve their long-term outcomes.

Miniaturized spectrometer for stand-off chemical detection

NASA Astrophysics Data System (ADS)

Henning, Patrick F.; Chadha, Suneet; Damren, Richard; Rowe, Rebecca C.; Stevenson, Chuck; Curtiss, Lawrence E.; DiGiuseppe, Thomas G.

2002-02-01

Advanced autonomous detection of both chemical warfare agents and toxic industrial chemicals has long been of major military concern and is becoming an increasingly realistic need. Foster-Miller has successfully designed and demonstrated a high spectral throughput monolithic wedge spectrometer capable of providing early, stand-off detection of chemical threats. Recent breakthrough innovations in IR source technologies, high D* multispectral array detectors, and IR waveguide materials has allowed for the development of a robust, miniature, monolithic infrared spectrometer. Foster-Miller recently demonstrated a high resolution spectrometer operating in the 8 to 12 micron region for chemical agent detection. Results will be presented demonstrating the feasibility of adapting the wedge spectrometer to operate as an upward looking ground sensor for stand-off chemical detection. Our miniaturized spectrometer forms the basis for deploying low cost, lightweight sensors which may be used for reconnaissance missions or delivered to remote locations for unattended operation. The ability of perform passive stand-off infrared chemical agent and chemical emissions detection with a low cost, compact device that can operate autonomously in remote environments has broad applications in both the military and commercial marketplace.

Standoff detection of explosives and chemical agents using broadly tuned external-cavity quantum cascade lasers (EC-QCLs)

NASA Astrophysics Data System (ADS)

Takeuchi, Eric B.; Rayner, Timothy; Weida, Miles; Crivello, Salvatore; Day, Timothy

2007-10-01

Civilian soft targets such as transportation systems are being targeted by terrorists using IEDs and suicide bombers. Having the capability to remotely detect explosives, precursors and other chemicals would enable these assets to be protected with minimal interruption of the flow of commerce. Mid-IR laser technology offers the potential to detect explosives and other chemicals in real-time and from a safe standoff distance. While many of these agents possess "fingerprint" signatures in the mid-IR (i.e. in the 3-20 micron regime), their effective interrogation by a practical, field-deployable system has been limited by size, complexity, reliability and cost constraints of the base laser technology. Daylight Solutions has addressed these shortcomings by developing compact, portable, broadly tunable mid-IR laser sources based upon external-cavity quantum cascade technology. This technology is now being applied by Daylight in system level architectures for standoff and remote detection of explosives, precursors and chemical agents. Several of these architectures and predicted levels of performance will be presented.

Establishment of a cell model for screening antibody drugs against rheumatoid arthritis with ADCC and CDC.

PubMed

Yan, Li; Hu, Rui; Tu, Song; Cheng, Wen-Jun; Zheng, Qiong; Wang, Jun-Wen; Kan, Wu-Sheng; Ren, Yi-Jun

2015-01-01

TNFα played a dominant role in the development and progression of rheumatoid arthritis (RA). Clinical trials proved the efficacies of anti-TNFα agents for curing RA. However, most researchers were concentrating on their abilities of neutralizing TNFα, the potencies of different anti-TNFα agents varied a lot due to the antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). For better understanding and differentiating the potentiality of various candidate anti-TNF reagents at the stage of new drug research and development, present study established a cell model expressing the transmembrane TNFα for usage in in vitro ADCC or CDC assay, meanwhile, the assay protocol described here could provide guidelines for screening macromolecular antibody drugs. A stable cell subline bearing transmembrane TNFα was first established by conventional transfection method, the expression of transmembrane TNFα was approved by flow cytometer, and the performance of the stable subline in ADCC and CDC assay was evaluated, using human peripheral blood mononuclear cells as effector cells, and Adalimumab as the anti-TNFα reagent. The stable cell subline demonstrated high level of surface expression of transmembrane TNFα, and Adalimumab exerted both ADCC and CDC effects on this cell model. In conclusion, the stable cell line we established in present research could be used in ADCC or CDC assay for screening antibody drugs, which would provide in-depth understanding of the potencies of candidate antibody drugs in addition to the traditional TNFα neutralizing assay.

Resource Control in Large-Scale Mobile-Agents Systems

DTIC Science & Technology

2005-07-01

wakeup node schedule , much energy can be conserved. We also designed several protocols for global clock synchronization. The most interesting one is...choice as to which remote hosts to visit and in which order. Scheduling mobile-agent migration in a way that minimizes bandwidth and other resource...use, therefore, is both feasible and attractive. Dartmouth considered several variations of the scheduling problem, and devel- oped an algorithm for

Activities for the remediation of TEPCO's Fukushima Daiichi nuclear power plant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kinoshita, Hirofumi; Kometani, Yutaka; Asano, Takashi

2013-07-01

With the aim of fulfilling recovery work for the Fukushima Daiichi NPP, technological efforts have been made for the development of a survey robot system, adequate communication infrastructure technologies, high radiation environment compatible gamma cameras, heavy machinery-type robots (ASTACO-SoRa), remote decontamination devices (AROUNDER), and contaminated waste water treatment system. We have developed a new type of absorbents which remove cesium (Cs) and strontium (Sr) simultaneously at a high removal rate of 99 % or more. We will provide valuable solutions and rational systems for waste water treatment using this developed adsorbent as well as other various adsorbents for the recoverymore » of Fukushima Daiichi NPP.« less

Integrating CLIPS applications into heterogeneous distributed systems

NASA Technical Reports Server (NTRS)

Adler, Richard M.

1991-01-01

SOCIAL is an advanced, object-oriented development tool for integrating intelligent and conventional applications across heterogeneous hardware and software platforms. SOCIAL defines a family of 'wrapper' objects called agents, which incorporate predefined capabilities for distributed communication and control. Developers embed applications within agents and establish interactions between distributed agents via non-intrusive message-based interfaces. This paper describes a predefined SOCIAL agent that is specialized for integrating C Language Integrated Production System (CLIPS)-based applications. The agent's high-level Application Programming Interface supports bidirectional flow of data, knowledge, and commands to other agents, enabling CLIPS applications to initiate interactions autonomously, and respond to requests and results from heterogeneous remote systems. The design and operation of CLIPS agents are illustrated with two distributed applications that integrate CLIPS-based expert systems with other intelligent systems for isolating and mapping problems in the Space Shuttle Launch Processing System at the NASA Kennedy Space Center.

Estimating Vegetation Primary Production in the Heihe River Basin of China with Multi-Source and Multi-Scale Data.

PubMed

Cui, Tianxiang; Wang, Yujie; Sun, Rui; Qiao, Chen; Fan, Wenjie; Jiang, Guoqing; Hao, Lvyuan; Zhang, Lei

2016-01-01

Estimating gross primary production (GPP) and net primary production (NPP) are significant important in studying carbon cycles. Using models driven by multi-source and multi-scale data is a promising approach to estimate GPP and NPP at regional and global scales. With a focus on data that are openly accessible, this paper presents a GPP and NPP model driven by remotely sensed data and meteorological data with spatial resolutions varying from 30 m to 0.25 degree and temporal resolutions ranging from 3 hours to 1 month, by integrating remote sensing techniques and eco-physiological process theories. Our model is also designed as part of the Multi-source data Synergized Quantitative (MuSyQ) Remote Sensing Production System. In the presented MuSyQ-NPP algorithm, daily GPP for a 10-day period was calculated as a product of incident photosynthetically active radiation (PAR) and its fraction absorbed by vegetation (FPAR) using a light use efficiency (LUE) model. The autotrophic respiration (Ra) was determined using eco-physiological process theories and the daily NPP was obtained as the balance between GPP and Ra. To test its feasibility at regional scales, our model was performed in an arid and semi-arid region of Heihe River Basin, China to generate daily GPP and NPP during the growing season of 2012. The results indicated that both GPP and NPP exhibit clear spatial and temporal patterns in their distribution over Heihe River Basin during the growing season due to the temperature, water and solar influx conditions. After validated against ground-based measurements, MODIS GPP product (MOD17A2H) and results reported in recent literature, we found the MuSyQ-NPP algorithm could yield an RMSE of 2.973 gC m(-2) d(-1) and an R of 0.842 when compared with ground-based GPP while an RMSE of 8.010 gC m(-2) d(-1) and an R of 0.682 can be achieved for MODIS GPP, the estimated NPP values were also well within the range of previous literature, which proved the reliability of our modelling results. This research suggested that the utilization of multi-source data with various scales would help to the establishment of an appropriate model for calculating GPP and NPP at regional scales with relatively high spatial and temporal resolution.

Estimating Vegetation Primary Production in the Heihe River Basin of China with Multi-Source and Multi-Scale Data

PubMed Central

Cui, Tianxiang; Wang, Yujie; Sun, Rui; Qiao, Chen; Fan, Wenjie; Jiang, Guoqing; Hao, Lvyuan; Zhang, Lei

2016-01-01

Estimating gross primary production (GPP) and net primary production (NPP) are significant important in studying carbon cycles. Using models driven by multi-source and multi-scale data is a promising approach to estimate GPP and NPP at regional and global scales. With a focus on data that are openly accessible, this paper presents a GPP and NPP model driven by remotely sensed data and meteorological data with spatial resolutions varying from 30 m to 0.25 degree and temporal resolutions ranging from 3 hours to 1 month, by integrating remote sensing techniques and eco-physiological process theories. Our model is also designed as part of the Multi-source data Synergized Quantitative (MuSyQ) Remote Sensing Production System. In the presented MuSyQ-NPP algorithm, daily GPP for a 10-day period was calculated as a product of incident photosynthetically active radiation (PAR) and its fraction absorbed by vegetation (FPAR) using a light use efficiency (LUE) model. The autotrophic respiration (Ra) was determined using eco-physiological process theories and the daily NPP was obtained as the balance between GPP and Ra. To test its feasibility at regional scales, our model was performed in an arid and semi-arid region of Heihe River Basin, China to generate daily GPP and NPP during the growing season of 2012. The results indicated that both GPP and NPP exhibit clear spatial and temporal patterns in their distribution over Heihe River Basin during the growing season due to the temperature, water and solar influx conditions. After validated against ground-based measurements, MODIS GPP product (MOD17A2H) and results reported in recent literature, we found the MuSyQ-NPP algorithm could yield an RMSE of 2.973 gC m-2 d-1 and an R of 0.842 when compared with ground-based GPP while an RMSE of 8.010 gC m-2 d-1 and an R of 0.682 can be achieved for MODIS GPP, the estimated NPP values were also well within the range of previous literature, which proved the reliability of our modelling results. This research suggested that the utilization of multi-source data with various scales would help to the establishment of an appropriate model for calculating GPP and NPP at regional scales with relatively high spatial and temporal resolution. PMID:27088356

Shallow properties of faults in carbonate rocks - The Jandaíra Formation, Potiguar Basin, Brazil

NASA Astrophysics Data System (ADS)

Bezerra, F. H.; Bertotti, G.; Rabelo, J.; Silva, A. T.; Carneiro, M. A.; Cazarin, C. L.; Silva, C. C.; Vieira, M. M.; Bisdom, K.; Moraes, A.

2014-12-01

We studied the development of shallow faults in the Jandaíra Formation, a Turonian-Campanian carbonate platform in the Potiguar Basin, northeastern Brazil. Our main goal was to characterize fault geometry and properties such as porosity and permeability, and associate these results with fluid flow in shallow conditions. We used an integrated multidisciplinary approach, which combined Quickbird satellite and an unmanned aerial vehicle (UAV, drone) imagery, structural and sedimentary-facies mapping, and petrographic and petrophysical analyses. The Jandaíra Formation presents a variety of carbonate facies, which include mudstones to bioclastic, peloidal, intraclastic, and oolitic grainstones. We modeled our remote sensing and structural data using a finite element analysis system for 2D deformation modeling. We applied the magnitudes and directions of the present-day stress field to simulate depths as deep as 500 m. These stress data were derived from borehole breakout data and drilling-induced tensile fractures observed in resistivity image logs. Our results indicate the occurrence of dilation processes along three sets of joints that were reactivated as faults in the upper crust: N-S, NE-, and E-W-striking faults. These faults provided preferential leaching pathways to fresh water percolation, contributing to localized dissolution and increased secondary porosity and permeability. The results also indicate that the tectonic stresses are concentrated in preferred structural zones such as fault intersection and termination, which are sites of increased fracturing and dissolution. Dissolution by fluids increased permeability in carbonate rocks from primary values of 0.0-0.94 mD to as much as 1370.11 mD. This process is mostly Cenozoic.

Palonosetron (Aloxi): a second-generation 5-HT3 receptor antagonist for chemotherapy-induced nausea and vomiting

PubMed Central

2006-01-01

In July 2003, the Food and Drug Administration approved palonosetron hydrochloride injection for the treatment of chemotherapy-induced nausea and vomiting (CINV). The newest agent in the class of 5-HT3 receptor antagonists (5-HT3RAs), palonosetron differs from other agents in its class by its higher receptor-binding affinity and longer half-life. These pharmacological properties have resulted in improved antiemetic activity in clinical trials, particularly in the treatment of delayed CINV following moderate emetogenic chemotherapy. Based on the results of these clinical studies, palonosetron is the only 5-HT3RA approved for delayed CINV. Palonosetron is given as a single 0.25-mg intravenous dose 30 minutes before the initial dose of chemotherapy. Headache and constipation were the most common adverse events reported with palonosetron therapy. PMID:17106506

Installation Restoration Program. Phase 1: Records Search, Blytheville Air Force Base, Arkansas

DTIC Science & Technology

1985-08-01

AFB LOCATION OFI 0 LS U FC MIDDLE S RA EWATER MARKER MONITORING SITESI SL *LEGEND S SURFACE WATER QUALITY IMONITORING SITEI. iJ I WASTEWATER PLANTr j...burning is scored in a small above ground tank located near the FPTA. The extinguishing agent used during this time period was AFFF (aqueous film...receptors, "aste caracte,stics, and pst .ways. Receptors 54 Waste Char’acteristics 54 Pathways 74 Total 183 div~ied by 3 E ’I 3,’osi : --e E. P

Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register

PubMed Central

Galloway, James B; Mercer, Louise K; Moseley, Alison; Dixon, William G; Ustianowski, Andrew P; Helbert, Matthew; Watson, Kath D; Lunt, Mark; Hyrich, Kimme L; Symmons, Deborah PM

2013-01-01

Introduction Anti-tumour necrosis factor (TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). In 2001, BSRBR was established to evaluate the safety of these agents. This paper addresses the safety of anti-TNF therapy in RA with specific reference to serious skin and soft tissue infections (SSSI) and shingles. Methods A cohort of anti-TNF-treated patients was recruited alongside a comparator group with active RA treated with non-biological disease-modifying antirheumatic drugs (nbDMARD). 11 881 anti-TNF and 3673 nbDMARD patients were analysed. Follow-up was by 6-monthly questionnaires to patients and clinicians. Analyses considered SSSI and shingles separately. Incidence rates (IR) were calculated and then compared using survival analyses. Results The crude IR for SSSI were: anti-TNF 1.6/100 patient-years (95% CI 1.4 to 1.8); nbDMARD 0.7/100 patient-years (95% CI 0.5 to 1.0) and shingles: anti-TNF 1.6/100 patient-years (95% CI 1.3 to 2.0); nbDMARD 0.8/100 patient-years (95% CI 0.6 to 1.1). Adjusted HR were SSSI 1.4 (95% CI 0.9 to 2.4), shingles 1.8 (95% CI 1.2 to 2.8). For SSSI, no significant differences were seen between anti-TNF agents. For shingles, the lowest risk was observed for adalimumab (adjusted HR vs nbDMARD) 1.5 (95% CI 1.1 to 2.0) and highest for infliximab (HR 2.2; 95% CI 1.4 to 3.4)). Conclusion A significantly increased risk of shingles was observed in the anti-TNF-treated cohort. The risk of SSSI tended towards being greater with anti-TNF treatment but was not statistically significant. As with any observational dataset cause and effect cannot be established with certainty as residual confounding may remain. This finding would support the evaluation of zoster vaccination in this population. PMID:22532633

Determinants of Risk Infection During Therapy with Anti TNF-Alpha Blocking Agents in Rheumatoid Arthritis

PubMed Central

Benucci, M; Saviola, G; Baiardi, P; Manfredi, M; Sarzi Puttini, P; Atzeni, Fabiola

2012-01-01

The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections’ development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.6±10.4% vs ETA 48.4±15.7% vs INF 40.7±16.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN don’t reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence. PMID:22655000

Measuring the radium quartet (228Ra, 226Ra, 224Ra, 223Ra) in seawater samples using gamma spectrometry.

PubMed

van Beek, P; Souhaut, M; Reyss, J-L

2010-07-01

Radium isotopes are widely used in marine studies (eg. to trace water masses, to quantify mixing processes or to study submarine groundwater discharge). While 228Ra and 226Ra are usually measured using gamma spectrometry, short-lived Ra isotopes (224Ra and 223Ra) are usually measured using a Radium Delayed Coincidence Counter (RaDeCC). Here we show that the four radium isotopes can be analyzed using gamma spectrometry. We report 226Ra, 228Ra, 224Ra, 223Ra activities measured using low-background gamma spectrometry in standard samples, in water samples collected in the vicinity of our laboratory (La Palme and Vaccarès lagoons, France) but also in seawater samples collected in the plume of the Amazon river, off French Guyana (AMANDES project). The 223Ra and 224Ra activities determined in these samples using gamma spectrometry were compared to the activities determined using RaDeCC. Activities determined using the two techniques are in good agreement. Uncertainties associated with the 224Ra activities are similar for the two techniques. RaDeCC is more sensitive for the detection of low 223Ra activities. Gamma spectrometry thus constitutes an alternate method for the determination of short-lived Ra isotopes. 2009 Elsevier Ltd. All rights reserved.

Transcriptional changes in organoculture of full-thickness human skin following topical application of all-trans retinoic acid

PubMed Central

Gillbro, J M; Al-Bader, T; Westman, M; Olsson, M J; Mavon, A

2014-01-01

Synopsis Objective Retinoids are used as therapeutic agents for numerous skin diseases, for example, psoriasis, acne and keratinization disorders. The same substances have also been recognized in the treatment for hyperpigmentation disorders such as melasma. Other studies on photo-damaged skin have shown that retinoids reduce wrinkles, surface roughness, mottled pigmentation, and visual skin appearance as a whole. We tested the hypothesis that an organoculture of full-thickness human skin could be used as a preclinical model to investigate the retinoid transcriptional profile in human skin in vitro. Methods Full-thickness skin explants were exposed to topically applied all-trans retinoic acid (RA) for 24 h. The gene expression profile was analysed using oligonucleotide microarrays, and data were validated with real-time (RT) PCR. Results We showed that the expression of 93 genes was significantly altered more than twofold. Several of the altered genes, for example, KRT4, CYP26 and LCN2, have previously been shown to be affected by RA in keratinocyte monocultures, reconstructed epidermis and skin biopsies from patients treated topically or orally with RA. In addition, genes, such as SCEL, NRIP1, DGAT2, RDH12 EfnB2, MAPK14, SAMD9 and CEACAM6 not previously reported to be affected by RA in human skin, were identified for the first time in this study. Conclusion The results in the present study show that full-thickness human explants represent a valuable pre-clinical model for studying the effects of retinoids in skin. Résumé Objectif Les rétinoïdes sont utilisés comme agents thérapeutiques pour de nombreuses maladies de la peau, p.ex. le psoriasis, l'acné et les troubles de la kératinisation. Les mêmes substances ont également été reconnues dans le traitement des troubles de l' hyperpigmentation tels que le melasma. D'autres études sur la peau photo-endommagée ont montré que les rétinoïdes réduisent les rides, la rugosité de la surface, la pigmentation tachetée, et l'aspect visuel de la peau dans son ensemble. Nous avons testé l'hypothèse selon laquelle une organoculture de épaisseur intégrale de la peau humaine pourrait être utilisée comme modèle préclinique pour étudier le profil transcriptionnel des rétinoïdes dans la peau humaine in vitro. Méthodes Des explants de peau intégrale ont été exposés à l'application topique de all-trans acide rétinoïque (RA) pendant 24 heures. Le profil d' expression des gènes a été analysé en utilisant des puces DNA array et les données ont été validées par (RT) -PCR. Resultats Nous avons montré que l'expression de 93 gènes a été modifiée de façon significative par plus d'un facteur 2. Plusieurs des gènes modifiés par exemple KRT4, CYP26 et LCN2 ont été montrés précédemment d'être affectés par RA dans les monocultures de kératinocytes, dans l'épiderme reconstruit et dans des biopsies cutanées de patients traités par voie topique ou par voie orale avec RA. En outre, des gènes tels que SCEL, NRIP1, DGAT2, RDH12 EfnB2, MAPK14, SAMD9 et CEACAM6 non signalés précédemment, sont touchés par RA dans la peau humaine, et ont été identifiés pour la première fois dans cette étude. Conclusion Les résultats de la présente étude montrent que les explants humains de pleine épaisseur représentent un modèle préclinique précieux pour l'étude des effets des rétinoïdes dans la peau. PMID:24697191

Radium isotope ((223)Ra, (224)Ra, (226)Ra and (228)Ra) distribution near Brazil's largest port, Paranaguá Bay, Brazil.

PubMed

Dias, Thais H; de Oliveira, Joselene; Sanders, Christian J; Carvalho, Franciane; Sanders, Luciana M; Machado, Eunice C; Sá, Fabian

2016-10-15

This work investigates the (223)Ra, (224)Ra, (226)Ra and (228)Ra isotope distribution in river, estuarine waters and sediments of the Paranaguá Estuarine Complex (PEC). The stratification of the Ra isotopes along water columns indicate differing natural sources. In sediments, the radium isotope activities was inversely proportional to the particle size. The highest concentrations of (223)Ra, (224)Ra, (226)Ra and (228)Ra in the water column were found in the bottom more saline waters and towards the inner of the estuary. These relatively high concentrations towards the bottom of the estuary may be attributed to the influence of tidally driven groundwater source and desorption from particles at the maximum turbidity zone. The apparent river water ages from the radium isotope ratios, (223)Ra/(224)Ra and (223)Ra/(228)Ra, indicate that the principal rivers that flow into the estuary have residence times from between 6 and 11days. Copyright © 2016 Elsevier Ltd. All rights reserved.

Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report.

PubMed

Gómez-Reino, Juan J; Carmona, Loreto; Valverde, Vicente Rodríguez; Mola, Emilio Martín; Montero, Maria Dolores

2003-08-01

The long-term safety of therapeutic agents that neutralize tumor necrosis factor (TNF) is uncertain. Recent evidence based on spontaneous reporting shows an association with active tuberculosis (TB). We undertook this study to determine and describe the long-term safety of 2 of these agents, infliximab and etanercept, in rheumatic diseases based on a national active-surveillance system following the commercialization of the drugs. We analyzed the safety data actively collected in the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) database, which was launched in February 2000 by the Spanish Society of Rheumatology. For the estimation of TB risk, the annual incidence rate in patients treated with these agents was compared with the background rate and with the rate in a cohort of patients with rheumatoid arthritis (RA) assembled before the era of anti-TNF treatment. Seventy-one participating centers sent data on 1,578 treatments with infliximab (86%) or etanercept (14%) in 1,540 patients. Drug survival rates (reported as the cumulative percentage of patients still receiving medication) for infliximab and etanercept pooled together were 85% and 81% at 1 year and 2 years, respectively. Instances of discontinuation were essentially due to adverse events. Seventeen cases of TB were found in patients treated with infliximab. The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001. These findings represent a significant increased risk compared with background rates. In the first 5 months of 2002, after official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case was registered (in January). Therapy with infliximab is associated with an increased risk of active TB. Proper measures are needed to prevent and manage this adverse event.

46 CFR 95.16-20 - Extinguishing agent: Cylinder storage.

Code of Federal Regulations, 2014 CFR

2014-10-01

... cylinder storage room and the protected spaces must meet the insulation criteria for Class A-60, as defined... pneumatic heat actuator as well as a remote manual control. (c) The cylinder storage space must be properly...

46 CFR 95.16-20 - Extinguishing agent: Cylinder storage.

Code of Federal Regulations, 2012 CFR

2012-10-01

... cylinder storage room and the protected spaces must meet the insulation criteria for Class A-60, as defined... pneumatic heat actuator as well as a remote manual control. (c) The cylinder storage space must be properly...

46 CFR 95.16-20 - Extinguishing agent: Cylinder storage.

Code of Federal Regulations, 2013 CFR

2013-10-01

... cylinder storage room and the protected spaces must meet the insulation criteria for Class A-60, as defined... pneumatic heat actuator as well as a remote manual control. (c) The cylinder storage space must be properly...

Simple Technique for in Field Samples Collection in the Cases of Skin Rash Illness and Subsequent PCR Detection of Orthopoxviruses and Varicella Zoster Virus

PubMed Central

Magazani, Edmond K.; Garin, Daniel; Muyembe, Jean-Jacques T.; Bentahir, Mostafa; Gala, Jean-Luc

2014-01-01

Background In case of outbreak of rash illness in remote areas, clinically discriminating monkeypox (MPX) from severe form of chickenpox and from smallpox remains a concern for first responders. Objective The goal of the study was therefore to use MPX and chickenpox outbreaks in Democratic Republic of Congo (DRC) as a test case for establishing a rapid and specific diagnosis in affected remote areas. Methods In 2008 and 2009, successive outbreaks of presumed MPX skin rash were reported in Bena Tshiadi, Yangala and Ndesha healthcare districts of the West Kasai province (DRC). Specimens consisting of liquid vesicle dried on filter papers or crusted scabs from healing patients were sampled by first responders. A field analytical facility was deployed nearby in order to carry out a real-time PCR (qPCR) assay using genus consensus primers, consensus orthopoxvirus (OPV) and smallpox-specific probes spanning over the 14 kD fusion protein encoding gene. A PCR-restriction fragment length polymorphism was used on-site as backup method to confirm the presence of monkeypox virus (MPXV) in samples. To complete the differential diagnosis of skin rash, chickenpox was tested in parallel using a commercial qPCR assay. In a post-deployment step, a MPXV-specific pyrosequencing was carried out on all biotinylated amplicons generated on-site in order to confirm the on-site results. Results Whereas MPXV proved to be the agent causing the rash illness outbreak in the Bena Tshiadi, VZV was the causative agent of the disease in Yangala and Ndesha districts. In addition, each on-site result was later confirmed by MPXV-specific pyrosequencing analysis without any discrepancy. Conclusion This experience of rapid on-site dual use DNA-based differential diagnosis of rash illnesses demonstrates the potential of combining tests specifically identifying bioterrorism agents and agents causing natural outbreaks. This opens the way to rapid on-site DNA-based identification of a broad spectrum of causative agents in remote areas. PMID:24841633

Effectiveness of a web-based personalized rheumatoid arthritis risk tool with or without a health educator for knowledge of RA risk factors.

PubMed

Prado, Maria G; Iversen, Maura D; Yu, Zhi; Miller Kroouze, Rachel; Triedman, Nellie A; Kalia, Sarah S; Lu, Bing; Green, Robert C; Karlson, Elizabeth W; Sparks, Jeffrey A

2018-01-05

To assess knowledge of rheumatoid arthritis (RA) risk factors among unaffected first-degree relatives (FDRs) and to study whether a personalized RA education tool increases risk factor knowledge. We performed a randomized controlled trial assessing RA educational interventions among 238 FDRs. The web-based Personalized Risk Estimator for RA (PRE-RA) tool displayed personalized RA risk results (genetics, autoantibodies, demographics, and behaviors) and educated about risk factors. Subjects were randomly assigned to: Comparison arm (standard RA education, n=80), PRE-RA arm (PRE-RA alone, n=78), or PRE-RA Plus arm (PRE-RA and a one-on-one session with a trained health educator, n=80). The RA Knowledge Score (RAKS, the number of 8 established RA risk factors identified as related to RA) was calculated at baseline and post-education (immediate/6 weeks/6 months/12 months). We compared RAKS and its components at each post-education point by randomization arm. At baseline before education, few FDRs identified behavioral RA risk factors (15.9% for dental health, 31.9% for smoking, 47.5% for overweight/obesity, and 54.2% for diet). After education, RAKS increased in all arms, higher in PRE-RA and PRE-RA Plus than Comparison at all post-education points (p<0.05). PRE-RA were more likely to identify risk factors than those that received standard education (proportion agreeing smoking is a risk factor at 6 weeks: 83.1% in PRE-RA Plus arm, 71.8% in PRE-RA, and 43.1% in Comparison arms, p<0.05 for PRE-RA vs. Comparison). Despite being both familiar with RA and at increased risk, FDRs had low knowledge about RA risk factors. A web-based personalized RA education tool successfully increased RA risk factor knowledge. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

IDEA: Planning at the Core of Autonomous Reactive Agents

NASA Technical Reports Server (NTRS)

Muscettola, Nicola; Dorais, Gregory A.; Fry, Chuck; Levinson, Richard; Plaunt, Christian; Clancy, Daniel (Technical Monitor)

2002-01-01

Several successful autonomous systems are separated into technologically diverse functional layers operating at different levels of abstraction. This diversity makes them difficult to implement and validate. In this paper, we present IDEA (Intelligent Distributed Execution Architecture), a unified planning and execution framework. In IDEA a layered system can be implemented as separate agents, one per layer, each representing its interactions with the world in a model. At all levels, the model representation primitives and their semantics is the same. Moreover, each agent relies on a single model, plan database, plan runner and on a variety of planners, both reactive and deliberative. The framework allows the specification of agents that operate, within a guaranteed reaction time and supports flexible specification of reactive vs. deliberative agent behavior. Within the IDEA framework we are working to fully duplicate the functionalities of the DS1 Remote Agent and extend it to domains of higher complexity than autonomous spacecraft control.

A security architecture for interconnecting health information systems.

PubMed

Gritzalis, Dimitris; Lambrinoudakis, Costas

2004-03-31

Several hereditary and other chronic diseases necessitate continuous and complicated health care procedures, typically offered in different, often distant, health care units. Inevitably, the medical records of patients suffering from such diseases become complex, grow in size very fast and are scattered all over the units involved in the care process, hindering communication of information between health care professionals. Web-based electronic medical records have been recently proposed as the solution to the above problem, facilitating the interconnection of the health care units in the sense that health care professionals can now access the complete medical record of the patient, even if it is distributed in several remote units. However, by allowing users to access information from virtually anywhere, the universe of ineligible people who may attempt to harm the system is dramatically expanded, thus severely complicating the design and implementation of a secure environment. This paper presents a security architecture that has been mainly designed for providing authentication and authorization services in web-based distributed systems. The architecture has been based on a role-based access scheme and on the implementation of an intelligent security agent per site (i.e. health care unit). This intelligent security agent: (a). authenticates the users, local or remote, that can access the local resources; (b). assigns, through temporary certificates, access privileges to the authenticated users in accordance to their role; and (c). communicates to other sites (through the respective security agents) information about the local users that may need to access information stored in other sites, as well as about local resources that can be accessed remotely.

A new angle for glp-1 receptor agonist: the medical economics argument. Editorial on: Huetson P, Palmer JL, Levorsen A, et al. Cost-effectiveness of the once-daily glp-1 receptor agonist lixisenatide compared to bolus insulin both in combination with basal insulin for the treatment of patients with type 2 diabetes in Norway. J Med Econ 2015: 1-13 [Epub ahead of print].

PubMed

Valencia, Willy Marcos; Florez, Hermes Jose

2015-01-01

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are relatively new medications for diabetes that offer a weight-loss profile that can be considered desirable for patients with both type 2 diabetes (T2D) and obesity. GLP-1 RA are effective in combination with insulin, and even slightly superior or at least equal to short-acting insulin in T2D; however, since they work in the incretin system, they may not be effective in long-standing disease. Additionally, only recently have publications reported their cardiovascular safety, and there is limited evidence for long-term effectiveness. The work presented by Huetson et al. offers a much needed perspective through a medical economic model for the long term cost-effectiveness of GLP-1 RA. The authors found benefits in quality-adjusted life years and reduced lifetime healthcare costs. While there are a few limitations, this study contributes to the understanding of these agents and their impact on the epidemics of obesity in T2D, where weight management is no longer an option, but an essential component of the diabetes plan of care.

Recommendations for optimizing methotrexate treatment for patients with rheumatoid arthritis

PubMed Central

Bello, Alfonso E; Perkins, Elizabeth L; Jay, Randy; Efthimiou, Petros

2017-01-01

Methotrexate (MTX) remains the cornerstone therapy for patients with rheumatoid arthritis (RA), with well-established safety and efficacy profiles and support in international guidelines. Clinical and radiologic results indicate benefits of MTX monotherapy and combination with other agents, yet patients may not receive optimal dosing, duration, or route of administration to maximize their response to this drug. This review highlights best practices for MTX use in RA patients. First, to improve the response to oral MTX, a high initial dose should be administered followed by rapid titration. Importantly, this approach does not appear to compromise safety or tolerability for patients. Treatment with oral MTX, with appropriate dose titration, then should be continued for at least 6 months (as long as the patient experiences some response to treatment within 3 months) to achieve an accurate assessment of treatment efficacy. If oral MTX treatment fails due to intolerability or inadequate response, the patient may be “rescued” by switching to subcutaneous delivery of MTX. Consideration should also be given to starting with subcutaneous MTX given its favorable bioavailability and pharmacodynamic profile over oral delivery. Either initiation of subcutaneous MTX therapy or switching from oral to subcutaneous administration improves persistence with treatment. Upon transition from oral to subcutaneous delivery, MTX dosage should be maintained, rather than increased, and titration should be performed as needed. Similarly, if another RA treatment is necessary to control the disease, the MTX dosage and route of administration should be maintained, with titration as needed. PMID:28435338

Diffuse gas emissions at the Ukinrek Maars, Alaska: Implications for magmatic degassing and volcanic monitoring

USGS Publications Warehouse

Evans, William C.; Bergfeld, D.; McGimsey, R.G.; Hunt, A.G.

2009-01-01

Diffuse CO2 efflux near the Ukinrek Maars, two small volcanic craters that formed in 1977 in a remote part of the Alaska Peninsula, was investigated using accumulation chamber measurements. High CO2 efflux, in many places exceeding 1000 g m-2 d-1, was found in conspicuous zones of plant damage or kill that cover 30,000-50,000 m2 in area. Total diffuse CO2 emission was estimated at 21-44 t d-1. Gas vents 3-km away at The Gas Rocks produce 0.5 t d-1 of CO2 that probably derives from the Ukinrek Maars basalt based on similar ??13C values (???-6???), 3He/4He ratios (5.9-7.2 RA), and CO2/3He ratios (1-2 ?? 109) in the two areas. A lower 3He/4He ratio (2.7 RA) and much higher CO2/3He ratio (9 ?? 1010) in gas from the nearest arc-front volcanic center (Mount Peulik/Ugashik) provide a useful comparison. The large diffuse CO2 emission at Ukinrek has important implications for magmatic degassing, subsurface gas transport, and local toxicity hazards. Gas-water-rock interactions play a major role in the location, magnitude and chemistry of the emissions.

High frame rate imaging systems developed in Northwest Institute of Nuclear Technology

NASA Astrophysics Data System (ADS)

Li, Binkang; Wang, Kuilu; Guo, Mingan; Ruan, Linbo; Zhang, Haibing; Yang, Shaohua; Feng, Bing; Sun, Fengrong; Chen, Yanli

2007-01-01

This paper presents high frame rate imaging systems developed in Northwest Institute of Nuclear Technology in recent years. Three types of imaging systems are included. The first type of system utilizes EG&G RETICON Photodiode Array (PDA) RA100A as the image sensor, which can work at up to 1000 frame per second (fps). Besides working continuously, the PDA system is also designed to switch to capture flash light event working mode. A specific time sequence is designed to satisfy this request. The camera image data can be transmitted to remote area by coaxial or optic fiber cable and then be stored. The second type of imaging system utilizes PHOTOBIT Complementary Metal Oxygen Semiconductor (CMOS) PB-MV13 as the image sensor, which has a high resolution of 1280 (H) ×1024 (V) pixels per frame. The CMOS system can operate at up to 500fps in full frame and 4000fps partially. The prototype scheme of the system is presented. The third type of imaging systems adopts charge coupled device (CCD) as the imagers. MINTRON MTV-1881EX, DALSA CA-D1 and CA-D6 camera head are used in the systems development. The features comparison of the RA100A, PB-MV13, and CA-D6 based systems are given in the end.

Rapid Pneumatic Transport of Radioactive Samples - RaPToRS

NASA Astrophysics Data System (ADS)

Padalino, S.; Barrios, M.; Sangster, C.

2005-10-01

Some ICF neutron activation diagnostics require quick retrieval of the activated sample. Minimizing retrieval times is particularly important when the half-life of the activated material is on the order of the transport time or the degree of radioactivity is close to the background counting level. These restrictions exist in current experiments performed at the Laboratory for Laser Energetics, thus motivating the development of the RaPToRS system. The system has been designed to minimize transportation time while requiring no human intervention during transport or counting. These factors will be important if the system is to be used at the NIF where radiological hazards will be present during post activation. The sample carrier is pneumatically transported via a 4 inch ID PVC pipe to a remote location in excess of 100 meters from the activation site at a speed of approximately 7 m/s. It arrives at an end station where it is dismounted robotically from the carrier and removed from its hermetic package. The sample is then placed by the robot in a counting station. This system is currently being developed to measure back-to-back gamma rays produced by positron annihilation which were emitted by activated graphite. Funded in part by the U.S. DOE under sub contract with LLE at the University of Rochester.

Remote viewing.

PubMed

Scott, C

1988-04-15

Remote viewing is the supposed faculty which enables a percipient, sited in a closed room, to describe the perceptions of a remote agent visiting an unknown target site. To provide convincing demonstration of such a faculty poses a range of experimental and practical problems, especially if feedback to the percipient is allowed after each trial. The precautions needed are elaborate and troublesome; many potential loopholes have to be plugged and there will be strong temptations to relax standards, requiring exceptional discipline and dedication by the experimenters. Most reports of remote viewing experiments are rather superficial and do not permit assessment of the experimental procedures with confidence; in many cases there is clear evidence of particular loopholes left unclosed. Any serious appraisal of the evidence would have to go beyond the reports. Meanwhile the published evidence is far from compelling, and certainly insufficient to justify overthrow of well-established scientific principles.

Spatial Control of Cell Transfection Using Soluble or Solid-Phase Redox Agents and a Redox-Active Ferrocenyl Lipid

PubMed Central

Aytar, Burcu S.; Muller, John P. E.; Kondo, Yukishige; Abbott, Nicholas L.; Lynn, David M.

2013-01-01

We report principles for active, user-defined control over the locations and timing with which DNA is expressed in cells. Our approach exploits unique properties of a ferrocenyl cationic lipid that is inactive when oxidized, but active when chemically reduced. We show that methods that exert spatial control over the administration of reducing agents can lead to local activation of lipoplexes and spatial control over gene expression. The versatility of this approach is demonstrated using both soluble and solid-phase reducing agents. These methods provide control over cell transfection, including methods for remote activation and the patterning of expression using solid-phase redox agents, that are difficult to achieve using conventional lipoplexes. PMID:23965341

Spatial control of cell transfection using soluble or solid-phase redox agents and a redox-active ferrocenyl lipid.

PubMed

Aytar, Burcu S; Muller, John P E; Kondo, Yukishige; Abbott, Nicholas L; Lynn, David M

2013-09-11

We report principles for active, user-defined control over the locations and timing with which DNA is expressed in cells. Our approach exploits unique properties of a ferrocenyl cationic lipid that is inactive when oxidized, but active when chemically reduced. We show that methods that exert spatial control over the administration of reducing agents can lead to local activation of lipoplexes and spatial control over gene expression. The versatility of this approach is demonstrated using both soluble and solid-phase reducing agents. These methods provide control over cell transfection, including methods for remote activation and the patterning of expression using solid-phase redox agents, that are difficult to achieve using conventional lipoplexes.

Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial): study protocol for a randomised controlled trial.

PubMed

Hartman, Linda; Rasch, Linda A; Klausch, Thomas; Bijlsma, Hans W J; Christensen, Robin; Smulders, Yvo M; Ralston, Stuart H; Buttgereit, Frank; Cutolo, Maurizio; Da Silva, Jose A P; Opris, Daniela; Rovenský, Jozef; Szamosi, Szilvia; Middelink, Leonie M; Lems, Willem F; Boers, Maarten

2018-01-25

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA. The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions. Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA. ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.

Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy.

PubMed

Alam, Javaid; Jantan, Ibrahim; Bukhari, Syed Nasir Abbas

2017-08-01

An autoimmune disease is defined as a clinical syndrome resulted from an instigation of both T cell and B cell or individually, in the absence of any present infection or any sort of distinguishable cause. Clonal deletion of auto reactive cells remains the central canon of immunology for decades, keeping the role of T cell and B cell aside, which are actually the guards to recognize the entry of foreign body. According to NIH, 23.5 million Americans are all together affected by these diseases. They are rare, but with the exception of RA. Rheumatoid arthritis is chronic and systemic autoimmune response to the multiple joints with unknown ethology, progressive disability, systemic complications, early death and high socioeconomic costs. Its ancient disease with an old history found in North American tribes since 1500 BCE, but its etiology is yet to be explored. Current conventional and biological therapies used for RA are not fulfilling the need of the patients but give only partial responses. There is a lack of consistent and liable biomarkers of prognosis therapeutic response, and toxicity. Rheumatoid arthritis is characterized by hyperplasic synovium, production of cytokines, chemokines, autoantibodies like rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA), osteoclastogensis, angiogenesis and systemic consequences like cardiovascular, pulmonary, psychological, and skeletal disorders. Cytokines, a diverse group of polypeptides, play critical role in the pathogenesis of RA. Their involvement in autoimmune diseases is a rapidly growing area of biological and clinical research. Among the proinflammatory cytokines, IL-1α/β and TNF-α trigger the intracellular molecular signalling pathway responsible for the pathogenesis of RA that leads to the activation of mesenchymal cell, recruitment of innate and adaptive immune system cells, activation of synoviocytes which in term activates various mediators including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8), resulting in inflamed synovium, increase angiogenesis and decrease lymphangiogensis. Their current pharmacotherapy should focus on their three phases of progression i.e. prearthritis phase, transition phase and clinical phase. In this way we will be able to find a way to keep the balance between the pro and anti-inflammatory cytokines that is believe to be the dogma of pathogenesis of RA. For this we need to explore new agents, whether from synthetic or natural source to find the answers for unresolved etiology of autoimmune diseases and to provide a quality of life to the patients suffering from these diseases specifically RA. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study

PubMed Central

2012-01-01

Background 1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Methods Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics’ (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Results Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p < 0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p < 0.05). Conclusions Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV. PMID:22823909

Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study.

PubMed

Lin, Swu-Jane; Hatoum, Hind T; Buchner, Deborah; Cox, David; Balu, Sanjeev

2012-07-23

1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p<0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p<0.05). Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV.

[Treatment of tuberculosis in patients with comorbidities].

PubMed

Abe, Masahiro; Fujita, Akira

2013-12-01

Early detection and appropriate treatment are the keys to tuberculosis control. In particular, providing appropriate treatment for tuberculosis in patients with HIV infection, rheumatoid arthritis (RA), chronic hepatic disease, or renal failure necessitating hemodialysis, and taking appropriate measures against adverse reactions to antituberculosis drugs are issues of critical importance. This mini-symposium, four experts explained the current status of "treatment of tuberculosis in patients with comorbidities" and proposed measures to address these problems. Dr. Aoki talked about "HIV infection complicated by tuberculosis." To the next, Dr. Yoshinaga gave a talk on "treatment of tuberculosis in RA patients receiving biological agents. Further, Dr. Sasaki lectured on "tuberculosis in patients with hepatic disease/impairment". Lastly, Dr. Takamori gave a lecture on "tuberculosis in patients with renal disease and those on hemodialysis. Tuberculosis patients often have some underlying diseases, and adverse reactions caused by antituberculosis drugs, such as hepatic and renal impairments, are matters of concern. I believe that this mini-symposium has provided useful information for physicians engaged in tuberculosis treatment and for many other healthcare professionals as well.

Dietary Phytochemicals: Natural Swords Combating Inflammation and Oxidation-Mediated Degenerative Diseases

PubMed Central

2016-01-01

Cumulatively, degenerative disease is one of the most fatal groups of diseases, and it contributes to the mortality and poor quality of life in the world while increasing the economic burden of the sufferers. Oxidative stress and inflammation are the major pathogenic causes of degenerative diseases such as rheumatoid arthritis (RA), diabetes mellitus (DM), and cardiovascular disease (CVD). Although a number of synthetic medications are used to treat these diseases, none of the current regimens are completely safe. Phytochemicals (polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes) from natural products such as dietary fruits, vegetables, and spices are potential sources of alternative medications to attenuate the oxidative stress and inflammation associated with degenerative diseases. Based on in vitro, in vivo, and clinical trials, some of these active compounds have shown good promise for development into novel agents for treating RA, DM, and CVD by targeting oxidative stress and inflammation. In this review, phytochemicals from natural products with the potential of ameliorating degenerative disease involving the bone, metabolism, and the heart are described. PMID:27721914

Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association.

PubMed

Kim, Hyun Jin; Park, Seok O; Ko, Seung Hyun; Rhee, Sang Youl; Hur, Kyu Yeon; Kim, Nan Hee; Moon, Min Kyong; Lee, Byung Wan; Kim, Jin Hwa; Choi, Kyung Mook

2017-12-01

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin in the position statement of the Korean Diabetes Association 2017 for pharmacological therapy. Many randomized clinical trials and systematic reviews report that GLP-1RAs have considerable glucose-lowering effect and lead to weight reduction and low risk of hypoglycemia when used as a monotherapy or combination therapy. The cardiovascular safety of GLP-1RAs has been assessed in several randomized clinical trials and systematic reviews. The results of cardiovascular outcome trials of long-acting GLP-1RAs (liraglutide, semaglutide) demonstrated cardiovascular benefits in subjects with type 2 diabetes mellitus and a high risk of cardiovascular disease. The GLP-1RA may be a choice of therapy when weight control and avoidance of hypoglycemia are important, and patients with high risk of cardiovascular disease might also favor choosing GLP-1RA. Copyright © 2017 Korean Diabetes Association.

Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence

PubMed Central

Kawanami, Daiji; Matoba, Keiichiro; Sango, Kazunori; Utsunomiya, Kazunori

2016-01-01

An increase in the rates of morbidity and mortality associated with diabetic complications is a global concern. Glycemic control is important to prevent the development and progression of diabetic complications. Various classes of anti-diabetic agents are currently available, and their pleiotropic effects on diabetic complications have been investigated. Incretin-based therapies such as dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are now widely used in the treatment of patients with type 2 diabetes. A series of experimental studies showed that incretin-based therapies have beneficial effects on diabetic complications, independent of their glucose-lowering abilities, which are mediated by anti-inflammatory and anti-oxidative stress properties. Based on these findings, clinical studies to assess the effects of DPP-4 inhibitors and GLP-1RA on diabetic microvascular and macrovascular complications have been performed. Several but not all studies have provided evidence to support the beneficial effects of incretin-based therapies on diabetic complications in patients with type 2 diabetes. We herein discuss the experimental and clinical evidence of incretin-based therapy for diabetic complications. PMID:27483245

The bacterial adhesion on and the cytotoxicity of various dental cements used for implant-supported fixed restorations.

PubMed

Winkler, Cornelia; Schäfer, Lina; Felthaus, Oliver; Allerdings, Juri; Hahnel, Sebastian; Behr, Michael; Bürgers, Ralf

2014-05-01

Bacterial adhesion on and cytotoxicity of eight luting agents used for implant-supported restorations were investigated. Surface roughness (Ra), surface free energy (SFE) values and three-dimensional images by atomic-force microscopy of circular specimens were determined. Bacterial suspensions of Streptococcus sanguinis and Streptococcus epidermidis were incubated at 37°C for 2 h. Adhering bacteria were examined with fluorescence dye CytoX-Violet, stained with 4',6-diamidino-2-phenylindole (DAPI) and visualized by fluorescence-microscopy. Cytotoxicity-testing was done with WST-1-tests (water soluble tetrazolium). No significant differences, neither with regard to Ra nor regarding SFE were determined. Adherence of S. sanguinis was less on titanium, TempBondNE and TempBond. TempBond, TempBondNE, RelyX Unicem and Implantlink Semi Classic presented low amounts of S. epidermidis. WST-testing showed high cytotoxic potential of Harvard, Aqualox, TempBondNE and TempBond. No combination of low adherent bacteria with low cytotoxicity was found. From a biological in-vitro perspective, none of the cements may be recommended for implant-supported restorations.

Contributions of Familial Rheumatoid Arthritis or Lupus and Environmental Factors to Risk of Rheumatoid Arthritis in Women: a Prospective Cohort Study

PubMed Central

Sparks, Jeffrey A.; Chen, Chia-Yen; Hiraki, Linda T.; Malspeis, Susan; Costenbader, Karen H.; Karlson, Elizabeth W.

2014-01-01

Objective We assessed the contributions of familial rheumatoid arthritis (RA) or lupus and environmental factors to risk of RA. Methods Among 121,700 women in the Nurses’ Health Study, 65,457 provided data on familial RA/lupus. Among these, 493 RA cases (301 seropositive and 192 seronegative) were validated. We estimated hazard ratios (HR) for RA comparing those with and without familial RA/lupus, adjusting for environmental factors (smoking, alcohol, body mass index [BMI], parity, breastfeeding, menopause, hormone use, early menarche, and menstrual regularity) using Cox proportional hazards models. Population attributable risks (PAR) for RA within this cohort were calculated for familial RA/lupus, smoking, alcohol, BMI, parity, and breastfeeding. Results Familial RA/lupus was significantly associated with RA (HR 3.67), seropositive RA (HR 3.90) and seronegative RA (HR 3.95). After adjusting for environmental factors, familial RA/lupus was significantly associated with RA (HR 3.59, 95% confidence interval 2.94–4.37). Smoking >10 pack-years, alcohol intake 5–10 g/day, overweight, breastfeeding ≥12 months, and pre-menopausal status remained significantly associated with RA after adjusting for familial RA/lupus. For RA in this cohort, the PAR for smoking, BMI, alcohol, parity, or breastfeeding collectively was 41%; the PAR due to heredity from familial RA/lupus was 21%. Conclusion In this large, prospective cohort, women with familial RA/lupus had a four-fold increased risk for RA that remained significant after adjusting for environmental factors. A large proportion of RA risk was attributable to environmental factors even among those with familial RA/lupus. PMID:25103278

Development of the relaxation-assisted 2DIR method for accessing structures of molecules and its application for studying the energy transport on a molecular level

NASA Astrophysics Data System (ADS)

Kasyanenko, Valeriy Mitrofanovich

Measuring the three-dimensional structure of molecules, dynamics of structural changes, and energy transport on a molecular scale is important for many areas of natural science. Supplementing the widely used methods of x-ray diffraction, NMR, and optical spectroscopies, a two-dimensional infrared spectroscopy (2DIR) method was introduced about a decade ago. The 2DIR method measures pair-wise interactions between vibrational modes in molecules, thus acquiring molecular structural constraints such as distances between vibrating groups and the angles between their transition dipoles. The 2DIR method has been applied to a variety of molecular systems but in studying larger molecules such as proteins and peptides the method is facing challenges associated with the congestion of their vibrational spectra and delocalized character of their vibrational modes. To help extract structural information from such spectra and make efficient use of vibrational modes separated by large distances, a novel relaxation-assisted 2DIR method (RA 2DIR) has recently been proposed, which exploits the transport of excess vibrational energy from the initially excited mode. With the goal of further development of RA 2DIR, we applied it to a variety of molecular systems, including model compounds, transition-metal complexes, and isomers. The experiments revealed several novel effects which both enhance the power of RA 2DIR and bring a deeper understanding to the fundamental process of energy transport on a molecular level. We demonstrated that RA 2DIR can enhance greatly (27-fold) the cross-peak amplitude among spatially remote modes, which leads to an increase of the range of distances accessible for structural measurements by several fold. We demonstrated that the energy transport time correlates with the intermode distance. This correlation offers a new way for identifying connectivity patterns in molecules. We developed two models of energy transport in molecules. In one, a spatial overlap of vibrational modes determines the rate of energy transfer. Another model uses generalizations of Marcus theory of electron transfer applied to anharmonic vibrational transitions. These theoretical models reproduce well the main features of RA 2DIR measurements in a set of isomers where the energy transport is found to be affected by the three-dimensional structure as well as in transition-metal complexes, where the energy transport has to go through relatively weak coordination bonds and can be different from that occurring via covalent bonds.

Molecular targets of organophosphorus compounds and antidotal agents on nicotinic, glutamatergic and gabaergic synapses. Appendix 1. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albuquerque, E.X.

1994-03-16

There are several major motivators behind this work. We need to understand OP intoxication sufficiently to provide insight and direction for development of improved antidotal therapy. The persistent environmental use of chemical insecticides, which some feel is necessary for optimal agricultural production but others challenge vehemently, requires that we understand the toxicological consequences of such use. Also, OPs have such a powerful effect or, vital functions, it could be immensely beneficial to understand in great detail the physiological mechanisms that are targeted by OPs. Such information could benefit medical treatments of diseases and pathologies other than those directly caused bymore » OPs. Finally, we hope to present the material in a manner that will be instructive to a broad spectrum of professionals in pharmacology and toxicology. Where it is appropriate, we may draw heavily from other topical reviews. In all cases, we will provide citations to original work and/or well-referenced RA I, Lab Animals, Rats, Frogs, Compounds, Nerve Agents, Organophosphorous, BD, CD Agents, XCSM, Neurotransmitters, Receptors, Ion Channel, Oximes.« less

Plan execution monitoring with distributed intelligent agents for battle command

NASA Astrophysics Data System (ADS)

Allen, James P.; Barry, Kevin P.; McCormick, John M.; Paul, Ross A.

2004-07-01

As military tactics evolve toward execution centric operations the ability to analyze vast amounts of mission relevant data is essential to command and control decision making. To maintain operational tempo and achieve information superiority we have developed Vigilant Advisor, a mobile agent-based distributed Plan Execution Monitoring system. It provides military commanders with continuous contingency monitoring tailored to their preferences while overcoming the network bandwidth problem often associated with traditional remote data querying. This paper presents an overview of Plan Execution Monitoring as well as a detailed view of the Vigilant Advisor system including key features and statistical analysis of resource savings provided by its mobile agent-based approach.

REmote SUpervision to Decrease HospitaLization RaTe. Unified and integrated platform for data collected from devices manufactured by different companies: Design and rationale of the RESULT study.

PubMed

Tajstra, Mateusz; Sokal, Adam; Gwóźdź, Arkadiusz; Wilczek, Marcin; Gacek, Adam; Wojciechowski, Konrad; Gadula-Gacek, Elżbieta; Adamowicz-Czoch, Elżbieta; Chłosta-Niepiekło, Katarzyna; Milewski, Krzysztof; Rozentryt, Piotr; Kalarus, Zbigniew; Gąsior, Mariusz; Poloński, Lech

2017-07-01

The number of patients with heart failure implantable cardiac electronic devices (CIEDs) is growing. Hospitalization rate in this group is very high and generates enormous costs. To avoid the need for hospital treatment, optimized monitoring and follow-up is crucial. Remote monitoring (RM) has been widely put into practice in the management of CIEDs but it may be difficult due to the presence of differences in systems provided by device manufacturers and loss of gathered data in case of device reimplantation. Additionally, conclusions derived from studies about usefulness of RM in clinical practice apply to devices coming only from a single company. An integrated monitoring platform allows for more comprehensive data analysis and interpretation. Therefore, the primary objective of Remote Supervision to Decrease Hospitalization Rate (RESULT) study is to evaluate the impact of RM on the clinical status of patients with ICDs or CRT-Ds using an integrated platform. Six hundred consecutive patients with ICDs or CRT-Ds implanted will be prospectively randomized to either a traditional or RM-based follow-up model. The primary clinical endpoint will be a composite of all-cause mortality or hospitalization for cardiovascular reasons within 12 months after randomization. The primary technical endpoint will be to construct and evaluate a unified and integrated platform for the data collected from RM devices manufactured by different companies. This manuscript describes the design and methodology of the prospective, randomized trial designed to determine whether remote monitoring using an integrated platform for different companies is safe, feasible, and efficacious (ClinicalTrials.gov Identifier: NCT02409225). © 2016 Wiley Periodicals, Inc.

Induction of IL-1, in the testes of adult mice, following subcutaneous administration of turpentine.

PubMed

Elhija, Mahmoud Abu; Lunenfeld, Eitan; Huleihel, Mahmoud

2006-02-01

Interleukin-1 family is present in the testicular homogenates and its cellular compartments. It has been suggested that IL-1 is involved in physiological and pathological functions of the testicular tissues. In the present study we examined the effect of acute mostly localized inflammation, using turpentine, on the expression levels of testicular IL-1 system. Mice were subcutaneously injected with steam-distilled turpentine or saline (control). Three hours to 10 days following the injection, mice were killed and testis and spleen were homogenized and examined for interleukin (IL)-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1ra) levels by enzyme-linked immunosorbent assay and polymerase chain reaction. Subcutaneous injection of turpentine induced mice systemic inflammation, as indicated by significant increase in serum IL-1beta levels, and IL-1alpha, IL-1beta and IL-1ra in spleen homogenates. The levels of IL-1alpha, IL-1beta and IL-1ra were significantly induced in testicular homogenates of adult mice following subcutaneous injection of turpentine. The significant induction of testicular IL-1alpha was detected after 3-24 hr of turpentine injection and decreased later (after 3-10 days) to levels similar to the control. However, significant induction of testicular IL-1beta was detected only after 3-10 days of turpentine injection, and for testicular IL-1ra levels was detected after 3 hr to 6 days of turpentine injection, and after 10 days the levels were similar to the control. These results were also confirmed by mRNA expression of these factors. Our results demonstrate for the first time the distant effect of acute localized inflammation on testicular IL-1 levels. Thus, transient inflammatory response to infectious/inflammatory agents at non-testicular sites that elicit systemic IL-1 response should be considered during clinical treatment as a possible factor of male infertility.

Effect of Toothpaste Application Prior to Dental Bleaching on Whitening Effectiveness and Enamel Properties.

PubMed

Vieira-Junior, W F; Lima, D A N L; Tabchoury, C P M; Ambrosano, G M B; Aguiar, F H B; Lovadino, J R

2016-01-01

The purpose of this study was to investigate the effects on the enamel properties and effectiveness of bleaching using 35% hydrogen peroxide (HP) when applying toothpastes with different active agents prior to dental bleaching. Seventy enamel blocks (4 × 4 × 2 mm) were submitted to in vitro treatment protocols in a tooth-brushing machine (n=10): with distilled water and exposure to placebo gel (negative control [NC]) or HP bleaching (positive control [PC]); and brushing with differing toothpastes prior to HP bleaching, including potassium nitrate toothpaste (PN) containing NaF, conventional sodium monofluorophosphate toothpaste (FT), arginine-based toothpastes (PA and SAN), or a toothpaste containing bioactive glass (NM). Color changes were determined using the CIE L*a*b* system (ΔE, ΔL, Δa, and Δb), and a roughness (Ra) analysis was performed before and after treatments. Surface microhardness (SMH) and cross-sectional microhardness (CSMH) were analyzed after treatment. Data were analyzed with repeated measures ANOVA for Ra, one-way ANOVA (SMH, ΔE, ΔL, Δa, and Δb), split-plot ANOVA (CSMH), and Tukey post hoc test (α<0.05). The relationship between the physical surface properties and color properties was evaluated using a multivariate Canonical correlation analysis. Color changes were statistically similar in the bleached groups. After treatments, SMH and CSMH decreased in PC. SMH increased significantly in the toothpaste groups vs the negative and positive control (NM > PA = SAN > all other groups) or decreased HP effects (CSMH). Ra increased in all bleached groups, with the exception of NM, which did not differ from the NC. The variation in the color variables (ΔL, Δa, and Δb) explained 21% of the variation in the physical surface variables (Ra and SMH). The application of toothpaste prior to dental bleaching did not interfere with the effectiveness of treatment. The bioactive glass based toothpaste protected the enamel against the deleterious effects of dental bleaching.

Formatted anti-tumor necrosis factor alpha VHH proteins derived from camelids show superior potency and targeting to inflamed joints in a murine model of collagen-induced arthritis.

PubMed

Coppieters, Ken; Dreier, Torsten; Silence, Karen; de Haard, Hans; Lauwereys, Marc; Casteels, Peter; Beirnaert, Els; Jonckheere, Heidi; Van de Wiele, Christophe; Staelens, Ludovicus; Hostens, Jeroen; Revets, Hilde; Remaut, Erik; Elewaut, Dirk; Rottiers, Pieter

2006-06-01

The advent of tumor necrosis factor (TNF)-blocking drugs has provided rheumatologists with an effective, but highly expensive, treatment for the management of established rheumatoid arthritis (RA). Our aim was to explore preclinically the application of camelid anti-TNF VHH proteins, which are single-domain antigen binding (VHH) proteins homologous to human immunoglobulin V(H) domains, as TNF antagonists in a mouse model of RA. Llamas were immunized with human and mouse TNF, and antagonistic anti-TNF VHH proteins were isolated and cloned for bacterial production. The resulting anti-TNF VHH proteins were recombinantly linked to yield bivalent mouse and human TNF-specific molecules. To increase the serum half-life and targeting properties, an anti-serum albumin anti-TNF VHH domain was incorporated into the bivalent molecules. The TNF-neutralizing potential was analyzed in vitro. Mouse TNF-specific molecules were tested in a therapeutic protocol in murine collagen-induced arthritis (CIA). Disease progression was evaluated by clinical scoring and histologic evaluation. Targeting properties were evaluated by 99mTc labeling and gamma camera imaging. The bivalent molecules were up to 500 times more potent than the monovalent molecules. The antagonistic potency of the anti-human TNF VHH proteins exceeded even that of the anti-TNF antibodies infliximab and adalimumab that are used clinically in RA. Incorporation of binding affinity for albumin into the anti-TNF VHH protein significantly prolonged its serum half-life and promoted its targeting to inflamed joints in the murine CIA model of RA. This might explain the excellent therapeutic efficacy observed in vivo. These data suggest that because of the flexibility of their format, camelid anti-TNF VHH proteins can be converted into potent therapeutic agents that can be produced and purified cost-effectively.

Combination of SGLT-2 inhibitors and GLP-1 receptor agonists: potential benefits in surrogate and hard endpoints.

PubMed

Doumas, Michael; Imprialos, Κonstantinos; Stavropoulos, Konstantinos; Reklou, Andromachi; Sachinidis, Alexandros; Athyros, Vasilios G

2018-06-03

The treatment of type 2 diabetes mellitus (T2DM) is complex; only few patients successfully attain glycemic targets with monotherapy, most requiring drug combination therapy. The goal of this review was to identify in PubMed the complimentary ways of action leading to clinical benefit (in lowering HbA1c, body weight, renal, and cardiac risk factors and events) of the combination of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA). SGLT2i, an emerging class of antidiabetic agents with an insulin-independent mechanism of action, are suitable for use in combination with any other class of antidiabetics, including insulin. The use of SGLT2i causes a reduction in cardiovascular disease (CVD) morbidity (mainly heart failure-HF) as well as total and CVD mortality. Besides insulin, SGLT2i may also be combined with incretin-based therapies, such as GLP-1 RA. The later appear to reduce the rate or the progression of both macrovascular (mainly myocardial infarction-MI and stroke) and microvascular complications of DM, having a beneficial effect on all-cause mortality and CVD mortality, as well as CVD events. SGLT2i and GLP-1 RA may have a synergic effect on glucose reduction, weight reduction, renal impairment (both an independent lethal disease and a CVD risk factor) improvement, and cardiac event reduction, because the first reduces HF and related events and the second decreases CVD risk (mainly MI and stroke). Both also reduce total mortality, especially when combined with a statin. The combination of metformin with SGLT2i, GLP-1 RA, and a potent statin, in high CVD risk patients with DM, is expected to substantially reduce CVD mortality and morbidity, improving the quality of life of patients with DM at the same time. Prospective studies are needed to confirm this finding. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report

PubMed Central

Fouladi, Maryam; Park, Julie R.; Stewart, Clinton F.; Gilbertson, Richard J.; Schaiquevich, Paula; Sun, Junfeng; Reid, Joel M.; Ames, Matthew M.; Speights, Roseanne; Ingle, Ashish M.; Zwiebel, James; Blaney, Susan M.; Adamson, Peter C.

2010-01-01

Purpose The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children. Patients and Methods Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC). Results Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination. Conclusion In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults. PMID:20606092

Laser Based Stand-Off Detection of Biological Agents (detection a distance des agents biologiques a l’aide du laser)

DTIC Science & Technology

2010-02-01

overview of their respective national up-date. Dr. Roy presented a new technique for evaluating the bioaerosol particle size based on a multiple...Field-of-View LIDAR technique . Mr. Levesque from INO gave an overview of their expertise in LIDAR and biophotonics. Dr. Chin from Laval University gave... techniques have the potential to detect particulate aerosols remotely at distances of many kilometres [1]. They can provide spatially resolved

The reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent does not influence the effect of a second TNF blocking agent in patients with rheumatoid arthritis.

PubMed

Blom, Marlies; Kievit, Wietske; Fransen, Jaap; Kuper, Ina H; den Broeder, Alfons A; De Gendt, Carla M A; Jansen, Tim L; Brus, Herman L M; van de Laar, Mart A F J; van Riel, Piet L C M

2009-10-01

To investigate whether the reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent influences the effect of a second TNF blocking agent. Data were used from 2 Dutch registries including patients with rheumatoid arthritis (RA) treated with TNF blocking agents. Patients were divided into 3 groups based on reason for discontinuation of the first: nonresponse, loss of response, or adverse events. The primary outcome was the change from baseline of the disease activity (by DAS28) at 6 months, corrected for the baseline DAS28 score. Secondary outcomes were the change from baseline at 3 months, EULAR response rates, and the percentages of patients who reached a DAS28 score < or = 3.2 at 3 and at 6 months. In total, 49 patients who failed due to nonresponse, 75 due to loss of response, and 73 due to adverse events were included. At 6 months, the change of DAS28 score from baseline did not differ significantly between the groups (-0.6 to -1.3; p > or = 0.173) and similar good and moderate response rates were found (12% to 18%, p > or = 0.523, and 34% to 55%, p > or = 0.078, respectively). The secondary outcomes were also comparable between the 3 groups. The results of our observational study suggest that a second TNF blocking agent may be effective after failure of the first, regardless of the reason for discontinuation of the first TNF blocking agent.

Teratogenicity and transplacental pharmacokinetics of 13-cis-retinoic acid in rabbits.

PubMed

Eckhoff, C; Chari, S; Kromka, M; Staudner, H; Juhasz, L; Rudiger, H; Agnish, N

1994-03-01

No embryotoxic or teratogenic effects, considered to be treatment related, were observed in rabbits after daily oral doses of 3 mg/kg of 13-cis-retinoic acid (13-cis-RA) from Day 8 to Day 11 of gestation. In contrast, treatment with 15 mg/kg/day significantly increased the rate of fetal resorptions (22%) and 13 out of 68 surviving fetuses (16%) were malformed. Pharmacokinetic studies with both dosing regimens of 13-cis-RA in pregnant rabbits showed that on Day 11 of gestation, high concentrations of parent compound, 13-cis-RA, and its major metabolite, 13-cis-4-oxoRA, existed in maternal plasma. Much lower concentrations were found for all-trans-4-oxoRA and all-trans-RA. The area under the concentration-time curve (AUC) of all-trans-RA following the 15 mg/kg/day dosing regimen of 13-cis-RA was only 1.2% that of parent compound 13-cis-RA. At this dose, embryo levels of 13-cis-RA, 13-cis-4-oxoRA, and all-trans-4-oxoRA were 2.5-, 4.7-, and 3.6-fold higher by AUC comparison (24-hr period of Day 11) compared with the dose of 3 mg/kg. However, embryo levels of all-trans-RA were virtually identical at both doses and were, in fact, somewhat lower than endogenous concentrations measured in untreated rabbit embryos. In contrast to mice, where isomerization from 13-cis- to all-trans-RA was suggested to be crucial for the teratogenic action of 13-cis-RA, we found that the teratogenic action of 13-cis-RA (15 mg/kg/day) in rabbits is characterized by increased whole embryo concentrations of 13-cis-RA, 13-cis-4-oxoRA, and all-trans-4-oxoRA, but not of all-trans-RA.

Determination of low-level Radium isotope activities in fresh waters by gamma spectrometry.

PubMed

Molina Porras, Arnold; Condomines, Michel; Seidel, Jean Luc

2017-02-01

A new portable sampling system was developed to extract Radium isotopes from large volumes (up to 300L) of fresh surface- and ground-waters of low Ra-activities (<5mBq/L). Ra is quantitatively adsorbed on a small amount (6.5g) of MnO 2 -coated acrylic fibers, which are then dried and burned at 600°C in the laboratory. The resulting Mn-oxide powder (about 2cm 3 when compacted) is then analyzed through gamma-ray spectrometry which allows measurement of the whole Ra quartet ( 226 Ra, 228 Ra, 224 Ra and 223 Ra) in a single counting of a few days. The usual relative standard combined uncertainties (1σ) are 2-3% for 226 Ra, 228 Ra and 224 Ra; and less than 10% for 223 Ra. This method was applied to the analysis of Ra in karstic waters of the Lez aquifer, and surface- and ground-waters of the upper and middle Vidourle watershed (South of France). The analyzed waters have relatively low 226 Ra activities (1-4mBq/L) in both cases, regardless of the contrasted geology (Mesozoic limestone vs crystalline Variscan basement), but clearly distinct ( 228 Ra/ 226 Ra) ratios in agreement with the differences in Th/U ratios of the two drained areas. Short-lived Ra isotopes ( 224 Ra and 223 Ra) appear to be mainly influenced by near-surface desorption/recoil processes for most of the sampling sites. Copyright © 2016. Published by Elsevier Ltd.

The Roles of Cigarette Smoking and the Lung in the Transitions between Phases of Preclinical Rheumatoid Arthritis

PubMed Central

Sparks, Jeffrey A.; Karlson, Elizabeth W.

2016-01-01

While the etiology of rheumatoid arthritis (RA) remains to be fully elucidated, recent research has advanced the understanding of RA pathogenesis to the point where clinical trials for RA prevention are underway. The current paradigm for RA pathogenesis is that individuals progress through distinct preclinical stages prior to the onset of clinically apparent RA. These preclinical RA phases consist of genetic risk, local inflammation, presence of RA-related autoantibodies, asymptomatic systemic inflammation, and early non-specific symptoms prior to clinical seropositive RA. Epidemiologic studies have been important in forming hypotheses related to the biology occurring in preclinical RA. Specifically, studies associating cigarette smoking with overall RA risk as well as transitions between phases of preclinical RA were vital in helping to establish the lung as a potential important initiating site in the pathogenesis of seropositive RA. Herein, we review the epidemiology associating smoking with transitions in preclinical phases of RA as well as the recent literature supporting the lung as a critical site in RA pathogenesis. PMID:26951253

Metabolic characteristics of 13-cis-retinoic acid (isotretinoin) and anti-tumour activity of the 13-cis-retinoic acid metabolite 4-oxo-13-cis-retinoic acid in neuroblastoma

PubMed Central

Sonawane, Poonam; Cho, Hwang Eui; Tagde, Ashujit; Verlekar, Dattesh; Yu, Alice L; Reynolds, C Patrick; Kang, Min H

2014-01-01

Background and Purpose Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA. Experimental Approach Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples. Key Results Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-β mRNA and protein levels. Conclusions and Implications We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma. PMID:25039756

Metabolic characteristics of 13-cis-retinoic acid (isotretinoin) and anti-tumour activity of the 13-cis-retinoic acid metabolite 4-oxo-13-cis-retinoic acid in neuroblastoma.

PubMed

Sonawane, Poonam; Cho, Hwang Eui; Tagde, Ashujit; Verlekar, Dattesh; Yu, Alice L; Reynolds, C Patrick; Kang, Min H

2014-12-01

Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA. Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples. Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-β mRNA and protein levels. We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma. © 2014 The British Pharmacological Society.

Occurrence and geochemistry of radium in water from principal drinking-water aquifer systems of the United States

USGS Publications Warehouse

Szabo, Z.; dePaul, V.T.; Fischer, J.M.; Kraemer, T.F.; Jacobsen, E.

2012-01-01

A total of 1270 raw-water samples (before treatment) were collected from 15 principal and other major aquifer systems (PAs) used for drinking water in 45 states in all major physiographic provinces of the USA and analyzed for concentrations of the Ra isotopes 224Ra, 226Ra and 228Ra establishing the framework for evaluating Ra occurrence. The US Environmental Protection Agency Maximum Contaminant Level (MCL) of 0.185Bq/L (5pCi/L) for combined Ra ( 226Ra plus 228Ra) for drinking water was exceeded in 4.02% (39 of 971) of samples for which both 226Ra and 228Ra were determined, or in 3.15% (40 of 1266) of the samples in which at least one isotope concentration ( 226Ra or 228Ra) was determined. The maximum concentration of combined Ra was 0.755Bq/L (20.4pCi/L) in water from the North Atlantic Coastal Plain quartzose sand aquifer system. All the exceedences of the MCL for combined Ra occurred in water samples from the following 7PAs (in order of decreasing relative frequency of occurrence): the Midcontinent and Ozark Plateau Cambro-Ordovician dolomites and sandstones, the North Atlantic Coastal Plain, the Floridan, the crystalline rocks (granitic, metamorphic) of New England, the Mesozoic basins of the Appalachian Piedmont, the Gulf Coastal Plain, and the glacial sands and gravels (highest concentrations in New England).The concentration of Ra was consistently controlled by geochemical properties of the aquifer systems, with the highest concentrations most likely to be present where, as a consequence of the geochemical environment, adsorption of the Ra was slightly decreased. The result is a slight relative increase in Ra mobility, especially notable in aquifers with poor sorptive capacity (Fe-oxide-poor quartzose sands and carbonates), even if Ra is not abundant in the aquifer solids. The most common occurrence of elevated Ra throughout the USA occurred in anoxic water (low dissolved-O 2) with high concentrations of Fe or Mn, and in places, high concentrations of the competing ions Ca, Mg, Ba and Sr, and occasionally of dissolved solids, K, SO 4 and HCO 3. The other water type to frequently contain elevated concentrations of the Ra radioisotopes was acidic (low pH), and had in places, high concentrations of NO 3 and other acid anions, and on occasion, of the competing divalent cations, Mn and Al. One or the other of these broad water types was commonly present in each of the PAs in which elevated concentrations of combined Ra occurred. Concentrations of 226Ra or 228Ra or combined Ra correlated significantly with those of the above listed water-quality constituents (on the basis of the non-parametric Spearman correlation technique) and loaded on principal components describing the above water types from the entire data set and for samples from the PAs with the highest combined Ra concentrations.Concentrations of 224Ra and 226Ra were significantly correlated to those of 228Ra (Spearman's rank correlation coefficient, +0.236 and +0.326, respectively). Activity ratios of 224Ra/ 228Ra in the water samples were mostly near 1 when concentrations of both isotopes were greater than or equal to 0.037Bq/L (1pCi/L), the level above which analytical results were most reliable. Co-occurrence among these highest concentrations of the Ra radionuclides was most likely in those PAs where chemical conditions are most conducive to Ra mobility (e.g. acidic North Atlantic Coastal Plain). The concentrations of 224Ra were occasionally greater than 0.037Bq/L and the ratios of 224Ra/ 228Ra were generally highest in the PAs composed of alluvial sands and Cretaceous/Tertiary sandstones from the western USA, likely because concentrations of 224Ra are enhanced in solution relative to those of 228Ra by alpha recoil from the aquifer matrix. Rapid adsorption of the two Ra isotopes (controlled by the alkaline and oxic aquifer geochemistry) combined with preferential faster recoil of 224Ra generates a 224Ra/ 228Ra ratio much greater than

Autoantibodies to two novel peptides in seronegative and early rheumatoid arthritis.

PubMed

De Winter, Liesbeth M; Hansen, Wendy L J; van Steenbergen, Hanna W; Geusens, Piet; Lenaerts, Jan; Somers, Klaartje; Stinissen, Piet; van der Helm-van Mil, Annette H M; Somers, Veerle

2016-08-01

Despite recent progress in biomarker discovery for RA diagnostics, still over one-third of RA patients-and even more in early disease-present without RF or ACPA. The aim of this study was to confirm the presence of previously identified autoantibodies to novel Hasselt University (UH) peptides in early and seronegative RA. Screening for antibodies against novel UH peptides UH-RA.1, UH-RA.9, UH-RA.14 and UH-RA.21, was performed in two large independent cohorts. Peptide ELISAs were developed to screen for the presence of antibodies to UH-RA peptides. First, 292 RA patients (including 39 early patients), 90 rheumatic and 97 healthy controls from UH were studied. Antibody reactivity to two peptides (UH-RA.1 and UH-RA.21) was also evaluated in 600 RA patients, 309 patients with undifferentiated arthritis and 157 rheumatic controls from the Leiden Early Arthritis Clinic cohort. In both cohorts, 38% of RA patients were seronegative for RF and ACPA. Testing for autoantibodies to UH-RA.1 and UH-RA.21 reduced the serological gap from 38% to 29% in the UH cohort (P = 0.03) and from 38% to 32% in the Leiden Early Arthritis Clinic cohort (P = 0.01). Furthermore, 19-33% of early RA patients carried antibodies to these peptides. Specificities in rheumatic controls ranged from 82 to 96%. Whereas antibodies against UH-RA.1 were related to remission, anti-UH-RA.21 antibodies were associated with inflammation, joint erosion and higher tender and swollen joint counts. This study validates the presence of antibody reactivity to novel UH-RA peptides in seronegative and early RA. This might reinforce current diagnostics and improve early diagnosis and intervention in RA. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Allergic, Immunological and Infectious Disease Problems in Aerospace Medicine Held in Rome, Italy on 21 - 25 October 1991 (Les Problemes Causes par les Maladies Allergiques, Immunologiques et Contagieuses en Mdecine Aerospatiale).

DTIC Science & Technology

1992-04-01

whose lymphocytes displayed, at the identified. When assays for antibacterial activity time of lowest immune responses, a surface IL2Ra were performed...with these two agents SSD demon- level around 50% of the first day level (Figure 5), strated superior antibacterial activity in in vitro tests the...day At day 30, a significative increase of direct antibacterial activity 0 and 28. The second group was treated with Ty2la (Neotif, Scla- was observed

Placental transfer and developmental effects of 9-cis retinoic acid in mice.

PubMed

Kochhar, D M; Jiang, H; Penner, J D; Heyman, R A

1995-04-01

9-cis retinoic acid (RA) is a naturally occurring isomer of all-trans RA. While both isomers can bind with high affinity and activate RA receptors, only 9-cis RA is the specific ligand for the retinoid X receptors. 9-cis RA has also been shown to be much more potent than all-trans RA in inducing digit duplication in the chick embryo wing bud. To gain further insight into its mechanisms, here we investigated the teratogenic activity in pregnant mice of 9-cis RA and compared it with those of all-trans RA and 13-cis RA. Using frequency and severity of limb reduction defects as well as palatal clefts in the resultant fetuses as indicators, we found that orally administered 9-cis RA was one-half as potent a teratogen as all-trans RA. That 9-cis RA was intrinsically less active than all-trans RA was deduced by comparing the inhibitory activities of the two retinoids in the limb bud mesenchymal cell micromass cultures using chondrogenesis as an end-point. Since placental transfer of cis isomers of RA is generally poor, we monitored the identities and amounts of retinoids in the embryo after administration of 9-cis RA to the mother. We found that 9-cis RA undergoes extensive metabolism and isomerization during absorption resulting in a number of metabolites in the maternal circulation within 30 min after administration. Although some of these metabolites remain to be identified, the most abundant RA isomers in the plasma coeluted with 13-cis RA.(ABSTRACT TRUNCATED AT 250 WORDS)

Tools and Techniques to Collaborate and Connect with At-Risk Climate Communities UsingSensors, Remote Sensing Data, and Media

NASA Astrophysics Data System (ADS)

Drapkin, J. K.; Ramamurthy, P.; Vant-Hull, B.; Yuen, K.; Glenn, A.; Jusino, C.; Corbin, C.; Schuerman, M.; Keefe, J.; Brooke, H.

2016-12-01

Those most at risk during heat waves and floods are often the socio-economically vulnerable. Yet very few studies exist of indoor temperatures during heat waves or of standing water events at the neighborhood level during extreme events. ISeeChange, a community weather and climate journal, is developing tools and testing techniques in a series of community pilots in Harlem and New Orleans to assess if a combination of citizen science, remote sensing, and journalism can bridge the gap. Our consortium of media (WNYC,Adapt NYC, ISeeChange), scientists (CUNY, CoCoRaHS, NASAJPL), and community partners (WE ACT for Environmental Justice, tenant, and neighborhood associations) are collaborating to engage with residents, report radio stories, as well as develop scientifically valuableinformation for decision-making. Community volunteers place temperature and humidity sensors inside residences (Harlem) or photograph standing water using specific methodologies (New Orleans). Sensordata, photographs, and text documenting the impacts of extreme weather on residents are posted on the ISeeChange platform via mobile app or community ambassadors and compared to other remote sensing data products (surface temperature, precipitation, subsidence) Preliminary results of the Harlem pilot show that indoor temperatures are far more stable than outdoor temperatures, so can be both cooler during the day but warmer at night; preliminary work on the New Orleans pilot is set to begin in fall 2016. A full analysis of the Harlem pilot will be presented along with preliminary results of the New Orleans pilot.

Brahms Mobile Agents: Architecture and Field Tests

NASA Technical Reports Server (NTRS)

Clancey, William J.; Sierhuis, Maarten; Kaskiris, Charis; vanHoof, Ron

2002-01-01

We have developed a model-based, distributed architecture that integrates diverse components in a system designed for lunar and planetary surface operations: an astronaut's space suit, cameras, rover/All-Terrain Vehicle (ATV), robotic assistant, other personnel in a local habitat, and a remote mission support team (with time delay). Software processes, called agents, implemented in the Brahms language, run on multiple, mobile platforms. These mobile agents interpret and transform available data to help people and robotic systems coordinate their actions to make operations more safe and efficient. The Brahms-based mobile agent architecture (MAA) uses a novel combination of agent types so the software agents may understand and facilitate communications between people and between system components. A state-of-the-art spoken dialogue interface is integrated with Brahms models, supporting a speech-driven field observation record and rover command system (e.g., return here later and bring this back to the habitat ). This combination of agents, rover, and model-based spoken dialogue interface constitutes a personal assistant. An important aspect of the methodology involves first simulating the entire system in Brahms, then configuring the agents into a run-time system.

No meaningful association between suicidal behavior and the use of IL-17A-neutralizing or IL-17RA-blocking agents.

PubMed

Chiricozzi, Andrea; Romanelli, Marco; Saraceno, Rosita; Torres, Tiago

2016-12-01

An emerging class of agents blocking IL-17 signaling represents a very promising therapeutic approach. One of these agents, brodalumab, has been associated with an increased risk of suicide behavior. Areas covered: This review sought to provide an overview strictly focused on suicide behavior signals related to the use of IL-17 agents. Data collection regarding this peculiar safety aspect was primarily based on: (i) a revision of safety outcomes belonging to phase II and phase III trials; (ii) a systematic search using the Pubmed Medline database; and (iii) collecting recent data issued as posters or communications in eminent international meetings. Expert opinion: Whilst secukinumab and ixekizumab were not associated with increased signal of suicidal behavior, being recently approved for the treatment of psoriasis by EMA and FDA, brodalumab raised concern because of suicide behavior cases that led to pause momentarily its development program during pre-marketing stage before obtaining the positive recommendation by an FDA advisory panel for its approval. Indeed, a careful re-evaluation of brodalumab safety profile is being performed and no evidence clarified a significant association or a pathogenic mechanism linking brodalumab treatment to the risk of suicidal behavior, suggesting that cases of suicidal behavior accidentally occurred during brodalumab trials.

Development and Applications of Photo-triggered Theranostic Agents

PubMed Central

Rai, Prakash; Mallidi, Srivallesha; Zheng, Xiang; Rahmanzadeh, Ramtin; Mir, Youssef; Elrington, Stefan; Khurshid, Ahmat; Hasan, Tayyaba

2010-01-01

Theranostics, the fusion of therapy and diagnostics for optimizing efficacy and safety of therapeutic regimes, is a growing field that is paving the way towards the goal of personalized medicine for the benefit of patients. The use of light as a remote-activation mechanism for drug delivery has received increased attention due to its advantages in highly specific spatial and temporal control of compound release. Photo-triggered theranostic constructs could facilitate an entirely new category of clinical solutions which permit early recognition of the disease by enhancing contrast in various imaging modalities followed by the tailored guidance of therapy. Finally, such theranostic agents could aid imaging modalities in monitoring response to therapy. This article reviews recent developments in the use of light-triggered theranostic agents for simultaneous imaging and photoactivation of therapeutic agents. Specifically, we discuss recent developments in the use of theranostic agents for photodynamic-, photothermal- or photo-triggered chemo-therapy for several diseases. PMID:20858520

Antimalarial therapy selection for quinolone resistance among Escherichia coli in the absence of quinolone exposure, in tropical South America.

PubMed

Davidson, Ross J; Davis, Ian; Willey, Barbara M; Rizg, Keyro; Bolotin, Shelly; Porter, Vanessa; Polsky, Jane; Daneman, Nick; McGeer, Allison; Yang, Paul; Scolnik, Dennis; Rowsell, Roy; Imas, Olga; Silverman, Michael S

2008-07-16

Bacterial resistance to antibiotics is thought to develop only in the presence of antibiotic pressure. Here we show evidence to suggest that fluoroquinolone resistance in Escherichia coli has developed in the absence of fluoroquinolone use. Over 4 years, outreach clinic attendees in one moderately remote and five very remote villages in rural Guyana were surveyed for the presence of rectal carriage of ciprofloxacin-resistant gram-negative bacilli (GNB). Drinking water was tested for the presence of resistant GNB by culture, and the presence of antibacterial agents and chloroquine by HPLC. The development of ciprofloxacin resistance in E. coli was examined after serial exposure to chloroquine. Patient and laboratory isolates of E. coli resistant to ciprofloxacin were assessed by PCR-sequencing for quinolone-resistance-determining-region (QRDR) mutations. In the very remote villages, 4.8% of patients carried ciprofloxacin-resistant E. coli with QRDR mutations despite no local availability of quinolones. However, there had been extensive local use of chloroquine, with higher prevalence of resistance seen in the villages shortly after a Plasmodium vivax epidemic (p<0.01). Antibacterial agents were not found in the drinking water, but chloroquine was demonstrated to be present. Chloroquine was found to inhibit the growth of E. coli in vitro. Replica plating demonstrated that 2-step QRDR mutations could be induced in E. coli in response to chloroquine. In these remote communities, the heavy use of chloroquine to treat malaria likely selected for ciprofloxacin resistance in E. coli. This may be an important public health problem in malarious areas.

Effect of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitor on Disease Activity in Patients With Rheumatoid Arthritis

PubMed Central

Xing, Bin; Yin, Yu-Feng; Zhao, Li-Dan; Wang, Li; Zheng, Wen-Jie; Chen, Hua; Wu, Qing-Jun; Tang, Fu-Lin; Zhang, Feng-Chun; Shan, Guangliang; Zhang, Xuan

2015-01-01

Abstract HMG-CoA reductase inhibitors (also known as statins) are widely used as lipid-lowering agents in patients with rheumatoid arthritis (RA) to reduce their cardiovascular risk. However, whether they have an effect on RA disease activity is controversial. This study aimed to investigate the effect of statins on disease activity in RA patients. A systematic literature review was performed using the MEDLINE, EMBASE, Cochrane Library, ISI WEB of Knowledge, Scopus, and Clinical Trials Register databases. Only prospective randomized controlled trials or controlled clinical trials comparing the efficacy of statins with placebo on adult RA patients were included. The efficacy was measured according to the ACR criteria, EULAR criteria, DAS28, HAQ score, ESR, or CRP. The Jadad score was used for quality assessment. The inverse variance method was used to analyze continuous outcomes. A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was used. For stability of results, we performed leave-one-study-out sensitivity analysis by omitting individual studies one at a time from the meta-analysis. Publication bias was assessed using Egger test. A total 13 studies involving 737 patients were included in the meta-analysis; 11 studies were included in the meta-analysis based on DAS28, while the other 2 studies were only included in the meta-analysis based on ESR or CRP. The standardized mean difference (SMD) in DAS28 between the statin group and the placebo group was −0.55 (95% CI [−0.83, −0.26], P = 0.0002), with an I2 value of 68%. Subgroup analysis showed that patients with more active disease tended to benefit more from statin therapy (SMD −0.73, P = 0.01) than patients with moderate or low disease activity (SMD −0.38, P = 0.03). Statin therapy also significantly reduced tender joint counts, swollen joint counts, ESR, and CRP compared with placebo, but the reduction in HAQ score and VAS was not significant (P > 0.05). This meta-analysis suggested that statin therapy might be effective in the reduction of RA disease activity measured by DAS28, TJC, SJC, as well as ESR and CRP. PMID:25715256

Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guerra Liberal, Francisco D. C., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, Adriana Alexandre S., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, João Manuel R. S., E-mail: tavares@fe.up.pt

Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bonemore » metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ({sup 32}P), strontium-89 ({sup 89}Sr), yttrium-90 ({sup 90}Y ), tin-117 ({sup 117m}Sn), samarium-153 ({sup 153}Sm), holmium-166 ({sup 166}Ho), thulium-170 ({sup 170}Tm), lutetium-177 ({sup 177}Lu), rhenium-186 ({sup 186}Re), rhenium-188 ({sup 188}Re), and radium-223 ({sup 223}Ra). Results: {sup 223}Ra alpha particles, {sup 177}Lu beta minus particles, and {sup 170}Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by {sup 89}Sr and {sup 153}Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than {sup 177}Lu beta minus particles and {sup 223}Ra alpha particles. Conclusions: {sup 223}Ra and {sup 177}Lu hold the highest potential for palliative treatment of bone metastases of all radioisotopes compared in this study. Data reported here may prompt future in vitro and in vivo experiments comparing different radionuclides for palliative treatment of bone metastases, raise the need for the careful rethinking of the current widespread clinical use of {sup 89}Sr and {sup 153}Sm, and perhaps strengthen the use of {sup 223}Ra and {sup 177}Lu in the palliative treatment of bone metastases.« less

The effect of curcumin and its nanoformulation on adjuvant-induced arthritis in rats.

PubMed

Zheng, Zhaoling; Sun, YanHua; Liu, Ziliang; Zhang, Mingqin; Li, Chunqing; Cai, Hui

2015-01-01

Rheumatoid arthritis (RA), induced by the prolonged inappropriate inflammatory responses, is one of the most prevalent of all chronic inflammatory joint diseases. Curcumin (CM), a yellow hydrophobic polyphenol derived from the herb turmeric, has various pharmacological activities against many chronic diseases and acts by inhibiting cell proliferation and metastasis and downregulating various factors, including nuclear factor kappa B, interleukin-1β and TNF-α. Given the pathogenesis of RA, we hypothesized that the drug also has antiarthritic effects. The aims of the present study included the following: 1) examining the therapeutic effect of CM administered via intravenous (iv) injection on RA and 2) formulating the drug into oil-water nanoemulsions (Ns) to overcome the low oral bioavailability of CM and achieve oral delivery of the drug. The effect of CM administered through iv injection on adjuvant-induced arthritis in rats was studied in terms of paw swelling, weight indices of the thymus and spleen, and pathological changes in nuclear factor kappa B expression and inflammatory cytokines. Methotrexate was used as a positive control. The CM-Ns were prepared using a high-pressure homogenizing method and characterized with respect to the particle size and morphology. The stability of the CM-Ns in simulated gastrointestinal (GI) fluids and in vitro release were also investigated. A pharmacokinetic study of the CM-Ns and suspensions in which the plasma levels were determined using an high performance liquid chromatography method and the pharmacokinetic parameters were calculated based on a statistical moment theory was also performed in rats. CM administered via iv injection had a therapeutic effect on RA similar to methotrexate. CM-Ns with a diameter of approximately 150 nm were successfully prepared, and the drug was well encapsulated into the Ns without degradation in simulated GI conditions. The area under the curve (AUC) and Cmax for the CM-Ns were more than threefold greater than those for the suspensions; moreover, similar decreases in the levels of TNF-α and interleukin-1β in both synovial fluid and blood serum were obtained from oral administration of CM-Ns and iv injection. CM was an effective antiarthritic agent, and the present N formulation appeared to be a promising system that allowed RA therapy with CM to be converted from iv to oral administration.

Long-term blood pressure variability in patients with rheumatoid arthritis (RA) and its impact on cardiovascular events and all-cause mortality in RA: a population-based comparative cohort study

PubMed Central

Myasoedova, Elena; Crowson, Cynthia S.; Green, Abigail B.; Matteson, Eric L.; Gabriel, Sherine E.

2014-01-01

Objectives To examine long-term visit-to-visit blood pressure (BP) variability in rheumatoid arthritis (RA) vs non-RA subjects and to assess its impact on cardiovascular events and mortality in RA. Methods Clinic BP measures were collected in a population-based incident cohort of RA patients (1987 ACR criteria met between 1/1/1995 and 1/1/2008) and non-RA subjects. BP variability was defined as within-subject standard deviation (SD) in systolic and diastolic BP. Results Study included 442 RA patients (mean age 55.5 years, 70% females) and 424 non-RA subjects (mean age 55.7 years, 69% females). RA patients had higher visit-to-visit variability in systolic BP (13.8±4.7 mm Hg), than non-RA subjects (13.0±5.2 mm Hg, p=0.004). Systolic BP variability declined after the index date in RA (p<0.001), but not in the non-RA cohort (p=0.73), adjusting for age, sex and calendar year of RA. During the mean follow-up of 7.1 years, 33 cardiovascular events and 57 deaths occurred in RA cohort. Visit-to-visit systolic BP variability was associated with increased risk of cardiovascular events (hazard ratio [HR] per 1 mm Hg increase in BP variability 1.12, 95% confidence interval [CI] 1.01-1.25); diastolic BP variability was associated with all-cause mortality in RA (HR 1.14, 95%CI 1.03-1.27), adjusting for systolic and diastolic BP, body mass index, smoking, diabetes, dyslipidemia, use of antihypertensives. Conclusion Patients with RA had higher visit-to-visit systolic BP variability vs non-RA subjects. There was a significant decline in systolic BP variability after RA incidence. Higher visit-to-visit BP variability was associated with adverse cardiovascular outcomes and all-cause mortality in RA. PMID:24986852

Physiologically Based Pharmacokinetic Model of All-trans-Retinoic Acid with Application to Cancer Populations and Drug Interactions

PubMed Central

Jing, Jing; Nelson, Cara; Paik, Jisun; Shirasaka, Yoshiyuki; Amory, John K.

2017-01-01

All-trans retinoic acid (atRA) is a front-line treatment of acute promyelocytic leukemia (APL). Due to its activity in regulating the cell cycle, it has also been evaluated for the treatment of other cancers. However, the efficacy of atRA has been limited by atRA inducing its own metabolism during therapy, resulting in a decrease of atRA exposure during continuous dosing. Frequent relapse occurs in patients receiving atRA monotherapy. In an attempt to combat therapy resistance, inhibitors of atRA metabolism have been developed. Of these, ketoconazole and liarozole have shown some benefits, but their usage is limited by side effects and low potency toward the cytochrome P450 26A1 isoform (CYP26A1), the main atRA hydroxylase. We determined the pharmacokinetic basis of therapy resistance to atRA and tested whether the complex disposition kinetics of atRA could be predicted in healthy subjects and in cancer patients in the presence and absence of inhibitors of atRA metabolism using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of atRA disposition was developed and verified in healthy individuals and in cancer patients. The population-based PBPK model of atRA disposition incorporated saturable metabolic clearance of atRA, induction of CYP26A1 by atRA, and the absorption and distribution kinetics of atRA. It accurately predicted the changes in atRA exposure after continuous dosing and when coadministered with ketoconazole and liarozole. The developed model will be useful in interpretation of atRA disposition and efficacy, design of novel dosing strategies, and development of next-generation atRA metabolism inhibitors. PMID:28275201

Biologic interventions for fatigue in rheumatoid arthritis.

PubMed

Almeida, Celia; Choy, Ernest H S; Hewlett, Sarah; Kirwan, John R; Cramp, Fiona; Chalder, Trudie; Pollock, Jon; Christensen, Robin

2016-06-06

Fatigue is a common and potentially distressing symptom for patients with rheumatoid arthritis (RA), with no accepted evidence-based management guidelines. Evidence suggests that biologic interventions improve symptoms and signs in RA as well as reducing joint damage. To evaluate the effect of biologic interventions on fatigue in rheumatoid arthritis. We searched the following electronic databases up to 1 April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Controlled Trials Register, the National Research Register Archive, The UKCRN Portfolio Database, AMED, CINAHL, PsycINFO, Social Science Citation Index, Web of Science, and Dissertation Abstracts International. In addition, we checked the reference lists of articles identified for inclusion for additional studies and contacted key authors. We included randomised controlled trials if they evaluated a biologic intervention in people with rheumatoid arthritis and had self reported fatigue as an outcome measure. Two reviewers selected relevant trials, assessed methodological quality and extracted data. Where appropriate, we pooled data in meta-analyses using a random-effects model. We identified 32 studies for inclusion in this current review. Twenty studies evaluated five anti-tumour necrosis factor (anti-TNF) biologic agents (adalimumab, certolizumab, etanercept, golimumab and infliximab), and 12 studies focused on five non-anti-TNF biologic agents (abatacept, canakinumab, rituximab, tocilizumab and an anti-interferon gamma monoclonal antibody). All but two of the studies were double-blind randomised placebo-controlled trials. In some trials, patients could receive concomitant disease-modifying anti-rheumatic drugs (DMARDs). These studies added either biologics or placebo to DMARDs. Investigators did not change the dose of the latter from baseline. In total, these studies included 9946 participants in the intervention groups and 4682 participants in the control groups. Overall, quality of randomised controlled trials was moderate with a low to unclear risk of bias in the reporting of the outcome of fatigue. We downgraded the quality of the studies from high to moderate because of potential reporting bias (studies included post hoc analyses favouring reporting of positive result and did not always include all randomised individuals). Some studies recruited only participants with early disease. The studies used five different instruments to assess fatigue in these studies: the Functional Assessment of Chronic Illness Therapy Fatigue Domain (FACIT-F), Short Form-36 Vitality Domain (SF-36 VT), Visual Analogue Scale (VAS) (0 to 100 or 0 to 10) and the Numerical Rating Scale (NRS). We calculated standard mean differences for pooled data in meta-analyses. Overall treatment by biologic agents led to statistically significant reduction in fatigue with a standardised mean difference of -0.43 (95% confidence interval (CI) -0.38 to -0.49). This equates to a difference of 6.45 units (95% CI 5.7 to 7.35) of FACIT-F score (range 0 to 52). Both types of biologic agents achieved a similar level of improvement: for anti-TNF agents, this stood at -0.42 (95% CI -0.35 to -0.49), equivalent to 6.3 units (95% CI 5.3 to 7.4) on the FACIT-F score; and for non-anti-TNF agents, it was -0.46 (95% CI -0.39 to -0.53), equivalent to 6.9 units (95% CI 5.85 to 7.95) on the FACIT-F score. In most studies, the double-blind period was 24 weeks or less. No study assessed long-term changes in fatigue. Treatment with biologic interventions in patients with active RA can lead to a small to moderate improvement in fatigue. The magnitude of improvement is similar for anti-TNF and non-anti-TNF biologics. However, it is unclear whether the improvement results from a direct action of the biologics on fatigue or indirectly through reduction in inflammation, disease activity or some other mechanism.

A remote sensing tool to monitor and predict epidemiologic outbreaks of Hanta virus infections and Lyme disease

NASA Astrophysics Data System (ADS)

Barrios, J. M.

2009-04-01

Lyme disease and Hanta virus infection are the result of the conjunction of several climatic and ecological conditions. Although both affections have different causal agents, they share an important characteristic which is the fact that rodents play an important role in the contagium. One of the most important agents in the dispersion of these diseases is the bank vole (Clethrionomys glareoulus). The bank vole is a common host for both, the Borrelia bacteria which via the ticks (Ixodes ricinus) reaches the human body and causes the Lyme disease, and the Nephropatia epidemica which is caused by Puumala Hantavirus and affects kidneys in humans. The prefered habitat of bank voles is broad-leaf forests with an important presence of beeches (Fagus sylvatica) and oaks (Quercus sp.) and a relatively dense low vegetation layer. These vegetation systems are common in West-Europe and their dynamics have a great influence in the bank voles population and, therefore, in the spreading of the infections this study is concerned about. The fact that the annual seed production is not stable in time has an important effect in bank voles population and, as it has been described in other studies, in the number of reported cases of Hanta virus infections and Lyme disease. The years in which an abundant production of seeds is observed are referred to as mast years which are believed to obey to cyclic patterns and to certain climatological characteristics of the preceding years. Statistical analysis have confirmed the correlation in the behaviour of the number of infected cases and the presence of mast years. This project aims at the design of a remote sensing based system (INFOPRESS - INFectious disease Outbreak Prediction REmote Sensing based System) that should enable local and national health care instances to predict and locate the occurrence of infection outbreaks and design policies to counteract undesired effects. The predictive capabilities of the system are based on the understanding and modelling of the interactions between relevant climatic parameters (temperature, humidity, precipitation) and the main features of vegetation systems which host the vectors and determine the survival and infectious potential of the causal agents. Among the most important study subjects in this research initiative one can mention the time series analysis of vegetation parameters derived from satellite remote sensing and its relatation to climatic time series and historical records of infected cases; with special attention to the assessment of remotely sensed evidences of the mast phenomenon. These analysis will constitute important buildind bricks in the construction of the INFOPRESS system in what concerns the assessment of the potentials of satellite remote sensing as information source for the prediction of infection outbreaks. The bank voles habitat description will also be supported by on-gound remote sensing techniques, specially Lidar technology and soil humidity modelling. These measurements are to be coupled to bank voles and ticks epidemiologic features obtained from field capturing and lab analysis.

Temporal Patterns of Airborne Pesticides in Alpine Lakes of the Sierra Nevada, California

EPA Science Inventory

Airborne agricultural pesticides are being transported many tens of kilometers to remote mountain areas, and have been implicated as a causal agent for recent, dramatic population declines of several amphibian species in such locations. Largely unmeasured, however, are the magnit...

46 CFR 162.161-4 - Construction.

Code of Federal Regulations, 2014 CFR

2014-10-01

...: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Fixed Clean Agent Fire Extinguishing Systems § 162.161-4... mechanical or pneumatic means. (d) Automatically actuated systems must be released by pneumatic or fusible... actuation and have a remote backup manual mechanical actuator. (f) Each container charged with nitrogen must...

46 CFR 162.161-4 - Construction.

Code of Federal Regulations, 2012 CFR

2012-10-01

...: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Fixed Clean Agent Fire Extinguishing Systems § 162.161-4... mechanical or pneumatic means. (d) Automatically actuated systems must be released by pneumatic or fusible... actuation and have a remote backup manual mechanical actuator. (f) Each container charged with nitrogen must...

46 CFR 162.161-4 - Construction.

Code of Federal Regulations, 2013 CFR

2013-10-01

...: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Fixed Clean Agent Fire Extinguishing Systems § 162.161-4... mechanical or pneumatic means. (d) Automatically actuated systems must be released by pneumatic or fusible... actuation and have a remote backup manual mechanical actuator. (f) Each container charged with nitrogen must...

The isotype repertoire of antibodies against novel UH-RA peptides in rheumatoid arthritis.

PubMed

De Winter, Liesbeth M; Geusens, Piet; Lenaerts, Jan; Vanhoof, Johan; Stinissen, Piet; Somers, Veerle

2016-06-07

Recently, autoantibodies against novel UH-RA peptides (UH-RA.1 and UH-RA.21) were identified as candidate biomarkers for patients with rheumatoid arthritis (RA) who are seronegative for the current diagnostic markers rheumatoid factor and anticitrullinated protein antibodies. Previously, screening for anti-UH-RA autoantibodies was based on measuring the immunoglobulin (Ig) G response. We aimed to investigate whether measurement of other isotypes could improve the performance of diagnostic testing. In addition, assigning the isotype profile might provide valuable information on effector functions of the antibodies. The isotype profile of antibodies against UH-RA.1 and UH-RA.21 was studied. The IgG, IgM, and IgA classes, together with the 4 different IgG subclasses, were determined in 285 patients with RA, 88 rheumatic control subjects, and 90 healthy control subjects. Anti-UH-RA.1 antibodies were primarily of the IgM isotype and twice as prevalent as IgG (IgG3-dominated) and IgA. RA sensitivity when testing for anti-UH-RA.1 IgM was shown to be higher than when testing for the IgG isotype: 18 % versus 9 % sensitivity when RA specificity was set to 90 %. Within antibodies against UH-RA.21, IgG and IgA were more common than IgM. Different anti-UH-RA.21 IgG subclasses were found, with the highest prevalence found for IgG2. Combined testing for IgG and IgA slightly increased RA sensitivity of UH-RA.21-specific antibody testing to 27 % compared with solely testing for IgG (23 %). Notably, a higher number of anti-UH-RA.21 antibody isotypes was related to increased levels of erythrocyte sedimentation rate. Finally, for both antibody responses, the full antibody isotype use was demonstrated in early and seronegative disease. The isotype distribution of anti-UH-RA.1 and anti-UH-RA.21 antibodies was successfully outlined, and, for antibodies against UH-RA.1, we found that isotype-specific testing might have implications for diagnostic testing. The exact mechanisms by which the different antibody isotypes act still have to be unraveled.

An SNMP-based solution to enable remote ISO/IEEE 11073 technical management.

PubMed

Lasierra, Nelia; Alesanco, Alvaro; García, José

2012-07-01

This paper presents the design and implementation of an architecture based on the integration of simple network management protocol version 3 (SNMPv3) and the standard ISO/IEEE 11073 (X73) to manage technical information in home-based telemonitoring scenarios. This architecture includes the development of an SNMPv3-proxyX73 agent which comprises a management information base (MIB) module adapted to X73. In the proposed scenario, medical devices (MDs) send information to a concentrator device [designated as compute engine (CE)] using the X73 standard. This information together with extra information collected in the CE is stored in the developed MIB. Finally, the information collected is available for remote access via SNMP connection. Moreover, alarms and events can be configured by an external manager in order to provide warnings of irregularities in the MDs' technical performance evaluation. This proposed SNMPv3 agent provides a solution to integrate and unify technical device management in home-based telemonitoring scenarios fully adapted to X73.

Rebamipide attenuates autoimmune arthritis severity in SKG mice via regulation of B cell and antibody production

PubMed Central

Byun, J-K; Moon, S-J; Jhun, J-Y; Kim, E-K; Park, J-S; Youn, J; Min, J-K; Park, S-H; Kim, H-Y; Cho, M-L

2014-01-01

Oxidative stress is involved in the pathophysiology of rheumatoid arthritis (RA). We investigated the therapeutic potential of rebamipide, a gastroprotective agent with a property of reactive oxygen species scavenger, on the development of inflammatory polyarthritis and the pathophysiological mechanisms by which rebamipide might confer anti-arthritic effects in SKG mice, an animal model of RA. Intraperitoneal (i.p.) injection of rebamipide attenuated the severity of clinical and histological arthritis. Rebampide treatment reduced the number of T helper type 1 (Th1), Th2, Th17, inducible T cell co-stimulator (ICOS)+ follicular helper T (Tfh) transitional type (T2) and mature B cells in the spleen, but increased the number of regulatory T (Treg), CD19+ CD1dhigh CD5high, CD19+ CD25high forkhead box protein 3 (FoxP3)+ regulatory B (Breg) cells, memory B cells, and transitional type 1 (T1) B cells. In addition, flow cytometric analysis revealed significantly decreased populations of FAS+GL-7+ germinal centre B cells and B220− CD138+ plasma cells in the spleens of rebamipide-treated SKG mice compared to controls. Rebamipide decreased germinal centre B cells and reciprocally induced Breg cells in a dose-dependent manner in vitro. Rebamipide-induced Breg cells had more suppressive capacity in relation to T cell proliferation and also inhibited Th17 differentiation from murine CD4+ T cells. Together, these data show that i.p. administration of rebamipide suppresses arthritis severity by inducing Breg and Treg cells and suppressing Tfh and Th17 cells in a murine model of RA. PMID:24749771

Heart failure risk among patients with rheumatoid arthritis starting a TNF antagonist.

PubMed

Solomon, Daniel H; Rassen, Jeremy A; Kuriya, Bindee; Chen, Lang; Harrold, Leslie R; Graham, David J; Lewis, James D; Lii, Joyce; Liu, Liyan; Griffin, Marie R; Curtis, J R

2013-11-01

While heart failure (HF) is associated with elevations in tumor necrosis factor (TNF)α, several trials of TNF antagonists showed no benefit and possibly worsening of disease in those with known severe HF. We studied the risk of new or recurrent HF among a group of patients receiving these agents to treat rheumatoid arthritis (RA). We used data from four different US healthcare programmes. Subjects with RA receiving methotrexate were eligible to enter the study cohort if they added or switched to a TNF antagonist or another non-biological disease modifying antirheumatic drug (nbDMARD). These groups were compared in Cox regression models stratified by propensity score decile and adjusted for oral glucocorticoid dosage, prior HF hospitalisations, and the use of loop diuretics. We compared 8656 new users of a nbDMARD with 11 587 new users of a TNF antagonist with similar baseline covariates. The HR for the TNF antagonists compared with nbDMARD was 0.85 (95% CI 0.63 to 1.14). The HR was also not elevated in subjects with a history of HF. But, it was elevated prior to 2002 (HR 2.17, 95% CI 0.45 to 10.50, test for interaction p=0.036). Oral glucocorticoids were associated with a dose-related gradient of HF risk: compared with no use, 1≤5 mg HR 1.30 (95% CI 0.91 to 1.85), ≥5 mg HR 1.54 (95% CI 1.09 to 2.19). TNF antagonists were not associated with a risk of HF hospital admissions compared with nbDMARDs in this RA population.

Development of macromolecular prodrug for rheumatoid arthritis☆

PubMed Central

Yuan, Fang; Quan, Ling-dong; Cui, Liao; Goldring, Steven R.; Wang, Dong

2012-01-01

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is considered to be one of the major public health problems worldwide. The development of therapies that target tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and co-stimulatory pathways that regulate the immune system have revolutionized the care of patients with RA. Despite these advances, many patients continue to experience symptomatic and functional impairment. To address this issue, more recent therapies that have been developed are designed to target intracellular signaling pathways involved in immunoregulation. Though this approach has been encouraging, there have been major challenges with respect to off-target organ side effects and systemic toxicities related to the widespread distribution of these signaling pathways in multiple cell types and tissues. These limitations have led to an increasing interest in the development of strategies for the macromolecularization of anti-rheumatic drugs, which could target them to the inflamed joints. This approach enhances the efficacy of the therapeutic agent with respect to synovial inflammation, while markedly reducing non-target organ adverse side effects. In this manuscript, we provide a comprehensive overview of the rational design and optimization of macromolecular prodrugs for treatment of RA. The superior and the sustained efficacy of the prodrug may be partially attributed to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS) in the arthritic joints. This biologic process provides a plausible mechanism, by which macromolecular prodrugs preferentially target arthritic joints and illustrates the potential benefits of applying this therapeutic strategy to the treatment of other inflammatory diseases. PMID:22433784

Fumagillin Prodrug Nanotherapy Suppresses Macrophage Inflammatory Response via Endothelial Nitric Oxide

PubMed Central

2015-01-01

Antiangiogenesis has been extensively explored for the treatment of a variety of cancers and certain inflammatory processes. Fumagillin, a mycotoxin produced by Aspergillus fumigatus that binds methionine aminopeptidase 2 (MetAP-2), is a potent antiangiogenic agent. Native fumagillin, however, is poorly soluble and extremely unstable. We have developed a lipase-labile fumagillin prodrug (Fum-PD) that eliminated the photoinstability of the compound. Using αvβ3-integrin-targeted perfluorocarbon nanocarriers to deliver Fum-PD specifically to angiogenic vessels, we effectively suppressed clinical disease in an experimental model of rheumatoid arthritis (RA). The exact mechanism by which Fum-PD-loaded targeted nanoparticles suppressed inflammation in experimental RA, however, remained unexplained. We herein present evidence that Fum-PD nanotherapy indirectly suppresses inflammation in experimental RA through the local production of endothelial nitric oxide (NO). Fum-PD-induced NO activates AMP-activated protein kinase (AMPK), which subsequently modulates macrophage inflammatory response. In vivo, NO-induced AMPK activation inhibits mammalian target of rapamycin (mTOR) activity and enhances autophagic flux, as evidenced by p62 depletion and increased autolysosome formation. Autophagy in turn mediates the degradation of IkappaB kinase (IKK), suppressing the NF-κB p65 signaling pathway and inflammatory cytokine release. Inhibition of NO production by NG-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, reverses the suppression of NF-κB-mediated inflammatory response induced by Fum-PD nanotherapy. These unexpected results uncover an activity of Fum-PD nanotherapy that may be further explored in the treatment of angiogenesis-dependent diseases. PMID:24941020

Protective effects of anti-ricin A-chain RNA aptamer against ricin toxicity

PubMed Central

Fan, Shaoan; Wu, Feng; Martiniuk, Frank; Hale, Martha L; Ellington, Andrew D; Tchou-Wong, Kam-Meng

2008-01-01

AIM: To investigate the therapeutic potential of an RNA ligand (aptamer) specific for the catalytic ricin A-chain (RTA), the protective effects of a 31-nucleotide RNA aptamer (31RA), which formed a high affinity complex with RTA, against ricin-induced toxicity in cell-based luciferase translation and cell cytotoxicity assays were evaluated. METHODS: To test the therapeutic potential of anti-RTA aptamers in Chinese hamster ovary (CHO) AA8 cells stably transfected with a tetracycline regulatable promoter, ricin ribotoxicity was measured using luciferase and ricin-induced cytotoxicity was ascertained by MTS cell proliferation assay with tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]. RESULTS: Inhibition of protein synthesis by ricin in CHO AA8 cells resulted in diminished luciferase activity and treatment with polyclonal antibody against deglycosylated RTA (dgA) neutralized the inhibitory effects of ricin on luciferase activity and protected against ricin-induced cytotoxicity as measured by MTS assay. The 31RA anti-RTA aptamer inhibited the translation of luciferase mRNA in cell-free reticulocyte translation assay. 31RA aptamer also partially neutralized the inhibitory effects of ricin on luciferase activity and partially protected against ricin-induced cytotoxicity in CHO AA8 cells. CONCLUSION: We have shown that anti-RTA RNA aptamer can protect against ricin ribotoxicity in cell-based luciferase and cell cytotoxicity assays. Hence, RNA aptamer that inhibits RTA enzymatic activity represents a novel class of nucleic acid inhibitor that has the potential to be developed as a therapeutic agent for the treatment of ricin intoxication. PMID:19009652

Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers.

PubMed

Dörner, Thomas; Kinnman, Nils; Tak, Paul P

2010-03-01

B cell-depletion therapy, particularly using anti-CD20 treatment, has provided proof of concept that targeting B cells and the humoral response may result in clinical improvements in immune-mediated inflammatory disease. In this review, the mechanisms of action of B cell-targeting drugs are investigated, and potential biomarkers associated with response to treatment in patients with autoimmune diseases are identified. Most available data relate to B cell depletion using anti-CD20 therapy (rituximab) in patients with rheumatoid arthritis (RA). Treatment leads to significant clinical benefit, but apparently fails to deplete long-lived plasma cells, and discontinuation is associated with relapse. Biomarkers commonly used in studies of B cell-targeted therapies include rheumatoid factor, anti-citrullinated peptide antibodies, and immunoglobulin (Ig) levels. More recently, there has been interest in markers such as B cell phenotype analysis, and B lymphocyte stimulator (BLyS)/a proliferation-inducing ligand (APRIL), the latter particularly in studies of the IgG Fc-transmembrane activator and CAML interactor (TACI) fusion protein (atacicept) and anti-BLyS therapy (belimumab). Data from clinical trials of B cell-depleting agents in RA suggest that specific autoantibodies, BLyS, APRIL, and circulating and synovial B lineage cell levels may have potential as biomarkers predictive of response to treatment. Further trials validating these markers against clinical outcomes in RA are required. In patients with systemic lupus erythematosus, Fc receptors and levels of circulating immune cells (including B cells and natural killer cells) may be relevant markers. 2010 Elsevier Inc. All rights reserved.

Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammatory joint disorders: new insights from emerging data. An expert consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

PubMed

Cooper, Cyrus; Bardin, Thomas; Brandi, Maria-Luisa; Cacoub, Patrice; Caminis, John; Civitelli, Roberto; Cutolo, Maurizio; Dere, Willard; Devogelaer, Jean-Pierre; Diez-Perez, Adolfo; Einhorn, Thomas A; Emonts, Patrick; Ethgen, Olivier; Kanis, John A; Kaufman, Jean-Marc; Kvien, Tore K; Lems, Willem F; McCloskey, Eugene; Miossec, Pierre; Reiter, Susanne; Ringe, Johann; Rizzoli, René; Saag, Kenneth; Reginster, Jean-Yves

2016-02-01

This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate. This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized. The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects. Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation. Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach.

Increased Numbers of CD4+CD25+ and CD8+CD25+ T-Cells in Peripheral Blood of Patients with Rheumatoid Arthritis with Parvovirus B19 Infection.

PubMed

Naciute, Milda; Maciunaite, Gabriele; Mieliauskaite, Diana; Rugiene, Rita; Zinkeviciene, Aukse; Mauricas, Mykolas; Murovska, Modra; Girkontaite, Irute

2017-01-01

To investigate T-cell subpopulations in peripheral blood of human parvovirus B19 DNA-positive (B19 + ) and -negative (B19 - ) patients with rheumatoid arthritis (RA) and healthy persons. Blood samples were collected from 115 patients with RA and 47 healthy volunteers; 27 patients with RA and nine controls were B19 + Cluster of differentiation (CD) 4, 8, 25 and 45RA were analyzed on blood cells. CD25 expression on CD4 + CD45RA + , CD4 + CD45RA - , CD8 + CD45RA + , CD8 + CD45RA - subsets were analyzed by flow cytometry. The percentage of CD25 low and CD25 hi cells was increased on CD4 + CD45RA + , CD4 + CD45RA - T-cells and the percentage of CD25 + cells was increased on CD8 + CD45RA + , CD8 + CD45RA - T-cells of B19 + patients with RA in comparison with B19 - patients and controls. Raised levels of CD4 and CD8 regulatory T-cells in B19 + RA patients could cause down-regulation of antiviral clearance mechanisms and lead to activation of persistent human parvovirus B19 infection in patients with RA. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Tretinoin cyclodextrin complex (RA/CyD) causes less irritation with an equal antiwrinkle effect compared with conventional tretinoin: clinical and histologic studies of photoaged skin.

PubMed

Miura, Tomoe; Takada, Akiyoshi; Ooe, Masahiko

2012-08-01

Topical tretinoin [all-trans-retinoic acid (RA)] currently is widely used to treat photoaged skin. However, undesirable side effects such as erythema, irritation, and scaling are unavoidable and limit the use of tretinoin. To address these issues, the authors developed the tretinoin cyclodextrin complex (RA/CyD), which is tretinoin encapsulated by cyclodextrin. Cyclodextrins are cyclic oligosaccharides commonly used in food additives and fabric fresheners. This study aimed to evaluate the antiwrinkle effect of RA/CyD and alleviation of the side effects compared with RA treatment alone. In this study, 12 photoaged patients completed an 8 week study using RA and RA/CyD in a double-blind manner. Before and after the treatment, the patients' evaluations, wrinkle scores, skin elasticity, and wrinkle area measurement using skin replica were evaluated. Three men were recruited for histologic analysis. The patients reported that undesirable irritant reactions were more moderate with RA/CyD than with RA. In the assessment of wrinkle scores, skin elasticity, and wrinkle area measurement, RA/CyD demonstrated an antiwrinkle effect statistically equal to that of RA. In histology, both RA/CyD and RA demonstrated epidermal hyperplasia. In immunohistochemistry, inflammation induced by RA/CyD was more moderate than that induced by RA. The findings show that RA and RA/CyD result in the equivalent clinical improvement for patients with photoaging. The use of RA/CyD overcomes the drawbacks of RA while possessing equal effect. It is expected that CyD will broaden tretinoin treatment. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.

Dual-contrast agent photon-counting computed tomography of the heart: initial experience.

PubMed

Symons, Rolf; Cork, Tyler E; Lakshmanan, Manu N; Evers, Robert; Davies-Venn, Cynthia; Rice, Kelly A; Thomas, Marvin L; Liu, Chia-Ying; Kappler, Steffen; Ulzheimer, Stefan; Sandfort, Veit; Bluemke, David A; Pourmorteza, Amir

2017-08-01

To determine the feasibility of dual-contrast agent imaging of the heart using photon-counting detector (PCD) computed tomography (CT) to simultaneously assess both first-pass and late enhancement of the myocardium. An occlusion-reperfusion canine model of myocardial infarction was used. Gadolinium-based contrast was injected 10 min prior to PCD CT. Iodinated contrast was infused immediately prior to PCD CT, thus capturing late gadolinium enhancement as well as first-pass iodine enhancement. Gadolinium and iodine maps were calculated using a linear material decomposition technique and compared to single-energy (conventional) images. PCD images were compared to in vivo and ex vivo magnetic resonance imaging (MRI) and histology. For infarct versus remote myocardium, contrast-to-noise ratio (CNR) was maximal on late enhancement gadolinium maps (CNR 9.0 ± 0.8, 6.6 ± 0.7, and 0.4 ± 0.4, p < 0.001 for gadolinium maps, single-energy images, and iodine maps, respectively). For infarct versus blood pool, CNR was maximum for iodine maps (CNR 11.8 ± 1.3, 3.8 ± 1.0, and 1.3 ± 0.4, p < 0.001 for iodine maps, gadolinium maps, and single-energy images, respectively). Combined first-pass iodine and late gadolinium maps allowed quantitative separation of blood pool, scar, and remote myocardium. MRI and histology analysis confirmed accurate PCD CT delineation of scar. Simultaneous multi-contrast agent cardiac imaging is feasible with photon-counting detector CT. These initial proof-of-concept results may provide incentives to develop new k-edge contrast agents, to investigate possible interactions between multiple simultaneously administered contrast agents, and to ultimately bring them to clinical practice.

32 CFR 65.8 - Reporting requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... assigned Report Control Symbols DD-P&R(AR)1221, DD-P&R(Q)2077, DD-RA(M)1147, DD-RA(D)1148, DD-RA(D)2170, DD-RA(M)2171, DD-RA(D)2302, and DD-RA(M)2303 in accordance with the requirements of DoD 8910.1-M...

Exposure to infectious agents in dogs in remote coastal British Columbia: Possible sentinels of diseases in wildlife and humans

PubMed Central

Bryan, Heather M.; Darimont, Chris T.; Paquet, Paul C.; Ellis, John A.; Goji, Noriko; Gouix, Maëlle; Smits, Judit E.

2011-01-01

Ranked among the top threats to conservation worldwide, infectious disease is of particular concern for wild canids because domestic dogs (Canis familiaris) may serve as sources and reservoirs of infection. On British Columbia’s largely undeveloped but rapidly changing central and north coasts, little is known about diseases in wolves (Canis lupus) or other wildlife. However, several threats exist for transfer of diseases among unvaccinated dogs and wolves. To gain baseline data on infectious agents in this area, including those with zoonotic potential, we collected blood and stool samples from 107 dogs in 5 remote communities in May and September 2007. Serology revealed that the dogs had been exposed to canine parvovirus, canine distemper virus, Bordetella bronchiseptica, canine respiratory coronavirus, and Leptospira interrogans. No dogs showed evidence of exposure to Ehrlichia canis, Anaplasma phagocytophilum, Borrelia burgdorferi, Dirofilaria immitis, or Cryptococcus gattii. Of 75 stool samples, 31 contained at least 1 parasitic infection, including Taeniid tapeworms, the nematodes Toxocara canis and Toxascaris leonina, and the protozoans Isospora sp., Giardia sp., Cryptosporidium sp., and Sarcocystis sp. This work provides a sound baseline for future monitoring of infectious agents that could affect dogs, sympatric wild canids, other wildlife, and humans. PMID:21461190

Diet and Rheumatoid Arthritis Symptoms: Survey Results From a Rheumatoid Arthritis Registry.

PubMed

Tedeschi, Sara K; Frits, Michelle; Cui, Jing; Zhang, Zhi Zack; Mahmoud, Taysir; Iannaccone, Christine; Lin, Tzu-Chieh; Yoshida, Kazuki; Weinblatt, Michael E; Shadick, Nancy A; Solomon, Daniel H

2017-12-01

Patients with rheumatoid arthritis (RA) often ask whether specific foods, popularized as inflammatory or antiinflammatory, can improve or worsen their RA. Patients with RA took a survey on diet and RA symptoms, and the survey data were collected and analyzed. A dietary survey was mailed to 300 subjects in a single-center RA registry at a large academic center. Subjects were asked about their consumption of 20 foods and whether these foods make their RA symptoms better, worse, or unchanged. Semiannual registry data include demographics, medications, comorbidities, and disease activity scores. Fisher's exact test and Wilcoxon's rank sum tests evaluated associations between subject characteristics from the most recent registry assessment and changes in RA symptoms from specific foods. Of the 217 subjects (72% response rate), 83% were female; the median RA duration was 17 years (interquartile range 9-27 years), and 58% were taking a biologic disease-modifying antirheumatic drug. Twenty-four percent of subjects reported that foods affect their RA symptoms, with 15% reporting improvement and 19% reporting worsening. Blueberries and spinach were the foods most often reported to improve RA symptoms, while soda with sugar and desserts were those most often reported to worsen RA symptoms. Younger age and noting that sleep, warm room temperature, and vitamin/mineral supplements improve RA were each associated with reporting that foods affect RA symptoms. Medication use, sex, body mass index, smoking, disease duration, disease activity scores, and self-reported RA flares were not associated with reporting that foods affect RA. Nearly one-quarter of RA subjects with longstanding disease reported that diet had an effect on their RA symptoms. © 2017, American College of Rheumatology.

The Impact of Statin Use on Lipid Levels in Statin-Naive Patients with Rheumatoid Arthritis (RA) vs. non-RA Subjects: Results from a Population-Based Study

PubMed Central

Myasoedova, Elena; Gabriel, Sherine E.; Green, Abigail B.; Matteson, Eric L.; Crowson, Cynthia S.

2013-01-01

Objectives To examine lipid profiles among statin-naive patients with rheumatoid arthritis (RA) and those without RA before and after the initiation of statins. Methods Information regarding lipid measures and statin use was gathered in a population-based incident cohort of patients with RA (1987 ACR criteria first met between 1/1/1988 and 1/1/2008) and in a cohort of non-RA subjects from the same underlying population. Only patients with no prior history of statin use were included. Results The study included 161 patients with RA (mean age 56.3 years, 57% female) and 221 non-RA subjects (mean age 56.0 years, 66% female). Prior to the start of statins, the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) were lower in RA vs non-RA cohort (p<0.001 and p=0.003, respectively). The absolute and percent change in LDL after at least 90 days of statin use tended to be smaller in RA vs non-RA cohort (p=0.03 and p=0.09). After at least 90 days of statin use patients with RA were less likely to achieve therapeutic goals for LDL than the non-RA subjects (p=0.046). Increased erythrocyte sedimentation rate (ESR) at baseline (OR 0.47; 95% CI 0.26, 0.85) was associated with lower likelihood of achieving therapeutic LDL goals. Conclusion Patients with RA had lower TC and LDL levels before statin initiation and lower likelihood of achieving therapeutic LDL goals following statin use than the non-RA subjects. Some RA disease characteristics, in particular ESR at baseline, may have an adverse impact on achieving therapeutic LDL goals. PMID:23592565

Effects of retinoic acids on the dendritic morphology of cultured hippocampal neurons.

PubMed

Liu, Ying; Kagechika, Hiroyuki; Ishikawa, Junko; Hirano, Hitoshi; Matsukuma, Satoshi; Tanaka, Kazuko; Nakamura, Shoji

2008-08-01

Vitamin A-derived retinoic acids (RAs) are known to exert a variety of biological actions, including modulatory effects on cell differentiation and apoptosis. A recent study has demonstrated that 13-cis-RA and all-trans-RA suppressed neurogenesis in the dentate gyrus of the hippocampus in adult mice. The present experiments were performed to see whether 13-cis-RA and all-trans-RA could alter the dendritic morphology of cultured hippocampal neurons via RA receptors: retinoic acid receptor (RAR) and retinoid X receptor (RXR). High doses of 13-cis-RA and all-trans-RA exerted a negative effect on the cultured hippocampal neurons, while a low dose of 13-cis-RA but not all-trans-RA caused a positive effect. The negative changes induced by 13-cis-RA and all-trans-RA were antagonized by RXR antagonists and RAR antagonists, respectively. The positive changes induced by a low dose of 13-cis-RA were blocked by both RXR antagonists and RAR antagonists. These results suggest that RAs at high concentrations cause a negative effect on the dendritic morphology of cultured hippocampal neurons through RA receptors, while RAs at low concentrations exert a positive influence on cultured hippocampal neurons.

Metabolism of 13-cis-retinoic acid by a rat liver 9000g supernatant preparation.

PubMed

Vane, F M; Buggé, C J; Williams, T H

1982-01-01

The in vitro metabolites formed on incubation of 13-cis-retinoic acid (13-cis-RA, isotretinoin) with a 9000g rat liver supernatant system were isolated by HPLC and identified by their mass and NMR spectra. The major metabolic pathway was hydroxylation at C4 to give 4-hydroxy-13-cis-RA, which was rapidly oxidized to 4-oxo-13-cis-RA, the major isolated metabolite. Further metabolism of this 4-oxo metabolite led to two novel compounds, 2-hydroxy-4-oxo-13-cis-RA and 3-hydroxy-4-oxo-13-cis-RA. In addition, small amounts of 13-cis-RA and 4-oxo-13-cis-RA were enzymatically converted to their all-trans isomers. Support for these pathways was obtained by the metabolism of reference samples of 4-hydroxy-13-cis-RA, 4-oxo-13-cis-RA, all-trans-RA, and 4-oxo-all-trans-RA. The predominant formation of 4-oxo metabolites of 13-cis-RA in this in vitro rat system and the results from previously reported in vivo metabolism studies suggest that oxidation at C4 is a major metabolic pathway of 13-cis-RA in both rats and humans.

Semaglutide for type 2 diabetes mellitus: a systematic review and meta-analysis.

PubMed

Andreadis, Panagiotis; Karagiannis, Thomas; Malandris, Konstantinos; Avgerinos, Ioannis; Liakos, Aris; Manolopoulos, Apostolos; Bekiari, Eleni; Matthews, David R; Tsapas, Apostolos

2018-05-13

To assess the efficacy and safety of semaglutide, a recently approved glucagon-like peptide 1 receptor agonist (GLP-1 RA) for type 2 diabetes. We searched major electronic databases and grey literature sources for randomised controlled trials comparing semaglutide with placebo or other antidiabetic agents. Primary outcome was change from baseline in HbA 1c . Secondary endpoints included change from baseline in body weight, blood pressure, heart rate, and incidence of hypoglycaemia, gastrointestinal adverse effects, pancreatitis and diabetic retinopathy. Six placebo-controlled and seven active-controlled studies with subcutaneous semaglutide were included. We identified only one trial with oral semaglutide. Compared with placebo, subcutaneous semaglutide 0.5 and 1 mg reduced HbA 1c by 1.01% (95% CI 0.56 to 1.47) and 1.38% (1.05 to 1.70) respectively. Both doses demonstrated superior glycaemic efficacy compared to other antidiabetic agents, including sitagliptin, exenatide, liraglutide, dulaglutide and insulin glargine. Semaglutide also had a beneficial effect on body weight (mean difference versus placebo -4.11 kg, 95% CI -4.85 to -3.37 for semaglutide 1 mg) and systolic blood pressure. We did not observe increased hypoglycaemia rates with semaglutide; nevertheless, we noted an increased incidence of nausea, vomiting and diarrhoea. Cases of pancreatitis were infrequent and odds ratio for diabetic retinopathy compared with placebo was 1.32 (95% CI 0.98 to 1.77). Semaglutide is a potent once-weekly GLP-1 RA, reducing significantly HbA 1c , body weight and systolic blood pressure. However, it is associated with increased incidence of gastrointestinal adverse events. Results for pancreatitis and retinopathy require further assessment in post-approval pharmacovigilance studies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Differences in utilisation of gastroprotective drugs between 2001 and 2005 in Australia and Nova Scotia, Canada.

PubMed

Tett, Susan E; Sketris, Ingrid; Cooke, Charmaine; van Zanten, Sander Veldhuyzen; Barozzi, Nadia

2013-07-01

This study aimed to compare use of histamine H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), 2001-2005, in the elderly and social security beneficiaries in Australia (AUS) and Nova Scotia, Canada (NS). Prescription dispensing data were collected for all subsidised H2RAs and PPIs. In AUS, dispensing data for concession beneficiaries were obtained from the Pharmaceutical Benefits Scheme database. In NS, data were sourced from the Pharmacare database. Relevant population data were used to convert to World Health Organisation Anatomic Therapeutic Chemical defined daily doses (2005) per 1000 beneficiaries per day (DDD/1000/day). Overall use of gastroprotective agents was similar and rising in NS and AUS (100-160 DDD/1000/day) over this 5-year time window. However, the proportion of this use accounted for by PPIs was far higher in AUS (over 85% by 2005) than in NS (23% rising to 35% over the 5 years). In AUS, PPI use rose from 50 to about 140 DDD/1000/day over the 5 years, whereas PPI use in NS rose slowly to less than 60 DDD/1000/day by 2005. H2RA use in NS was always high (over 100 DDD/1000/day), whereas in AUS, H2RA use fell from 54 to around 24 DDD/1000/day over this period. AUS had much higher use of PPIs than NS over 2001-2005. The proportion of PPIs in all gastroprotective agents rose in AUS to be nearly 90%. The differences in utilisation during this time window could lead to differences in health outcomes from either lower gastro-intestinal bleeding risk or higher long-term adverse effects of PPIs. Copyright © 2013 John Wiley & Sons, Ltd.

Radium Isotopes in Nubian Aquifer Groundwater, Western Desert, Egypt

NASA Astrophysics Data System (ADS)

Sherif, M. I.; Sturchio, N. C.

2016-12-01

The purpose of this study is to investigate the extent of natural radioactivity from Ra isotopes in groundwater from the Nubian Sandstone Aquifer System (NSAS) in northeast Africa. Activities of long-lived Ra isotopes (226Ra and 228Ra) were analyzed in 40 groundwater samples from the NSAS in the Western Desert of Egypt; including Baharyia, Farafra, Dakhla, and Kharga Oases. The activities of 226Ra and 228Ra ranged from 0.012 Bq/L to 1.512 Bq/L and from 0.012 Bq/L to 2.136 Bq/L, respectively. High activities of Ra isotopes, up to 2000% higher than the USEPA maximum contaminant level (MCL) of 0.185 Bq/L (combined 226Ra + 228Ra) for drinking water were measured in groundwater from some locations. Groundwater samples from Bahariya Oasis had the highest activities of Ra isotopes among the samples collected. No correlation between salinity and Ra activities was observed. The two radium isotopes are highly correlated in most samples with a 228Ra/226Ra activity ratio ranging from 1.04 to 3.12 and a median of 2.08; this indicates a high Th/U ratio in the aquifer materials. The weak correlation between Ra activities and salinity indicates that adsorption/desorption processes are not the primary mechanism of Ra release to groundwater. Recoil input of Ra from the aquifer rocks may be the dominant input mechanism. These results indicate that groundwater within the Western Desert must be used with caution for domestic and agricultural purposes, and radium removal may be necessary before water is used for human consumption.

Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors

PubMed Central

Cunningham, Thomas J.; Colas, Alexandre

2016-01-01

ABSTRACT Bipotent neuromesodermal progenitors (NMPs) residing in the caudal epiblast drive coordinated body axis extension by generating both posterior neuroectoderm and presomitic mesoderm. Retinoic acid (RA) is required for body axis extension, however the early molecular response to RA signaling is poorly defined, as is its relationship to NMP biology. As endogenous RA is first seen near the time when NMPs appear, we used WNT/FGF agonists to differentiate embryonic stem cells to NMPs which were then treated with a short 2-h pulse of 25 nM RA or 1 µM RA followed by RNA-seq transcriptome analysis. Differential expression analysis of this dataset indicated that treatment with 25 nM RA, but not 1 µM RA, provided physiologically relevant findings. The 25 nM RA dataset yielded a cohort of previously known caudal RA target genes including Fgf8 (repressed) and Sox2 (activated), plus novel early RA signaling targets with nearby conserved RA response elements. Importantly, validation of top-ranked genes in vivo using RA-deficient Raldh2−/− embryos identified novel examples of RA activation (Nkx1-2, Zfp503, Zfp703, Gbx2, Fgf15, Nt5e) or RA repression (Id1) of genes expressed in the NMP niche or progeny. These findings provide evidence for early instructive and permissive roles of RA in controlling differentiation of NMPs to neural and mesodermal lineages. PMID:27793834

ROADSIDE AMMONIA MEASUREMENTS USING OPTICAL REMOTE SENSING INSTRUMENTS

EPA Science Inventory

Fine particles less than 2.5 microns in diameter have been identified as a causal agent of excess mortality and other undesirable health impacts. A large part of these airborne particles, generally more than one-half, are formed in the atmosphere by reactions of ammonia with acid...

Novel autoantibody markers for early and seronegative rheumatoid arthritis.

PubMed

Somers, Klaartje; Geusens, Piet; Elewaut, Dirk; De Keyser, Filip; Rummens, Jean-Luc; Coenen, Marieke; Blom, Marlies; Stinissen, Piet; Somers, Veerle

2011-02-01

Approximately one-third of rheumatoid arthritis (RA) patients are seronegative for the 2 serological RA markers, rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (ACCP). Moreover, the sensitivities of both markers are lower in the diagnostically important early disease phase. The aim of this study was to identify additional autoantibody markers for early RA and for RF-negative, ACCP-negative (seronegative) RA. We screened an RA synovium cDNA phage display library with autoantibodies in plasma from 10 early (symptoms of maximum 1 year) and 10 seronegative (RF-negative, ACCP-negative) RA patients with validation in 72 additional RA patients and 121 controls (38 healthy controls, 43 patients with other inflammatory rheumatic diseases, 20 osteoarthritis patients and 20 subjects with mechanical joint complaints). Fourteen novel autoantibodies were identified that showed a 54% sensitivity and 90% specificity for RA. For 11 of these autoantibodies, an exclusive presence was demonstrated in RA patients (100% specificity, 37% sensitivity) as compared to controls. All early RA patients were positive for at least one of the identified autoantibodies and antibody-positivity was associated with a shorter disease duration (P = 0.0087). 52% of RA patients who initially tested negative for RF and ACCP, tested positive for at least one of the 14 novel autoantibodies, resulting in a 19% increase in sensitivity compared to current serological testing. Moreover, 5 identified autoantibodies were detected more frequently in seronegative RA patients, indicating that these autoantibodies constitute novel candidate markers for this RA subtype. We demonstrated that the targets of 3 of these 5 autoantibodies had an increased expression in RA synovial tissue compared to control synovial tissue, pointing towards a biological rationale for these auto antibody targets in RA. In conclusion, we identified novel candidate autoantibody markers for RA that can be detected in early and seronegative RA patients indicating the potential added value for RA diagnostics. Copyright © 2010 Elsevier Ltd. All rights reserved.

Socioeconomic and employment status of patients with rheumatoid arthritis in Korea.

PubMed

Kwon, Jeong-Mi; Rhee, Jinnie; Ku, Hyemin; Lee, Eui-Kyung

2012-01-01

This study investigates the prevalence of rheumatoid arthritis (RA) by gender and socio-economic characteristics. It also explores the differences in the employment status between RA patients and the general population without RA in Korea. We analyzed data from the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV) conducted from 2007 to 2009. Prevalence rates were estimated for female and male patients with RA in terms of age, residence, education, income level, and occupation type. The female respondents aged 45 to 64 were divided into the RA population and the non-RA population in order to compare the employment status between the two groups. The annual physician-diagnosed RA prevalence rate was 1.45%. The prevalence rate was 2.27% for women and 0.62% for men. Individuals with RA had a significantly lower employment rate than individuals without RA (41.7 vs. 68.1%). The main reason for non-employment among RA patients was health-related problems (47.1%). There was statistically significant difference in employment type among the two groups. The experience rates for sick leave and sick-in-bed due to RA were 1.7 and 3.9%, respectively. Middle- and old-aged women accounted for the majority of the Korean RA population, which had a significant lower employment rate compared to the population without RA for both sexes. RA resulted in considerable productivity loss in Korea.

Radium and radon in ground water in the Chickies Quartzite, southeastern Pennsylvania

USGS Publications Warehouse

Senior, L.A.; Vogel, K.L.

1995-01-01

The Chickies Quartzite, a Lower Cambrian-age formation compromised of quartzite and slate overlying a basal conglomerate, forms a narrow ridges and crops out discontinuously over 112 square miles in the Piedmont physiographic province of southeastern Pennsylvania. The formation is a low-yielding, fractured- rock, water-table aquifer recharged primarily by local precipitation. It is the sole source of water supply for thousands of domestic users. Ground water in the Chickies Quartzite generally is soft and acidic. During 1986-88, the U.S. Geological Survey sampled water from 160 wells that penetrate the Chickies Quartzite to determine the magnitude and distribution of radium-226 (Ra-226), radium-228 (Ra-228), and radon-222 (Rn-222) activities in ground water in the formation and to characterize the geochemical environmental associated with elevated activities of radium (Ra). In addition, 28 wells penetrating adjacent geologic units and 1 well in the Hardyston Quartzite were sampled to determine relative background Ra and RN-222 activities in ground water. Analyses included determination of activities of dissolved Ra-226, Ra-228, and RN-222, and concentrations of dissolved uranium (U), dissolved organic carbon (DOC), and major and minor dissolved inorganic ions. Rock samples were analyzed for U and thorium (Th) and geophysical logs were run to determine sources of Ra and RN-222 in the Chickies Quartzite. Activities of up to 41 pCi/L (picocuries per liter) for Ra-226, 160 pCi/L for Ra-228, and 32,300 pCi/L for RN-222 were measured in ground water in the Chickies Quartzite. Forty-seven percent of the samples contained Ra-226 and Ra-228 activities greater than 5 pCi/L. Median activities measured were 1.2 pCi/L for Ra-226, 2.6 pCi/L for Ra-228, 4.2 pCi/L for combined Ra-226 and Ra-228, and 2,400 pCi/L for RN-222 Ra-228 activity exceeded Ra-226 activity in about 92 percent of 100 water samples; the median Ra-228/Ra226 activity ratio was 2.4. Ra-228/Ra-226 activity ratios commonly were greater in ground water than calculated Th/U ratios in rock samples, suggesting perferential leaching of Ra-228 from aquifer solids. Of ground water in the adjacent geologic units, the highest activities (up to 2.9 pCi/L for Ra-226, 12 pCi/L for Ra-228, and 25,300 pCi/L for RN-222) were measured in ground water in the Harpers Phyllite and Antietam Quartzite. Nonparametric (Spearman rho test) statistical correlations show that the activity of dissolved Ra is inversely related to pH and directly related to concentrations of total dissolved solids, DOC, barium, and sulfate. Low pH decreases absorption of Ra onto the aquifer matrix. The other factors may favor Ra mobility by enhancing complexation or increasing solubility. RN-222 activity does not correlate with and is not supported by the activity of its parent, Ra-226, in solution. Ra-226 activity correlates positively, but weakly, with U concentrations. Ra-226 does not appear to be supported by its parent, U-238, in solution. Observed distributions of Ra-228, Ra-226, and RN-222 activities in ground water in different lithologies of the Chickies Quartzite reflect different geochemical controls on absorption and distribution of parent thorium-232 (Th-232) and uranium-238 (U-238) in the formation. Radium activities were greatest in acidic ground water in the conglomerate and quartzite (median pH of 5.0 and 5.2, respectively) and least in the more neutral water in the slate (median pH of 6.4). For ground water in the conglomerate, quartzite, and slate, respectively, median activities measured were 1.3, 1.5, and .02 pCi/L for Ra-226; and 3.7, 2.5, and 1.0 pCi/L for Ra-228. Natural-gamma-ray geophysical logs and results of rock analyses indicate that the conglomerate may contain more Th and U than the quartzite and that the conglomerate may be more enriched in Th with respect to U than the quartzite; Th and U distribution in both lithogies is variable. Median RN-222 activities in gro

Measuring 226Ra/228Ra in Oceanic Lavas by MC-ICPMS

NASA Astrophysics Data System (ADS)

Standish, J. J.; Sims, K.; Ball, L.; Blusztajn, J.

2007-12-01

238U-230Th-226Ra disequilibrium in volcanic rocks provides an important and unique tool to evaluate timescales of recent magmatic processes. Determination of 230Th-226Ra disequilibria requires measurement of U and Th isotopes and concentrations as well as measurement of 226Ra. While measurement of U and Th by ICPMS is now well established, few published studies documenting 226Ra measurement via ICPMS exist. Using 228Ra as an isotope spike we have investigated two ion-counting methods; a 'peak-hopping' routine, where 226Ra and 228Ra are measured in sequence on the central discrete dynode ETP secondary electron multiplier (SEM), and simultaneous measurement of 226Ra and 228Ra on two multiple ion-counter system (MICS) channeltron type detectors mounted on the low end of the collector block. Here we present 226Ra measurement by isotope dilution using the Thermo Fisher NEPTUNE MC-ICPMS. Analysis of external rock standards TML and AThO along with mid-ocean ridge basalt (MORB) and ocean island basalt (OIB) samples show three issues that need to be considered when making precise and accurate Ra measurements: 1) mass bias, 2) background, and 3) relative efficiencies of the detectors when measuring in MICS mode. Due to the absence of an established 226Ra/228Ra standard, we have used U reference material NBL-112A to monitor mass bias. Although Ball et. al., (in press) have shown that U does not serve as an adequate proxy for Th (and thus not likely for Ra either), measurements of rock standards TML and AThO are repeatedly in equilibrium within the uncertainty of the measurements (where total uncertainty includes propagation of the uncertainty in the 226Ra standard used for calibrating the 228Ra spike). For this application, U is an adequate proxy for Ra mass bias at the 1% uncertainly level. The more important issue is the background correction. Because of the extensive chemistry required to separate and purify Ra (typically fg/g level in volcanic rocks), we observe large ambient backgrounds using both ion-counting techniques, which can significantly influence the measured 226Ra/228Ra ratio. Ra off-peak backgrounds need to be measured explicitly and quantitatively corrected. One advantage of using a 'peak-hopping' routine on the central SEM is the optional use of the high abundance sensitivity lens or repelling potential quadrapole (RPQ). This lens virtually eliminates the ambient background and significantly enhances the signal to noise ratio with only a small decrease in Ra ion transmission. Even with the diminished background levels observed using 'peak-hopping' on the SEM with the RPQ, accurate measurement of Ra isotopes requires off-peak background measurement. Finally, when using MICS it is important to account for the relative efficiency of the detectors. Multiple ion counting is, in principle, preferable to 'peak-hopping' because more time is spent counting each individual isotope. However, our results illustrate that proper calibration of detector yields requires dynamic switching of 226Ra between the two ion counters. This negates the inherent advantage of multiple ion counting. Therefore, when considering mass bias, background correction, and detector gain calibration, we conclude that 'peak-hopping' on the central SEM with the RPQ abundance filter is the preferred technique for 226Ra/228Ra isotopic measurement on the Neptune MC-ICPMS.

Radium mobility and the age of groundwater in public-drinking-water supplies from the Cambrian-Ordovician aquifer system, north-central USA

USGS Publications Warehouse

Stackelberg, Paul E.; Szabo, Zoltan; Jurgens, Bryant C.

2018-01-01

High radium (Ra) concentrations in potable portions of the Cambrian-Ordovician (C-O) aquifer system were investigated using water-quality data and environmental tracers (3H, 3Hetrit, SF6, 14C and 4Herad) of groundwater age from 80 public-supply wells (PSWs). Groundwater ages were estimated by calibration of tracers to lumped parameter models and ranged from modern (<50 yr) in upgradient, regionally unconfined areas to ancient (>1 Myr) in the most downgradient, confined portions of the potable system. More than 80 and 40 percent of mean groundwater ages were older than 1000 and 50,000 yr, respectively. Anoxic, Fe-reducing conditions and increased mineralization develop with time in the aquifer system and mobilize Ra into solution resulting in the frequent occurrence of combined Ra (Rac = 226Ra + 228Ra) at concentrations exceeding the USEPA MCL of 185 mBq/L (5 pCi/L). The distribution of the three Ra isotopes comprising total Ra (Rat = 224Ra + 226Ra + 228Ra) differed across the aquifer system. The concentrations of 224Ra and 228Ra were strongly correlated and comprised a larger proportion of the Rat concentration in samples from the regionally unconfined area, where arkosic sandstones provide an enhanced source for progeny from the 232Th decay series. 226Ra comprised a larger proportion of the Ratconcentration in samples from downgradient confined regions. Concentrations of Rat were significantly greater in samples from the regionally confined area of the aquifer system because of the increase in 226Ra concentrations there as compared to the regionally unconfined area. 226Ra distribution coefficients decreased substantially with anoxic conditions and increasing ionic strength of groundwater (mineralization), indicating that Ra is mobilized to solution from solid phases of the aquifer as adsorption capacity is diminished. The amount of 226Ra released from solid phases by alpha-recoil mechanisms and retained in solution increases relative to the amount of Ra sequestered by adsorption processes or co-precipitation with barite as adsorption capacity and the concentration of Ba decreases. Although 226Ra occurred at concentrations greater than 224Ra or 228Ra, the ingestion exposure risk was greater for 228Ra owing to its greater toxicity. In addition, 224Ra added substantial alpha-particle radioactivity to potable samples from the C-O aquifer system. Thus, monitoring for Ra isotopes and gross-alpha-activity (GAA) is important in upgradient, regionally unconfined areas as downgradient, and GAA measurements made within 72 h of sample collection would best capture alpha-particle radiation from the short-lived 224Ra.

Software agents for the dissemination of remote terrestrial sensing data

NASA Technical Reports Server (NTRS)

Toomey, Christopher N.; Simoudis, Evangelos; Johnson, Raymond W.; Mark, William S.

1994-01-01

Remote terrestrial sensing (RTS) data is constantly being collected from a variety of space-based and earth-based sensors. The collected data, and especially 'value-added' analyses of the data, are finding growing application for commercial, government, and scientific purposes. The scale of this data collection and analysis is truly enormous; e.g., by 1995, the amount of data available in just one sector, NASA space science, will reach 5 petabytes. Moreover, the amount of data, and the value of analyzing the data, are expected to increase dramatically as new satellites and sensors become available (e.g., NASA's Earth Observing System satellites). Lockheed and other companies are beginning to provide data and analysis commercially. A critical issue for the exploitation of collected data is the dissemination of data and value-added analyses to a diverse and widely distributed customer base. Customers must be able to use their computational environment (eventually the National Information Infrastructure) to obtain timely and complete information, without having to know the details of where the relevant data resides and how it is accessed. Customers must be able to routinely use standard, widely available (and, therefore, low cost) analyses, while also being able to readily create on demand highly customized analyses to make crucial decisions. The diversity of user needs creates a difficult software problem: how can users easily state their needs, while the computational environment assumes the responsibility of finding (or creating) relevant information, and then delivering the results in a form that users understand? A software agent is a self-contained, active software module that contains an explicit representation of its operational knowledge. This explicit representation allows agents to examine their own capabilities in order to modify their goals to meet changing needs and to take advantage of dynamic opportunities. In addition, the explicit representation allows agents to advertize their capabilities and results to other agents, thereby allowing the collection of agents to reuse each others work.

A Multinational Arab Genome-Wide Association Study Identifies New Genetic Associations for Rheumatoid Arthritis.

PubMed

Saxena, Richa; Plenge, Robert M; Bjonnes, Andrew C; Dashti, Hassan S; Okada, Yukinori; Gad El Haq, Wessam; Hammoudeh, Mohammed; Al Emadi, Samar; Masri, Basel K; Halabi, Hussein; Badsha, Humeira; Uthman, Imad W; Margolin, Lauren; Gupta, Namrata; Mahfoud, Ziyad R; Kapiri, Marianthi; Dargham, Soha R; Aranki, Grace; Kazkaz, Layla A; Arayssi, Thurayya

2017-05-01

Genetic factors underlying susceptibility to rheumatoid arthritis (RA) in Arab populations are largely unknown. This genome-wide association study (GWAS) was undertaken to explore the generalizability of previously reported RA loci to Arab subjects and to discover new Arab-specific genetic loci. The Genetics of Rheumatoid Arthritis in Some Arab States Study was designed to examine the genetics and clinical features of RA patients from Jordan, the Kingdom of Saudi Arabia, Lebanon, Qatar, and the United Arab Emirates. In total, >7 million single-nucleotide polymorphisms (SNPs) were tested for association with RA overall and with seropositive or seronegative RA in 511 RA cases and 352 healthy controls. In addition, replication of 15 signals was attempted in 283 RA cases and 221 healthy controls. A genetic risk score of 68 known RA SNPs was also examined in this study population. Three loci (HLA region, intergenic 5q13, and 17p13 at SMTNL2/GGT6) reached genome-wide significance in the analyses of association with RA and with seropositive RA, and for all 3 loci, evidence of independent replication was demonstrated. Consistent with the findings in European and East Asian populations, the association of RA with HLA-DRB1 amino acid position 11 conferred the strongest effect (P = 4.8 × 10 -16 ), and a weighted genetic risk score of previously associated RA loci was found to be associated with RA (P = 3.41 × 10 -5 ) and with seropositive RA (P = 1.48 × 10 -6 ) in this population. In addition, 2 novel associations specific to Arab populations were found at the 5q13 and 17p13 loci. This first RA GWAS in Arab populations confirms that established HLA-region and known RA risk alleles contribute strongly to the risk and severity of disease in some Arab groups, suggesting that the genetic architecture of RA is similar across ethnic groups. Moreover, this study identified 2 novel RA risk loci in Arabs, offering further population-specific insights into the pathophysiology of RA. © 2017, American College of Rheumatology.

Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA.

PubMed

Hutchinson, D; Shepstone, L; Moots, R; Lear, J T; Lynch, M P

2001-03-01

To investigate the potential relation between cumulative exposure to cigarette smoking in patients with or without rheumatoid arthritis (RA) and a positive family history of the disease. 239 outpatient based patients with RA were compared with 239 controls matched for age, sex, and social class. A detailed smoking history was recorded and expressed as pack years smoked. Conditional logistic regression was used to calculate the association between RA and pack years smoked. The patients with RA were also interviewed about a family history of disease and recorded as positive if a first or second degree relative had RA. The smoking history at the time of the study of the patients with RA with or without a family history of the disease was compared directly with that of their respective controls. Patients with RA with or without a family history of the disease were also compared retrospectively for current smoking at the time of disease onset. An increasing association between increased pack years smoked and RA was found. There was a striking association between heavy cigarette smoking and RA. A history for 41-50 pack years smoked was associated with RA (odds ratio (OR) 13.54, 95% confidence interval (95% CI) 2.89 to 63.38; p<0.001). The association between ever having smoked and RA was modest (OR 1.81, CI 1.22 to 2.19; p=0.002). Furthermore, cigarette smoking in the patients with RA without a positive family history of RA was more prevalent than in the patients with a positive family history of RA for ever having smoked (72% v 54%; p=0.006), the number of pack years smoked (median 25.0 v 4.0; p<0.001), and for smoking at the time of disease onset (58% v 39%; p=0.003). Heavy cigarette smoking, but not smoking itself, is strongly associated with RA requiring hospital follow up and is markedly more prevalent in patients with RA without a family history of RA.

A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS/MS

PubMed Central

Arnold, Samuel L. M.; Amory, John K.; Walsh, Thomas J.; Isoherranen, Nina

2012-01-01

Retinol (vitamin A) circulates at 1–4 μM concentration and is easily measured in serum. However, retinol is biologically inactive. Its metabolite, retinoic acid (RA), is believed to be responsible for biological effects of vitamin A, and hence the measurement of retinol concentrations is of limited value. A UHPLC-MS/MS method using isotope-labeled internal standards was developed and validated for quantitative analysis of endogenous RA isomers and metabolites. The method was used to measure retinoids in serum samples from 20 healthy men. In the fed state, the measured concentrations were 3.1 ± 0.2 nM for atRA, 0.1 ± 0.02 nM for 9-cisRA, 5.3 ± 1.3 nM for 13-cisRA, 0.4 ± 0.4 nM for 9,13-dicisRA, and 17.2 ± 6.8 nM for 4oxo-13-cisRA. The concentrations of the retinoids were not significantly different when measured after an overnight fast (3.0 ± 0.1 nM for atRA, 0.09 ± 0.01nM for 9-cisRA, 3.9 ± 0.2 nM for 13-cisRA, 0.3 ± 0.1 nM for 9,13-dicisRA, and 11.9 ± 1.6 nM for 4oxo-13-cisRA). 11-cisRA and 4OH-RA were not detected in human serum. The high sensitivity of the MS/MS method combined with the UHPLC separation power allowed detection of endogenous 9-cisRA and 4oxo-atRA for the first time in human serum. PMID:22192917

Trends in Joint Replacement Surgery in Patients with Rheumatoid Arthritis.

PubMed

Young, Bradley L; Watson, Shawna L; Perez, Jorge L; McGwin, Gerald; Singh, Jasvinder A; Ponce, Brent A

2018-02-01

This study analyzed trends in large total joint arthroplasties (TJA) and in the proportion of these procedures performed on patients with rheumatoid arthritis (RA). The US Nationwide Inpatient Sample (2002-2012) was used to identify the incidences of total shoulder (TSA), elbow (TEA), knee (TKA), hip (THA), and ankle (TAA) arthroplasty and the proportion of these performed with coexisting RA. The prevalence of RA among patients with TJA increased 3.0%. The prevalence of RA among cases of TEA and TSA decreased by 50% (p < 0.0001) and 18% (p = 0.0016), respectively; a 38.0% decrease occurred in the prevalence of RA among TAA (p = 0.06); and nonsignificant increases were seen among THA and TKA. The average age difference between RA and non-RA patients undergoing TJA narrowed by 2 years (p < 0.0001). There was a greater reduction in the proportion of TSA, TEA, and TAA groups among women with RA than men with RA. In the TSA and TEA groups, there was a reduction in the proportion of whites with RA, but not blacks. The proportion of privately insured TSA and TAA patients with RA decreased, while patients with RA undergoing TSA, TEA, or TAA who were receiving Medicaid (government medical insurance) remained relatively stable over time. The prevalence of RA has decreased among TSA and TEA patients. A nonsignificant decline occurred among TAA patients. The average age of TJA patients with RA is beginning to mirror those without RA. Sex ratios for TSA, TEA, and TAA patients are following a similar pattern. These results may be evidence of the success of modern RA treatment strategies.

Cardiovascular risk factor management in patients with RA compared to matched non-RA patients

PubMed Central

Cawston, Helene; Bourhis, Francois; Al, Maiwenn; Rutten-van Mölken, Maureen P. M. H.; Liao, Katherine P.; Solomon, Daniel H.

2016-01-01

Objective. RA is associated with a 50–60% increase in risk of cardiovascular (CV) death. This study aimed to compare management of CV risk factors in RA and matched non-RA patients. Methods. A retrospective cohort study was conducted using UK clinical practice data. Patients presenting with an incident RA diagnosis were matched 1:4 to non-RA patients based on a propensity score for RA, entry year, CV risk category and treatment received at index date (date of RA diagnosis). Patients tested and treated for CV risk factors as well as those attaining CV risk factor management goals were evaluated in both groups. Results. Between 1987 and 2010, 24 859 RA patients were identified and matched to 87 304 non-RA patients. At index date, groups had similar baseline characteristics. Annual blood pressure, lipids and diabetes-related testing were similar in both groups, although CRP and ESR were higher in RA patients at diagnosis and decreased over time. RA patients prescribed antihypertensives increased from 38.2% at diagnosis to 45.7% at 5 years, from 14.0 to 20.6% for lipid-lowering treatments and from 5.1 to 6.4% for antidiabetics. Similar treatment percentages were observed in non-RA patients, although slightly lower for antihypertensives. Modest (2%) but significantly lower attainment of lipid and diabetes goals at 1 year was observed in RA patients. Conclusion. There were no differences between groups in the frequency of testing and treatment of CV risk factors. Higher CV risk in RA patients seems unlikely to be driven by differences in traditional CV risk factor management. PMID:26705329

Cardiovascular risk factor management in patients with RA compared to matched non-RA patients.

PubMed

Alemao, Evo; Cawston, Helene; Bourhis, Francois; Al, Maiwenn; Rutten-van Mölken, Maureen P M H; Liao, Katherine P; Solomon, Daniel H

2016-05-01

RA is associated with a 50-60% increase in risk of cardiovascular (CV) death. This study aimed to compare management of CV risk factors in RA and matched non-RA patients. A retrospective cohort study was conducted using UK clinical practice data. Patients presenting with an incident RA diagnosis were matched 1:4 to non-RA patients based on a propensity score for RA, entry year, CV risk category and treatment received at index date (date of RA diagnosis). Patients tested and treated for CV risk factors as well as those attaining CV risk factor management goals were evaluated in both groups. Between 1987 and 2010, 24 859 RA patients were identified and matched to 87 304 non-RA patients. At index date, groups had similar baseline characteristics. Annual blood pressure, lipids and diabetes-related testing were similar in both groups, although CRP and ESR were higher in RA patients at diagnosis and decreased over time. RA patients prescribed antihypertensives increased from 38.2% at diagnosis to 45.7% at 5 years, from 14.0 to 20.6% for lipid-lowering treatments and from 5.1 to 6.4% for antidiabetics. Similar treatment percentages were observed in non-RA patients, although slightly lower for antihypertensives. Modest (2%) but significantly lower attainment of lipid and diabetes goals at 1 year was observed in RA patients. There were no differences between groups in the frequency of testing and treatment of CV risk factors. Higher CV risk in RA patients seems unlikely to be driven by differences in traditional CV risk factor management. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology.

Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA.

PubMed

Gizinski, Alison M; Mascolo, Margherita; Loucks, Jennifer L; Kervitsky, Alma; Meehan, Richard T; Brown, Kevin K; Holers, V Michael; Deane, Kevin D

2009-05-01

The purpose of this study was to identify rheumatoid arthritis (RA)-related autoantibodies in subjects with interstitial lung disease (ILD) and no articular findings of RA, supporting the hypothesis that RA-related autoimmunity may be generated in non-articular sites, such as the lung. This was a retrospective chart review utilizing clinic databases of patients with ILD to identify cases with lung disease, RA-related autoantibody positivity, and no clinical evidence of articular RA. Four patients with ILD, RF, and anti-CCP positivity and no articular findings of RA were identified. All four patients were male with a mean age at time of diagnosis of ILD of 70 years old. All had a history of smoking. Three patients died within 2 years of diagnosis of ILD and never developed articular symptoms consistent with RA; the final case met full criteria for articular RA several months after stopping immunosuppressive treatment for ILD. RF and anti-CCP can be present in smokers with ILD without clinical evidence of articular RA and in one case symptomatic ILD and autoantibody positivity preceded the development of articular RA. These findings suggest that RA-specific autoimmunity may be generated due to immunologic interactions in the lung and may be related to environmental factors such as smoking.

Inhibitory effect of the Agrobacterium rhizogenes rolC gene on rabdosiin and rosmarinic acid production in Eritrichium sericeum and Lithospermum erythrorhizon transformed cell cultures.

PubMed

Bulgakov, Victor P; Veselova, M V; Tchernoded, G K; Kiselev, K V; Fedoreyev, S A; Zhuravlev, Yu N

2005-06-01

Rabdosiin and related caffeic acid metabolites have been proposed as active pharmacological agents demonstrating potent anti-HIV and antiallergic activities. We transformed Eritrichium sericeum and Lithospermum erythrorhizon seedlings by the rolC gene, which has been recently described as an activator of plant secondary metabolism. Surprisingly, the rolC-transformed cell cultures of both plants yielded two- to threefold less levels of rabdosiin and rosmarinic acid (RA) than respective control cultures. This result establishes an interesting precedent when the secondary metabolites are differently regulated by a single gene. We show that the rolC gene affects production of rabdosiin and RA irrespective of the methyl jasmonate (MeJA)-mediated and the Ca(2+)-dependent NADPH oxidase pathways. Cantharidin, an inhibitor of serine/threonine phosphatases, partly diminishes the rolC-gene inhibitory effect that indicates involvement of the rolC-gene-mediated signal in plant regulatory controls, mediated by protein phosphatases. We also show that the control MeJA-stimulated E. sericeum root culture produces (-)-rabdosiin up to 3.41% dry weight, representing the highest level of this substance for plant cell cultures reported so far.

Periodontal microbioma and rheumatoid arthritis: The role of Porhyromonas gingivalis.

PubMed

Azzi, L; Rania, S; Vinci, R; Spadari, F; Croveri, F; Scognamiglio, C; Farronato, D; Tettamanti, L; Tagliabue, A; Silvestre-Rangil, J; Bellintani, C

2017-01-01

Rheumatoid Arthritis is a disease, which can be described as an autoimmune response after molecular mimicry caused by infective agents. The current study aims at evaluating the correlation between Rhematoid Arthritis (RA) and Periodontal Disease (PD), with special attention to the microbioma detected in the gums. Thirty-four patients with RD were recruited into the current study. Among rheumatic parameters, Rheumatoid Factor (RF), anti-citrullinated protein antibody (CCP), HLA-BDR1 and DAS28 were collected. A dental clinician evaluated the periodontal screening record (PSR). Afterwards, 1 paper cone was inserted for 30 seconds into the gingival sulcus then sent to the laboratory for evaluation. Quantitative PCR of 16S rRNA genes was performed with the hydrolysis probes method to identify and evaluate the amount Porphyromonas gingivalis, Tannerella forsythensis, Treponema denticola, Fusobacterium nucleatum and Campylobacter rectus. There were no statistical differences in the composition of oral microbioma between PSR groups. There were no statistical significant differences between bacterial loads and serum values. On the contrary, a positive correlation was found between the presence of Porphyromonas gingivalis in periodontal pockets on one side and RF and CCP on the other. Therefore, the presence of Porhyromonas gingivalis in periodontal pockets is associated to RA inflammatory indices.

Could Pomegranate Juice Help in the Control of Inflammatory Diseases?

PubMed Central

2017-01-01

Fruits rich in polyphenols, such as pomegranates, have been shown to have health benefits relating to their antioxidant and anti-inflammatory properties. Using data obtained from PubMed and Scopus, this article provides a brief overview of the therapeutic effects of pomegranate on chronic inflammatory diseases (CID) such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), metabolic and cardiovascular disorders, and other inflammatory-associated conditions, with an emphasis on fruit-derived juices. Most studies regarding the effects of pomegranate juice have focused on its ability to treat prostate cancer, diabetes, and atherosclerosis. However, pomegranate juice has shown therapeutic potential for many other illnesses. For instance, a small number of human clinical trials have highlighted the positive effects of pomegranate juice and extract consumption on cardiovascular health. The beneficial effects of pomegranate components have also been observed in animal models for respiratory diseases, RA, neurodegenerative disease, and hyperlipidaemia. Furthermore, there exists strong evidence from rodent models suggesting that pomegranate juice can be used to effectively treat IBD, and as an anti-inflammatory agent to treat CID. The effects of pomegranate intake should be further investigated by conducting larger and more well-defined human trials. PMID:28867799

Could Pomegranate Juice Help in the Control of Inflammatory Diseases?

PubMed

Danesi, Francesca; Ferguson, Lynnette R

2017-08-30

Fruits rich in polyphenols, such as pomegranates, have been shown to have health benefits relating to their antioxidant and anti-inflammatory properties. Using data obtained from PubMed and Scopus, this article provides a brief overview of the therapeutic effects of pomegranate on chronic inflammatory diseases (CID) such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), metabolic and cardiovascular disorders, and other inflammatory-associated conditions, with an emphasis on fruit-derived juices. Most studies regarding the effects of pomegranate juice have focused on its ability to treat prostate cancer, diabetes, and atherosclerosis. However, pomegranate juice has shown therapeutic potential for many other illnesses. For instance, a small number of human clinical trials have highlighted the positive effects of pomegranate juice and extract consumption on cardiovascular health. The beneficial effects of pomegranate components have also been observed in animal models for respiratory diseases, RA, neurodegenerative disease, and hyperlipidaemia. Furthermore, there exists strong evidence from rodent models suggesting that pomegranate juice can be used to effectively treat IBD, and as an anti-inflammatory agent to treat CID. The effects of pomegranate intake should be further investigated by conducting larger and more well-defined human trials.

Rheumatoid arthritis significantly increased recurrence risk after ischemic stroke/transient ischemic attack.

PubMed

Chen, Yih-Ru; Hsieh, Fang-I; Lien, Li-Ming; Hu, Chaur-Jong; Jeng, Jiann-Shing; Peng, Giia-Sheun; Tang, Sung-Chun; Chi, Nai-Fang; Sung, Yueh-Feng; Chiou, Hung-Yi

2018-06-02

The effect of RA on recurrent stroke is unknown. Therefore, we examined effects of rheumatoid arthritis (RA) on risk of stroke recurrence and investigated the interaction between RA and traditional cardiovascular risk factors on recurrence risk after ischemic stroke (IS) or transient ischemic attack (TIA). Of 3190 patients with IS or TIA recruited in this cohort study, 638 were comorbid with RA and 2552 without RA. Stroke recurrence, RA, lifestyle, lipid variables and other comorbidities were identified through linkage between a nationwide stroke database in Taiwan and the National Health Insurance claims database. Cox proportional hazard models with competing risk adjustment were used to evaluate the relationship between RA and recurrent stroke. Patients with RA showed a significantly increased risk of recurrent stroke, particular in recurrent IS/TIA. The increased risk of recurrent IS/TIA in RA patients may through the changes of triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C) ratio. A positive additive interaction was observed between RA and current smoking on the risk of recurrent IS/TIA. Significantly increased risks for recurrent IS/TIA were observed among RA patients who smoked > 40 years or those who smoked > 20 cigarettes/day. This study provides the first evidence that RA significantly increased recurrence IS/TIA risk. The changes of TG/HDL-C ratio may play some roles in the recurrence IS/TIA risk in RA patients. In addition, our results suggest that smoking increases the risk of recurrent IS/TIA in RA patients and reinforces the need for aggressive smoking cessation efforts in RA patients.

Improved performance of epidemiologic and genetic risk models for rheumatoid arthritis serologic phenotypes using family history

PubMed Central

Sparks, Jeffrey A.; Chen, Chia-Yen; Jiang, Xia; Askling, Johan; Hiraki, Linda T.; Malspeis, Susan; Klareskog, Lars; Alfredsson, Lars; Costenbader, Karen H.; Karlson, Elizabeth W.

2014-01-01

Objective To develop and validate rheumatoid arthritis (RA) risk models based on family history, epidemiologic factors, and known genetic risk factors. Methods We developed and validated models for RA based on known RA risk factors, among women in two cohorts: the Nurses’ Health Study (NHS, 381 RA cases and 410 controls) and the Epidemiological Investigation of RA (EIRA, 1244 RA cases and 971 controls). Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in logistic regression models for the study population and for those with positive family history. The joint effect of family history with genetics, smoking, and body mass index (BMI) was evaluated using logistic regression models to estimate odds ratios (OR) for RA. Results The complete model including family history, epidemiologic risk factors, and genetics demonstrated AUCs of 0.74 for seropositive RA in NHS and 0.77 for anti-citrullinated protein antibody (ACPA)-positive RA in EIRA. Among women with positive family history, discrimination was excellent for complete models for seropositive RA in NHS (AUC 0.82) and ACPA-positive RA in EIRA (AUC 0.83). Positive family history, high genetic susceptibility, smoking, and increased BMI had an OR of 21.73 for ACPA-positive RA. Conclusions We developed models for seropositive and seronegative RA phenotypes based on family history, epidemiologic and genetic factors. Among those with positive family history, models utilizing epidemiologic and genetic factors were highly discriminatory for seropositive and seronegative RA. Assessing epidemiological and genetic factors among those with positive family history may identify individuals suitable for RA prevention strategies. PMID:24685909

[Locoregional anesthesia for pediatric surgery in remote rural settings: experience of an NGO in Bangladesh].

PubMed

Sleth, J C; Coulon, M; Fesseau, R; Rami, L

2010-12-01

Performing safe pediatric anesthesia in developing countries is a technical challenge for NGOs working in remote locations. The aim of this study is to describe our experience aboard a hospital ship working off the coast of northern Bangladesh. Anesthesia protocol records for a 3-year period were retrospectively reviewed. A total of 463 procedures were performed with no severe anesthetic complications. Regional anesthesia was performed in 83% of patients. It was carried out alone in 15% of patients and in association with IV or IM ketamine sedation in 68%. General anesthesia was performed using ketamine in 17% of patients. Tracheal intubation was carried out in only 3 cases. These findings indicate that regional anesthesia in association with ketamine as sedation agent is a simple and safe technique for pediatric anesthesia in remote rural settings.

Adaptive Sampling of Time Series During Remote Exploration

NASA Technical Reports Server (NTRS)

Thompson, David R.

2012-01-01

This work deals with the challenge of online adaptive data collection in a time series. A remote sensor or explorer agent adapts its rate of data collection in order to track anomalous events while obeying constraints on time and power. This problem is challenging because the agent has limited visibility (all its datapoints lie in the past) and limited control (it can only decide when to collect its next datapoint). This problem is treated from an information-theoretic perspective, fitting a probabilistic model to collected data and optimizing the future sampling strategy to maximize information gain. The performance characteristics of stationary and nonstationary Gaussian process models are compared. Self-throttling sensors could benefit environmental sensor networks and monitoring as well as robotic exploration. Explorer agents can improve performance by adjusting their data collection rate, preserving scarce power or bandwidth resources during uninteresting times while fully covering anomalous events of interest. For example, a remote earthquake sensor could conserve power by limiting its measurements during normal conditions and increasing its cadence during rare earthquake events. A similar capability could improve sensor platforms traversing a fixed trajectory, such as an exploration rover transect or a deep space flyby. These agents can adapt observation times to improve sample coverage during moments of rapid change. An adaptive sampling approach couples sensor autonomy, instrument interpretation, and sampling. The challenge is addressed as an active learning problem, which already has extensive theoretical treatment in the statistics and machine learning literature. A statistical Gaussian process (GP) model is employed to guide sample decisions that maximize information gain. Nonsta tion - ary (e.g., time-varying) covariance relationships permit the system to represent and track local anomalies, in contrast with current GP approaches. Most common GP models are stationary, e.g., the covariance relationships are time-invariant. In such cases, information gain is independent of previously collected data, and the optimal solution can always be computed in advance. Information-optimal sampling of a stationary GP time series thus reduces to even spacing, and such models are not appropriate for tracking localized anomalies. Additionally, GP model inference can be computationally expensive.

IL-1RA gene-transfected bone marrow-derived mesenchymal stem cells in APA microcapsules could alleviate rheumatoid arthritis.

PubMed

Hu, Jianhua; Li, Hongjian; Chi, Guanhao; Yang, Zhao; Zhao, Yi; Liu, Wei; Zhang, Chao

2015-01-01

In order to investigate the encapsulation of interleukin 1 receptor antagonist (IL-RA) gene-modified mesenchymal stem cells (MSCs) in alginate-poly-L-lysine (APA) microcapsules for the persistent delivery of interleukin 1 receptor antagonist (IL-RA) to treat Rheumatoid arthritis (RA). We transfect mesenchymal stem cells with IL-RA gene, and quantify the IL-RA proteins released from the encapsulated cells followed by microencapsulation of recombinant mesenchymal stem cells, and thus observe the permeability of APA microcapsules and evaluate clinical effects after induction and treatment of collagen-induced arthritis (CIA). The concentration of IL-RA in the supernatant was determined by IL-RA ELISA kit by run in technical triplicates using samples from three separate mice. Encapsulated IL-RA gene-transfected cells were capable of constitutive delivery of IL-RA proteins for at least 30 days. Moreover, the APA microcapsules could inhibit the permeation of fluorescein isothiocyanate-conjuncted immunoglobulin G. Also, it has been found that the APA microcapsules can significantly attenuate collagen induced arthritis after delivering of APA microcapsules to rats. Our results demonstrated that the nonautologous IL-RA gene-transfected stem cells are of potential utility for RA therapy.

Determination of 13-cis-retinoic acid and its major metabolite, 4-oxo-13-cis-retinoic acid, in human blood by reversed-phase high-performance liquid chromatography.

PubMed

Vane, F M; Stoltenborg, J K; Buggé, C J

1982-02-12

A high-performance liquid chromatography (HPLC) method for the quantitation of 13-cis-retinoic acid (13-cis-RA) and its major metabolite, 4-oxo-13-cis-RA, in human blood has been developed. The method includes extraction of 1 ml of blood with diethyl ether at pH 6 and the analysis of the extract by reversed-phase HPLC with solvent programming and detection at 365 nm. The quantitation ranges for 13-cis-RA and 4-oxo-13-cis-RA are 10--2000 and 50--2000 ng/ml of blood, respectively. The method also provides estimates of the concentrations of all-trans-RA and 4-oxo-all-trans-RA. The mean intra- and inter-assay variabilities for all four compounds were 6% or less. The method separates 13-cis-RA and 4-oxo-13-cis-RA from 9-cis-RA, all-trans-RA, 4-oxo-all-trans-RA, and some other possible metabolites, such as hydroxy and epoxy retinoic acids. The method has been successfully applied to the analyses of over 1200 blood samples from four 13-cis-RA clinical studies.

Radium release mechanisms during hydraulic fracturing of Marcellus Shale

NASA Astrophysics Data System (ADS)

Sharma, M.; Landis, J. D.; Renock, D. J.

2016-12-01

Wastewater co-produced with methane from Devonian Marcellus Shale is hypersaline and enriched in Ra. Recent studies find that water injected during hydraulic fracturing can leach out significant quantities of Na, Ca, Ba and Sr from solid phases in the shale over just hours to days. Here, we show with water-rock leaching experiments that the measured 226Ra/228Ra ratios of Marcellus wastewater could also derive from rapid leaching of mineral and organic phases of the shale. Radium isotopes 226Ra (t1/2 = 1600 a) and 228Ra (t1/2 = 5.8 a) are produced through radioactive decay of 238U (t1/2 = 4.5 Ga) and 232Th (t1/2 = 14 Ga), respectively. In the absence of processes that fractionate U, Th and Ra from one another, the decay rates of each parent-daughter pair become identical over 5 half-lives of the daughter radionuclide reaching a condition of secular equilibrium. Water-rock interaction may induce pronounced deviations from secular equilibrium in the water phase, however. Such is the case during hydraulic fracturing, where Ra is soluble and mobile, and is orphaned from insoluble U and Th parents. Once 226Ra and 228Ra are mobilized no fractionation between these isotopes is expected during their transport to the surface. Thus the 226Ra/228Ra ratio in wastewater provides a fingerprint of Ra source(s). Leaching Marcellus Shale with pure water under anoxic conditions releases mainly 228Ra from clays; extraction of 228Ra from radiation damaged sites is likely the dominant contributing mechanism. Using a novel isotope dilution technique we find that 90% of the Ra released in pure water partitions back onto rock (possibly clays). In comparison, leaching with high ionic strength solutions induces the release of 226Ra from mainly organics; the breakdown of organic matter in these solutions may be the driving mechanism controlling 226Ra release in solution. Radium released by high ionic strength solutions strongly partitions into water and results in the development of leachates with high 226Ra/228Ra ratios that are comparable to those of Marcellus wastewaters. Our results suggest that hydraulic fracturing using dilute HCl solution releases Ca and Na from the shale and effects rapid Ra release from the rock. Hypersaline and radioactive wastewater is thus a consequence of active leaching of shale during hydraulic fracturing.

Biological Therapies: Effects of Proinflammatory Pathways and their Inhibition on the Myocardium of Rheumatoid Athritis Patients.

PubMed

Obermair, Florian; Pieringer, Herwig

2015-01-01

The elevated risk of heart failure (HF) in rheumatoid arthritis (RA) is considered to be partly caused by the chronic low-grade systemic inflammation. As potent suppressors of inflammation, biologics were expected to influence HF development in RA. Unfortunately, case reports of HF in RA patients and non-RA HF studies have suggested that these drugs may even increase HF rates in RA. With this review we want to provide insight into the molecular mechanisms by which elevated cytokines, immune cell alterations and biologics influence myocardial function in RA patients. Beside preclinical data, clinical studies that assess the influence of biologics on HF development are reviewed. Preclinical studies suggest a bidirectional role of the investigated cytokines (TNF-alpha, IL- 1, IL-6) on myocardial function. Common mechanisms of immune cell alterations in HF and RA have been observed in preclinical studies. High doses of infliximab in non-RA patients with HF were found to be harmful. The vast majority of retrospective studies suggest that TNF-alpha inhibitors do not increase the risk of HF development in RA patients. Nevertheless randomized controlled trials are missing and TNF-alpha inhibitors are contraindicated in RA patients with HF NYHA III/IV and should be used with caution in RA patients with HF NYHA I/II based on non-RA HF studies. Due to rare adverse events of HF, rituximab is contraindicated in RA patients with HF NYHA IV. Cytokines seem to have a bidirectional influence on HF development in RA. According to the published evidence it is unlikely that TNFalpha inhibitors substantially increase the risk of HF development in an RA population. Nevertheless they are contraindicated in RA patients with HF NYHA III/IV and should be used with caution in RA patients with HF NYHA I/II. The influence of anakinra, tocilizumab, rituximab and abatacept needs to be investigated in future studies.

Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: a register-based case-control study in Sweden

PubMed Central

Frisell, Thomas; Hellgren, Karin; Alfredsson, Lars; Raychaudhuri, Soumya; Klareskog, Lars; Askling, Johan

2015-01-01

Objectives Our objective was to estimate the risk of developing rheumatoid arthritis (RA) associated with a family history of non-RA arthritis-related diseases. This familial co-aggregation is of clinical interest since it is often encountered when assessing family history of RA specifically, but also informative on the genetic overlap between these diseases. Since anticitrullinated peptide antibodies/rheumatoid factor (RF)-positive and RF-negative RA have both specific and shared genetic factors, the familial co-aggregation was assessed separately for seropositive and seronegative disease. Methods Nested case-control study in prospectively recorded Swedish total population data. The Multi-Generation Register identified first-degree relatives. RA and arthritis-related diseases were ascertained through the nationwide patient register. RA serology was based on International Classification of Diseases tenth revision coded diagnoses, mainly reflecting RF. Familial risks were calculated using conditional logistic regression. Results were replicated using the Swedish rheumatology register. Results Familial co-aggregation was found between RA and every studied arthritis-related disease, but the magnitude varied widely, from juvenile idiopathic arthritis (JIA) (seropositive RA OR=3.98 (3.01 to 5.26); seronegative RA OR=5.70 (3.47 to 9.36)) to osteoarthritis (seropositive RA OR=1.03 (1.00 to 1.06); seronegative RA OR=1.05 (1.00 to 1.09)). The familial co-aggregation pattern of non-RA arthritis-related diseases was overall similar for seropositive and seronegative RA. Among those with family history of RA, relatives’ other arthritis-related diseases conferred little or no additional risk. Conclusions Although family history of several arthritis-related diseases may be useful to predict RA (eg, lupus and JIA), others (eg, osteoarthritis and arthralgia) are less useful. Seropositive and seronegative RA had rather similar familial co-aggregation patterns with arthritis-related diseases, suggesting that the two RA subsets are similar in the genetic factors that overlap with these diseases. PMID:25498119

Test oracle automation for V&V of an autonomous spacecraft's planner

NASA Technical Reports Server (NTRS)

Feather, M. S.; Smith, B.

2001-01-01

We built automation to assist the software testing efforts associated with the Remote Agent experiment. In particular, our focus was upon introducing test oracles into the testing of the planning and scheduling system component. This summary is intended to provide an overview of the work.

25 CFR 543.16 - What are the minimum internal controls for information technology?

Code of Federal Regulations, 2010 CFR

2010-04-01

... technology? 543.16 Section 543.16 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR HUMAN... controls for information technology? (a) Physical security measures restricting access to agents, including... longer required. (2) In the event of remote access, the information technology employees must prepare a...

Prolong Exposure of NSAID in Patients With RA Will Decrease the Risk of Dementia

PubMed Central

Chang, Kuang-Hsi; Hsu, Yi-Chao; Hsu, Chih-Chao; Lin, Cheng-Li; Hsu, Chung Y.; Lee, Chang-Yin; Chong, Lee-Won; Liu, Hui-Chuan; Lin, Ming-Chia; Kao, Chia-Hung

2016-01-01

Abstract Rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder, primarily affects joints. Several studies have indicated that early inflammation, cardiovascular disease, and depression in patients were associated with a considerably increased risk of dementia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for treating RA. NSAIDs facilitate alleviating RA-associated chronic pain, inflammation, and swelling. Therefore, we conducted this nationwide study for evaluating the association between the dementia risk and NSAID treatment in patients with RA. The RA cohort comprised patients aged 20 years and older who were newly diagnosed with RA between 2000 and 2011, with data obtained from the Registry of Catastrophic Illnesses Patient Database (RCIPD). Patients without RA were frequency matched with the RA cohort at a 1:4 ratio according to age, sex, and year of RA diagnosis. The relative risks of dementia were estimated using Cox proportional hazard models. The risk of dementia in the RA cohort was not significantly higher than that in the non-RA cohort (adjusted HR [hazard ratio] = 0.95, 95% confidence interval [CI] = 0.87–1.02). Regarding the duration of NSAID treatment, the risk of dementia was significantly lower when the RA cohort used NSAIDs for >2191 days (HR = 0.56, 95% CI = 0.45–0.68). A longer duration of NSAID treatment possibly reduces the risk of dementia. Additional studies are warranted for verifying the association of dementia risk with NSAID treatment in patients with RA. PMID:26962833

De-repression of RaRF-mediated RAR repression by adenovirus E1A in the nucleolus.

PubMed

Um, Soo-Jong; Youn, Hye Sook; Kim, Eun-Joo

2014-02-21

Transcriptional activity of the retinoic acid receptor (RAR) is regulated by diverse binding partners, including classical corepressors and coactivators, in response to its ligand retinoic acid (RA). Recently, we identified a novel corepressor of RAR called the retinoic acid resistance factor (RaRF) (manuscript submitted). Here, we report how adenovirus E1A stimulates RAR activity by associating with RaRF. Based on immunoprecipitation (IP) assays, E1A interacts with RaRF through the conserved region 2 (CR2), which is also responsible for pRb binding. The first coiled-coil domain of RaRF was sufficient for this interaction. An in vitro glutathione-S-transferase (GST) pull-down assay was used to confirm the direct interaction between E1A and RaRF. Further fluorescence microscopy indicated that E1A and RaRF were located in the nucleoplasm and nucleolus, respectively. However, RaRF overexpression promoted nucleolar translocation of E1A from the nucleoplasm. Both the RA-dependent interaction of RAR with RaRF and RAR translocation to the nucleolus were disrupted by E1A. RaRF-mediated RAR repression was impaired by wild-type E1A, but not by the RaRF binding-defective E1A mutant. Taken together, our data suggest that E1A is sequestered to the nucleolus by RaRF through a specific interaction, thereby leaving RAR in the nucleoplasm for transcriptional activation. Copyright © 2014 Elsevier Inc. All rights reserved.

Radium-226 transfer factor from soils to crops and its simple estimation method using uranium and barium concentrations.

PubMed

Tagami, Keiko; Uchida, Shigeo

2009-09-01

Radium-226 ((226)Ra) should be assessed to determine the safety of geological disposal of high-level radioactive and transuranic wastes. Among the environmental transfer parameters that have been used in mathematical models for the environmental safety assessment, soil-to-plant transfer factor (F(v)) is of importance; it is defined as the plant/soil concentration ratio. Reported F(v) data for (226)Ra are still limited due to the low concentration of (226)Ra in plants in the natural environment. In this study, we collected F(v) of (226)Ra (F(v)-Ra) for crops and then applied a statistical approach to estimate F(v)-Ra instead of directly measuring the radionuclide. We found high correlations between (226)Ra and U concentrations in soils (because (226)Ra is a progeny in the (238)U series), and between (226)Ra and Ba concentrations in plants (because they are chemically similar in plant uptake). Using U in soil and Ba in plant values, we could estimate F(v)-Ra with good accuracy; the difference between estimated and measured F(v)-Ra values was a factor of 1.2 on average for crops. The method could estimate F(v)-Ra for the soil-to-plant systems where (226)Ra and Ba concentrations in soil are within the normal range, e.g. 8-100 Bq kg(-1)-dry for (226)Ra and 84-960 mg kg(-1)-dry for Ba.

Wireless network of stand-alone end effect probes for soil in situ permittivity measurements over the 100MHZ-6GHz frequency range

NASA Astrophysics Data System (ADS)

Demontoux, François; Bircher, Simone; Ruffié, Gilles; Bonnaudiin, Fabrice; Wigneron, Jean-Pierre; Kerr, Yann

2017-04-01

Microwave remote sensing and non-destructive analysis are a powerful way to provide properties estimation of materials. Numerous applications using microwave frequency behavior of materials (remote sensing above land surfaces, non-destructive analysis…) are strongly dependent on the material's permittivity (i.e. dielectric properties). This permittivity depends on numerous parameters such as moisture, texture, temperature, frequency or bulk density. Permittivity measurements are generally carried out in the laboratory. Additionally, dielectric mixing models allow, over a restricted range of conditions, the assessment of a material's permittivity. in-situ measurements are more difficult to obtain. Some in situ measurement probes based on permittivity properties of soil exist (e.g. Time Domain Reflectometers and Transmissometers, capacitance and impedance sensors). They are dedicated to the acquisition of soil moisture data based on permittivity (mainly the real part) estimations over a range of frequencies from around 50 MHz to 1 or 2 GHz. Other Dielectric Assessment Kits exist but they are expensive and they are rather dedicated to laboratory measurements. Furthermore, the user can't address specific issues related to particular materials (e.g. organic soils) or specific measurement conditions (in situ long time records). At the IMS Laboratory we develop probes for in situ soil permittivity measurements (real and imaginary parts) in the 0.5 - 6 GHz frequency range. They are based on the end effect phenomenon of a coaxial waveguide and so are called end effect probes in this paper. The probes can be connected to a portable Vector Network Analyzer (VNA, ANRITSU MS2026A) for the S11 coefficient measurements needed to compute permittivity. It is connected to a PC to record data using an USB connection. This measurement set-up is already used for in situ measurement of soil properties in the framework of the European Space Agency's (ESA) SMOS space mission. However, it should be useful to install many probes on the same site to obtain permittivity measurements over a large area. To reach this goal, the probes should communicate with each other to send data to a record device. Furthermore, it is needed to record measurements over a long time period (many months) to study the in-situ dielectric soil property variations according to changing weather conditions and seasonal trends. The goal of the research work presented is to develop a dielectric sensor system based on end effect probes able to communicate the data using wireless technology. It must be stand-alone from an electric and data recording point of view so it must integrate a VNA circuit instead of the ANRITSU VNA used for the moment. The LoRa wireless technology has been selected because of its low electric consumption and the large distance between equipment available. LoRaWAN™ is a Low Power Wide Area Network specification intended for wireless battery operated devices. The LoRaWAN data rates range from 0.3 kbps to 50 kbps which is sufficient for our probes' data exchanges. We will present the work done to perform the VNA and the LoRa communication board as well as the work done to improve the probes and the permittivity computation algorithm.

Concentrations and environmental fate of Ra in cation-exchange regeneration brine waste disposed to septic tanks and accumulation in sludge, New Jersey Coastal Plain, USA.

PubMed

Szabo, Zoltan; Jacobsen, Eric; Kraemer, Thomas F; Parsa, Bahman

2008-06-01

Concentrations of Ra in liquid and solid wastes generated from 15 softeners treating domestic well waters from New Jersey Coastal Plain aquifers (where combined Ra ((226)Ra plus (228)Ra) concentrations commonly exceed 0.185 Bq L(-1)) were determined. Softeners, when maintained, reduced combined Ra about 10-fold (<0.024 Bq L(-1)). Combined Ra exceeded 0.185 Bq L(-1) at 1 non-maintained system. Combined Ra was enriched in regeneration brine waste (maximum, 81.2 Bq L(-1)), but concentrations in septic-tank effluents receiving brine waste were less than in the untreated ground waters. The maximum combined Ra concentration in aquifer sands (40.7 Bq kg(-1) dry weight) was less than that in sludge from the septic tanks (range, 84-363 Bq kg(-1)), indicating Ra accumulation in sludge from effluent. The combined Ra concentration in sludge from the homeowners' septic systems falls within the range reported for sludge samples from publicly owned treatment works within the region.

Concentrations and environmental fate of Ra in cation-exchange regeneration brine waste disposed to septic tanks and accumulation in sludge, New Jersey Coastal Plain, USA

USGS Publications Warehouse

Szabo, Z.; Jacobsen, E.; Kraemer, T.F.; Parsa, B.

2008-01-01

Concentrations of Ra in liquid and solid wastes generated from 15 softeners treating domestic well waters from New Jersey Coastal Plain aquifers (where combined Ra (226Ra plus 228Ra) concentrations commonly exceed 0.185 Bq L-1) were determined. Softeners, when maintained, reduced combined Ra about 10-fold (<0.024 Bq L-1). Combined Ra exceeded 0.185 Bq L-1 at 1 non-maintained system. Combined Ra was enriched in regeneration brine waste (maximum, 81.2 Bq L-1), but concentrations in septic-tank effluents receiving brine waste were less than in the untreated ground waters. The maximum combined Ra concentration in aquifer sands (40.7 Bq kg-1 dry weight) was less than that in sludge from the septic tanks (range, 84-363 Bq kg-1), indicating Ra accumulation in sludge from effluent. The combined Ra concentration in sludge from the homeowners' septic systems falls within the range reported for sludge samples from publicly owned treatment works within the region.

Serum levels of albumin, triglycerides, total protein and glucose in rats are altered after oral treatment with low doses of 13-cis-retinoic acid or all-trans-retinoic acid.

PubMed

Cisneros, F J; Gough, B J; Patton, R E; Ferguson, S A

2005-01-01

Currently used to treat severe acne, 13-cis-retinoic acid (13-cis-RA) is under investigation for its anticancer effects as is the isomer, all-trans-retinoic acid (all-trans-RA). Here, the effects of oral 13-cis-RA or all-trans-RA treatment on serum chemistry, leptin and adiponectin levels were evaluated. Adult Sprague-Dawley rats were gavaged once daily for 7 consecutive days with 13-cis-RA (7.5 or 15 mg kg(-1)), all-trans-RA (10 or 15 mg kg(-1)) (n=24/sex/dose), or soy oil (n=16/sex) and blood was sampled 30-480 min after the last gavage. The body weight was unaffected; however, the liver/body weight ratios were increased by both doses of all-trans-RA. Sex differences were noted for levels of cholesterol, creatine, triglycerides, albumin, alanine aminotransferase and total protein. Both doses of all-trans-RA reduced albumin levels to approximately 90% of the control and total protein levels to approximately 93% of the control while substantially elevating triglyceride levels to approximately 66%-99% above the control. Additionally, triglyceride levels of the 15 mg kg(-1) 13-cis RA group were approximately 62% higher than the controls and total protein levels were approximately 5% less. Glucose levels were affected by sex and RA treatment in that males treated with 15 mg kg(-1) of 13-cis-RA or 10 mg kg(-1) all-trans-RA had lower (13%-19%) levels than the same-sex controls; however, females were not similarly affected. Neither 13-cis-RA nor all-trans-RA treatment had significant effects on the levels of blood urea nitrogen, aspartate amino transferase, leptin or adiponectin. On a mg kg(-1) basis, all-trans-RA was more potent than 13-cis-RA. These results replicate previous findings of RA-induced increased triglyceride levels. Additionally, several new findings indicate there may be sex-specific effects of RA treatment. Finally, neither treatment appeared to alter the typical diurnal cycles of these endpoints. Copyright (c) 2005 John Wiley & Sons, Ltd.

Evaluation of Surface Roughness of Ceramic and Resin Composite Material Used for Conservative Indirect Restorations, after Repolishing by Intraoral Means.

PubMed

Vrochari, Areti D; Petropoulou, Aikaterini; Chronopoulos, Vasilios; Polydorou, Olga; Massey, Ward; Hellwig, Elmar

2017-06-01

To evaluate and compare the mean surface roughness (Ra) of one ceramic and one resin composite material used for indirect restorations, after grinding and repolishing by intraoral means. The materials used were the lithium disilicate glass ceramic IPS e.max Press (EMP) and the indirect resin composite restoration system Gradia (GR). Twelve specimen disks were prepared from each material according to the manufacturer of each material. Five initial measurements of the Ra (Ra 1 ) were made on each specimen as a referral basis, and the specimens were ground with a fine (red) diamond bur. The specimens were repolished using (a) Komet Dialite Polishing Kit for EMP and (b) Enhance Finishing and Polishing System and Prisma Gloss Polishing Paste for GR. Five final Ra (Ra 2 ) measurements were performed on each specimen. All measurements were made using a laser profilometer. Scanning electron microscopy (SEM) was also used to visualize the initial surface morphology and the morphological changes on the specimens' surface after repolishing. A highly significant difference was found between Ra 1EMP and Ra 2EMP (p < 0.001), between Ra 1GR and Ra 2GR (p < 0.001), as well as between Ra 2EMP and Ra 2GR (p < 0.001), when compared in pairs. A highly significant difference (p < 0.001) was also found between ΔRa EMP and ΔRa GR , with ΔRa GR being higher than ΔRa EMP . The Ra GR values were higher than the Ra EMP values at all times. SEM revealed that both EMP and GR repolished surfaces presented with irregularities; however, in GR specimens major voids and craters were present. EMP was found to perform better when polished by intraoral means compared with GR. Both materials exhibited Ra 2 above the critical threshold for increased plaque accumulation and periodontal inflammation. If enamel-to-enamel roughness found in occlusal contact areas is considered as baseline, both materials were clinically acceptable after repolishing. © 2015 by the American College of Prosthodontists.

Occurrence of selected radionuclides in ground water used for drinking water in the United States; a reconnaissance survey, 1998

USGS Publications Warehouse

Focazio, Michael J.; Szabo, Zoltan; Kraemer, Thomas F.; Mullin, Ann H.; Barringer, Thomas H.; dePaul, Vincent T.

2001-01-01

The U.S. Geological Survey, in collaboration with the U.S. Environmental Protection Agency, the American Water Works Association, and the American Water Works Service Company, completed a targeted national reconnaissance survey of selected radionuclides in public ground-water supplies. Radionuclides analyzed included radium-224 (Ra-224), radium-226 (Ra-226), radium-228 (Ra-228), polonium-210 (Po-210) and lead-210 (Pb-210).This U.S. Geological Survey reconnaissance survey focused intentionally on areas with known or suspected elevated concentrations of radium in ground water to determine if Ra-224 was also present in the areas where other isotopes of radium had previously been detected and to determine the co-occurrence characteristics of the three radium isotopes (Ra-224, Ra-226, and Ra-228) in those areas. Ninety-nine raw-water samples (before water treatment) were collected once over a 6-month period in 1998 and 1999 from wells (94 of which are used for public drinking water) in 27 States and 8 physiographic provinces. Twenty-one of the 99 samples exceeded the current U.S. Environmental Protection Agency drinking-water maximum contaminant level of 5 picocuries per liter (pCi/L) for combined radium (Ra-226 + Ra-228). Concentrations of Ra-224 were reported to exceed 1 pCi/L in 30 percent of the samples collected, with a maximum concentration of 73.6 pCi/L measured in water from a nontransient, noncommunity, public-supply well in Maryland. Radium-224 concentrations generally were higher than those of the other isotopes of radium. About 5 percent of the samples contained concentrations of Ra-224 greater than 10 pCi/L, whereas only 2 percent exceeded 10 pCi/L for either Ra-226 or Ra-228. Concentrations of Ra-226 greater than 1 pCi/L were reported in 33 percent of the samples, with a maximum concentration of 16.9 pCi/L measured in water from a public-supply well in Iowa. Concentrations of Ra-228 greater than 1 pCi/L were reported in 22 samples, with a maximum concentration of 72.3 pCi/L measured in water from a non-transient, noncommunity, public-supply well in Maryland.Radium-224, which is a decay product of Ra-228 in the Th-232 decay series, was significantly correlated with Ra-228 (Spearman?s rank correlation coefficient ?r? equals 0.82) and to a lesser degree with Ra-226 (r equals 0.69), which is an isotope in the U-238 decay series. The rank correlation coefficient between Ra-226 and Ra-228 was 0.63. The high correlation between Ra-224 and Ra-228 concentrations and the corresponding isotopic ratios of the two (about 1:1 in 90 percent of the samples) indicates that the two radionuclides occur in approximately equal concentrations in most ground water sampled. Thus, Ra-228 can be considered as a reasonable proxy indicator for the occurrence of Ra-224 in ground water.The maximum concentration of Po-210 was 4.85 pCi/L and exceeded 1 pCi/L in only two samples. The maximum concentration of Pb-210 was 4.14 pCi/L, and about 10 percent of the samples exceeded 1 pCi/L. Areas with known, or suspected, elevated concentrations of polonium and lead were not targeted in this survey.Three major implications are drawn for future radionuclide monitoring on the basis of this information: (1) grossalpha particle analyses of ground water should be done within about 48?72 hours after collection to determine the presence of the short-lived, alpha-particle emitting isotopes, such as Ra-224, which was detected in elevated concentrations in many of the samples collected for this survey; (2) the isotope ratios of Ra-224 to Ra-228 in ground water are variable on a national scale, but the two radioisotopes generally occur in ratios near 1:1, therefore, the more commonly measured Ra-228 can be used as an indicator of Ra-224 occurrence for some general purposes other than compliance; and (3) the isotopic ratios of Ra-226 to Ra-228 were less than 3:2 in many samples. These ratios corroborate results of previous studies that have shown the presence of Ra-228

Quantifying and understanding reproductive allocation schedules in plants.

PubMed

Wenk, Elizabeth Hedi; Falster, Daniel S

2015-12-01

A plant's reproductive allocation (RA) schedule describes the fraction of surplus energy allocated to reproduction as it increases in size. While theorists use RA schedules as the connection between life history and energy allocation, little is known about RA schedules in real vegetation. Here we review what is known about RA schedules for perennial plants using studies either directly quantifying RA or that collected data from which the shape of an RA schedule can be inferred. We also briefly review theoretical models describing factors by which variation in RA may arise. We identified 34 studies from which aspects of an RA schedule could be inferred. Within those, RA schedules varied considerably across species: some species abruptly shift all resources from growth to reproduction; most others gradually shift resources into reproduction, but under a variety of graded schedules. Available data indicate the maximum fraction of energy allocated to production ranges from 0.1 to 1 and that shorter lived species tend to have higher initial RA and increase their RA more quickly than do longer-lived species. Overall, our findings indicate, little data exist about RA schedules in perennial plants. Available data suggest a wide range of schedules across species. Collection of more data on RA schedules would enable a tighter integration between observation and a variety of models predicting optimal energy allocation, plant growth rates, and biogeochemical cycles.

Evaporation Rates of Chemical Warfare Agents Measured using 5 cm Wind Tunnels III. Munition-Grade Sulfur Mustard on Concrete

DTIC Science & Technology

2010-02-01

tD O o o 1 1 1 1 — -_.-^_ 1 o in o...O < < < h- SH h Q 1 1-6 o o Is. c x X •g m LU o o O X o N O o c cj o LU ro ra Q "o tD w co tu o o c c s o 5...D Si a flj CO CD CO CJ o o a) » S. 8- 1 S Js 5 co 0 m 0 (£ £ £ o Q. 8 .9

Comparison of symptoms, treatment, and outcomes of coronary artery disease among rheumatoid arthritis and matched subjects undergoing percutaneous coronary intervention.

PubMed

Desai, Sonali P; Januzzi, James L; Pande, Ashvin N; Pomerantsev, Eugene V; Resnic, Frederic S; Fossel, Anne; Chibnik, Lori B; Solomon, Daniel H

2010-12-01

Rheumatoid arthritis (RA) is associated with an increased prevalence of coronary artery disease (CAD). We investigated the presenting symptoms of CAD, coronary anatomy (single versus multi-vessel CAD), and treatment among a group of subjects undergoing percutaneous coronary intervention (PCI) with angioplasty and/or stenting. We evaluated a retrospective cohort of 43 RA subjects and 43 matched non-RA subjects undergoing PCI at 2 academic referral centers. RA subjects were matched to non-RA subjects on age, gender, history of coronary artery bypass grafting, date of PCI, and interventional cardiologist. We compared cardiac risk factors, presentation, treatment, and outcomes. The mean age of the study cohort was 71 ± 10 years, and the distribution of traditional cardiac risk factors was similar in the subjects with RA compared with the matched non-RA subjects (all P values > 0.05). Seventy-four percent of subjects with RA compared with 67% of those without RA presented with an acute coronary syndrome before PCI (P = 0.48). All subjects in this cohort undergoing PCI had at least 1 stenosis in a major epicardial vessel and similar percentages of subjects with RA (44%) and without RA (40%) had multi-vessel CAD (P = 0.66). The administration of cardiac medications both at PCI and at hospital discharge was not different among subjects with RA compared with matched non-RA subjects. Among this cohort with significant CAD undergoing PCI, clinical characteristics, presentation, severity of CAD, treatment modalities, and outcomes were similar in subjects with RA and well-matched non-RA subjects. Copyright © 2010 Elsevier Inc. All rights reserved.

Improved performance of epidemiologic and genetic risk models for rheumatoid arthritis serologic phenotypes using family history.

PubMed

Sparks, Jeffrey A; Chen, Chia-Yen; Jiang, Xia; Askling, Johan; Hiraki, Linda T; Malspeis, Susan; Klareskog, Lars; Alfredsson, Lars; Costenbader, Karen H; Karlson, Elizabeth W

2015-08-01

To develop and validate rheumatoid arthritis (RA) risk models based on family history, epidemiologic factors and known genetic risk factors. We developed and validated models for RA based on known RA risk factors, among women in two cohorts: the Nurses' Health Study (NHS, 381 RA cases and 410 controls) and the Epidemiological Investigation of RA (EIRA, 1244 RA cases and 971 controls). Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in logistic regression models for the study population and for those with positive family history. The joint effect of family history with genetics, smoking and body mass index (BMI) was evaluated using logistic regression models to estimate ORs for RA. The complete model including family history, epidemiologic risk factors and genetics demonstrated AUCs of 0.74 for seropositive RA in NHS and 0.77 for anti-citrullinated protein antibody (ACPA)-positive RA in EIRA. Among women with positive family history, discrimination was excellent for complete models for seropositive RA in NHS (AUC 0.82) and ACPA-positive RA in EIRA (AUC 0.83). Positive family history, high genetic susceptibility, smoking and increased BMI had an OR of 21.73 for ACPA-positive RA. We developed models for seropositive and seronegative RA phenotypes based on family history, epidemiological and genetic factors. Among those with positive family history, models using epidemiologic and genetic factors were highly discriminatory for seropositive and seronegative RA. Assessing epidemiological and genetic factors among those with positive family history may identify individuals suitable for RA prevention strategies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Right Atrial Deformation in Predicting Outcomes in Pediatric Pulmonary Hypertension.

PubMed

Jone, Pei-Ni; Schäfer, Michal; Li, Ling; Craft, Mary; Ivy, D Dunbar; Kutty, Shelby

2017-12-01

Elevated right atrial (RA) pressure is a risk factor for mortality, and RA size is prognostic of adverse outcomes in pulmonary hypertension (PH). There is limited data on phasic RA function (reservoir, conduit, and pump) in pediatric PH. We sought to evaluate (1) the RA function in pediatric PH patients compared with controls, (2) compare the RA deformation indices with Doppler indices of diastolic dysfunction, functional capacity, biomarkers, invasive hemodynamics, and right ventricular functional indices, and (3) evaluate the potential of RA deformation indices to predict clinical outcomes. Sixty-six PH patients (mean age 7.9±4.7 years) were compared with 36 controls (7.7±4.4 years). RA and right ventricular deformation indices were obtained using 2-dimensional speckle tracking (2DCPA; TomTec, Germany). RA strain, strain rates, emptying fraction, and right ventricular longitudinal strain were measured. RA function was impaired in PH patients versus controls ( P <0.001). There were significant associations between RA function with invasive hemodynamics ( P <0.01). RA reservoir, pump function, the rate of RA filling, and atrial minimum volume predicted adverse clinical outcomes (hazard ratio [HR], 0.15; confidence interval [CI], 0.03-0.73; P <0.01; HR, 0.05; CI, 0.003-0.43; P <0.004; HR, 0.04; CI, 0.006-0.56; P <0.01; and HR, 8.6; CI, 1.6-37.2; P <0.01, respectively). RA deformation properties are significantly altered in pediatric PH patients. Progressive worsening of RA reservoir and conduit functions is related to changes in right ventricular diastolic dysfunction. RA reservoir function, pump function, the rate of atrial filling, and atrial minimum volume emerged as outcome predictors in pediatric PH. © 2017 American Heart Association, Inc.

Spatiotemporal manipulation of retinoic acid activity in zebrafish hindbrain development via photo-isomerization.

PubMed

Xu, Lijun; Feng, Zhiping; Sinha, Deepak; Ducos, Bertrand; Ebenstein, Yuval; Tadmor, Arbel D; Gauron, Carole; Le Saux, Thomas; Lin, Shuo; Weiss, Shimon; Vriz, Sophie; Jullien, Ludovic; Bensimon, David

2012-09-01

All-trans retinoic acid (RA) is a key player in many developmental pathways. Most methods used to study its effects in development involve continuous all-trans RA activation by incubation in a solution of all-trans RA or by implanting all-trans RA-soaked beads at desired locations in the embryo. Here we show that the UV-driven photo-isomerization of 13-cis RA to the trans-isomer (and vice versa) can be used to non-invasively and quantitatively control the concentration of all-trans RA in a developing embryo in time and space. This facilitates the global or local perturbation of developmental pathways with a pulse of all-trans RA of known concentration or its inactivation by UV illumination. In zebrafish embryos in which endogenous synthesis of all-trans RA is impaired, incubation for as little as 5 minutes in 1 nM all-trans RA (a pulse) or 5 nM 13-cis RA followed by 1-minute UV illumination is sufficient to rescue the development of the hindbrain if performed no later than bud stage. However, if subsequent to this all-trans RA pulse the embryo is illuminated (no later than bud stage) for 1 minute with UV light (to isomerize, i.e. deactivate, all-trans RA), the rescue of hindbrain development is impaired. This suggests that all-trans RA is sequestered in embryos that have been transiently exposed to it. Using 13-cis RA isomerization with UV light, we further show that local illumination at bud stage of the head region (but not the tail) is sufficient to rescue hindbrain formation in embryos whose all-trans RA synthetic pathway has been impaired.

Vitamin D3 and its synthetic analogue secocholestra-trien-1,2, 24-triol influence the metabolism and the isomerization of retinoic acid in human keratinocytes.

PubMed

Jugert, F K; Roos, T C; Notzon, I; Merk, H F

1998-01-01

Vitamin D and vitamin A acid share metabolic pathways thereby influencing their benefit as a given drug. Little is known concerning their metabolic interactions in epidermal cells. We compared the influence of 1,25-dihydroxycholecalciferol (vitamin D3 - VD3) and its synthetic analogue secocholestra-trien-1,3,24-triol (tacalcitol - TAC) in combination with different calcium concentrations (Ca) on the metabolism and the isomerization of retinoic acid (RA) in cultured primary human keratinocytes. After preincubation with 0.09, 0.6 and 1.2 mM Ca for 24 h, followed by the addition of 10(-6), 10(-8) or 10(-10) M VD3 or TAC, we added 10(-5) M 13-cis-RA (isotretinoin). 24 h later, concentrations of RA isomers and oxidated RA metabolites were measured by RP-HPLC. VD3 (10(-6) M) inhibited the isomerization of 13-cis-RA to all-trans-RA (tretinoin) and 9-cis-RA independently from the Ca concentration in the culture medium. 10(-6)-10(-10) M TAC equally inhibit the 4-hydroxylation of all-trans-RA significantly (12.8 vs. 6.7% of total RA), thereby reducing the amount of irreversible inactivated 4-oxo-all-trans-RA, leading to a higher persistence of all-trans-RA, the active hormone. Both VD3 and its analogue TAC influence the metabolism of RA, a well-known regulator of epithelial cell proliferation and differentiation processes, in two distinct ways. Further studies are necessary to test the hypothesis that the hormone activity of RA can be increased by concomitant treatment with VD3 which prolongs the persistence of 13-cis-RA, and TAC elevating the intracellular concentration of all-trans-RA.

Rheumatoid Arthritis, Anti-CCP Positivity, and Cardiovascular Disease Risk in the Women’s Health Initiative

PubMed Central

Mackey, Rachel H.; Kuller, Lewis H.; Deane, Kevin D.; Walitt, Brian T.; Chang, Yuefang F.; Holers, V. Michael; Robinson, William H.; Tracy, Russell P.; Hlatky, Mark A.; Eaton, Charles; Liu, Simin; Freiberg, Matthew S.; Talabi, Mehret Birru; Schelbert, Erik B.; Moreland, Larry W.

2015-01-01

Objective This report evaluates incidence of cardiovascular disease (CVD) morbidity and mortality over 10 years among the >160,000 postmenopausal women in the Women’s Health Initiative (WHI) in relation to self-reported RA, disease modifying anti-rheumatic drugs (DMARD) use, anti-CCP+, RF+, CVD risk factors, joint pain, and inflammation (white blood cell (WBC) count and IL-6.) Methods Anti-CCP and RF were measured on a sample (n=9,988) of WHI participants with self-reported RA. RA was classified as self-reported RA plus anti-CCP+ positivity and/or use of DMARDs. Self-reported RA that was both anti-CCP− and DMARD− was classified as “unverified RA.” Results Age-adjusted rates of coronary heart disease (CHD), stroke, CVD, fatal CVD and total mortality were higher for women with RA vs. no RA, with multivariable-adjusted HR(95%CI) of 1.46(1.17, 1.83) for CHD, and 2.55(1.86, 3.51) for fatal CVD. Within RA, anti-CCP+ and RF+ were not significantly associated with higher risk of any outcomes, despite slightly higher risk of fatal CVD and death for anti-CCP+ vs. anti-CCP− RA. Joint pain severity and CVD risk factors were strongly associated with CVD risk, even for women with no RA. CVD incidence was increased for RA vs. no RA at almost all risk factor levels, except low levels of joint pain or inflammation. Within RA, inflammation was more strongly associated with fatal CVD and total mortality than CHD or CVD. Conclusion Among postmenopausal women, RA was associated with 1.5-2.5 higher CVD risk, strongly associated with CV risk factors, joint pain severity, and inflammation, but similar for anti-CCP+ and RF+. Clinical Trial Registration clinicaltrials.gov identifier: NCT00000611 PMID:25988241

Can Rheumatoid Arthritis Be Prevented?

PubMed Central

Deane, Kevin

2013-01-01

The discovery of elevations of rheumatoid arthritis (RA)-related biomarkers prior to the onset of clinically apparent RA raises hopes that individuals who are at risk for future RA can be identified in a preclinical phase of disease that is defined as abnormalities of RA-related immune activity prior to the clinically apparent onset of joint disease. Additionally, there is a growing understanding of the immunologic processes that are occurring in preclinical RA, as well as a growing understanding of risk factors that may be mechanistically related to RA development. Furthermore, there are data supporting that treatment of early RA can lead to drug free remission. Taken as a whole, these findings suggest that it may be possible to use biomarkers and other factors to accurately identify the likelihood and timing of onset of future RA, and intervene with immunomodulatory therapies and/or risk factor modification to prevent the future onset of RA in at-risk individuals. Importantly, several clinical prevention trials for RA have already been tried, and one is underway. However, while our understanding of the growing understanding of the mechanisms and natural history of RA development may be leading us to the implementation of prevention strategies for RA, there are still several challenges to be met. These include developing sufficiently accurate methods of predicting those at high risk for future RA so that clinical trials can be developed based on accurate rates of development of arthritis and subjects can be adequately informed of their risk for disease, identifying the appropriate interventions and biologic targets for optimal prevention, and addressing the psychosocial and economic aspects that are crucial to developing broadly applicable prevention measures for RA. These issues notwithstanding, prevention of RA may be within reach in the near future. PMID:24315049

Tracing the Origin of Radioactivity in Groundwater from the Negev, Israel

NASA Astrophysics Data System (ADS)

Vengosh, A.; Pery, N.; Paytan, A.; Haquin, G.; Enhanany, S.; Pankratov, I.

2004-12-01

In normal groundwater conditions natural radionuclides are typically retained on the aquifer matrix and their activity in the groundwater is low. Radium is exceptional since the ratio between adsorbed and dissolved radium depends the ionic strength of the solution. Under high salinity radium is rapidly desorbed and accumulates in the liquid phase. Here we report the results of a geochemical study that investigates the origin of radioactivity in brackish to saline groundwater from the Negev and Arava Valley, Israel. We use the Ra isotope quartet (226Ra-half life 1600 y, 228Ra - 5.6 y, 224Ra - 3.6 d, 223Ra - 11.4 d) to discriminate between radioactivity derived from a thorium source (high 228Ra/226Ra and 224Ra/223Ra ratios) found in groundwater flowing in the Nubian Sandstone aquifer and an uranium source (low 228Ra/226Ra and 224Ra/223Ra ratios) in groundwater flowing in carbonate (Upper Cretaceous) aquifer. We show that the activity of 226Ra in groundwater from the carbonate aquifer is positively correlated with that of the salinity. In the Nubian Sandstone aquifer, however, no such correlation was found. Instead, we observed an inverse correlation between 228Ra activity and sulfate and a positive correlation with barium contents. Given the high H2S content of the ground water, we hypothesized that sulfate reduction process triggers radium leaching to the water, probably due to barite dissolution and anoxic conditions in the aquifer. These findings indicate that high radioactivity can also be found even in low-saline groundwater and that the isotopic ratios of radium are sensitive tracers for the water-rock interactions and thus reconstructing the flow paths in different aquifer matrix (i.e., carbonate versus sandstone).

Explanatory Style in Patients with Rheumatoid Arthritis: An Unrecognized Predictor of Mortality

PubMed Central

Crowson, Aaron D.; Colligan, Robert C.; Matteson, Eric L.; Davis, John M.; Crowson, Cynthia S.

2016-01-01

Objective To determine whether pessimistic explanatory style altered the risk for and mortality of rheumatoid arthritis (RA) patients. Methods The study included subjects from a population-based cohort with incident RA and non-RA comparison cohort who completed the Minnesota Multiphasic Personality Inventory (MMPI). Results Among 148 RA and 135 non-RA subjects, pessimism was associated with development of rheumatoid factor positive (RF+) RA. Pessimism was associated with an increased risk of mortality (hazard ratio [HR]:2.88 with similar magnitude to RF+ (HR:2.28). Conclusion Pessimistic explanatory style was associated with an increased risk of developing RA and increased mortality rate in patients with RA. PMID:28148754

Dynamics of submarine groundwater discharge and associated fluxes of dissolved nutrients, carbon, and trace gases to the coastal zone (Okatee River estuary, South Carolina)

USGS Publications Warehouse

Porubsky, W.P.; Weston, N.B.; Moore, W.S.; Ruppel, C.; Joye, S.B.

2014-01-01

Multiple techniques, including thermal infrared aerial remote sensing, geophysical and geological data, geochemical characterization and radium isotopes, were used to evaluate the role of groundwater as a source of dissolved nutrients, carbon, and trace gases to the Okatee River estuary, South Carolina. Thermal infrared aerial remote sensing surveys illustrated the presence of multiple submarine groundwater discharge sites in Okatee headwaters. Significant relationships were observed between groundwater geochemical constituents and 226Ra activity in groundwater with higher 226Ra activity correlated to higher concentrations of organics, dissolved inorganic carbon, nutrients, and trace gases to the Okatee system. A system-level radium mass balance confirmed a substantial submarine groundwater discharge contribution of these constituents to the Okatee River. Diffusive benthic flux measurements and potential denitrification rate assays tracked the fate of constituents in creek bank sediments. Diffusive benthic fluxes were substantially lower than calculated radium-based submarine groundwater discharge inputs, showing that advection of groundwater-derived nutrients dominated fluxes in the system. While a considerable potential for denitrification in tidal creek bank sediments was noted, in situ denitrification rates were nitrate-limited, making intertidal sediments an inefficient nitrogen sink in this system. Groundwater geochemical data indicated significant differences in groundwater chemical composition and radium activity ratios between the eastern and western sides of the river; these likely arose from the distinct hydrological regimes observed in each area. Groundwater from the western side of the Okatee headwaters was characterized by higher concentrations of dissolved organic and inorganic carbon, dissolved organic nitrogen, inorganic nutrients and reduced metabolites and trace gases, i.e. methane and nitrous oxide, than groundwater from the eastern side. Differences in microbial sulfate reduction, organic matter supply, and/or groundwater residence time likely contributed to this pattern. The contrasting features of the east and west sub-marsh zones highlight the need for multiple techniques for characterization of submarine groundwater discharge sources and the impact of biogeochemical processes on the delivery of nutrients and carbon to coastal areas via submarine groundwater discharge.

Surface elevation change over the Patagonia Ice Fields using CryoSat-2 swath altimetry

NASA Astrophysics Data System (ADS)

Foresta, Luca; Gourmelen, Noel; José Escorihuela, MarÍa; Garcia Mondejar, Albert; Wuite, Jan; Shepherd, Andrew; Roca, Mònica; Nagler, Thomas; Brockley, David; Baker, Steven; Nienow, Pete

2017-04-01

Satellite altimetry has been traditionally used in the past few decades to infer elevation of land ice, quantify changes in ice topography and infer mass balance estimates over large and remote areas such as the Greenland and Antarctic ice sheets. Radar Altimetry (RA) is particularly well suited to this task due to its all-weather year-round capability of observing the ice surface. However, monitoring of ice caps (area < 104 km^2) as well as mountain glaciers has proven more challenging. The large footprint of a conventional radar altimeter and relatively coarse ground track coverage are less suited to monitoring comparatively small regions with complex topography, so that mass balance estimates from RA rely on extrapolation methods to regionalize elevation change. Since 2010, the European Space Agency's CryoSat-2 (CS-2) satellite has collected ice elevation measurements over ice caps with its novel radar altimeter. CS-2 provides higher density of observations w.r.t. previous satellite altimeters, reduces the along-track footprint using Synthetic Aperture Radar (SAR) processing and locates the across-track origin of a surface reflector in the presence of a slope with SAR Interferometry (SARIn). Here, we exploit CS-2 as a swath altimeter [Hawley et al., 2009; Gray et al., 2013; Christie et al., 2016; Ignéczi et al., 2016, Foresta et al., 2016] over the Southern and Northern Patagonian Ice Fields (SPI and NPI, respectively). The SPI and NPI are the two largest ice masses in the southern hemisphere outside of Antarctica and are thinning very rapidly in recent decades [e.g Rignot et al., 2003; Willis et al, 2012]. However, studies of surface, volume and mass change in the literature, covering the entire SPI and NPI, are limited in number due to their remoteness, extremely complex topography and wide range of slopes. In this work, we present rates of surface elevation change for five glaciological years between 2011-2016 using swath-processed CS-2 SARIn heights and discuss the spatial and temporal coverage of elevation and its rate of change over the two regions.

A Reasoning Agent for Credit Card Fraud on the Internet Using the Event Calculus

NASA Astrophysics Data System (ADS)

Blackwell, Clive

We illustrate the design of an intelligent agent to aid a merchant to limit fraudulent payment card purchases over the Internet. This is important because increasing fraud may limit the rise of e-commerce, and difficult because of the uncertainty in identifying and authenticating people remotely. The agent can advise the merchant what actions to take to reduce risk without complete knowledge of the circumstances. It can also negotiate flexibly to conclude transactions successfully that would otherwise be rejected. We use the Event Calculus to model the transaction system including the participants and their actions. The idea has applications in other distributed systems where incomplete knowledge of a system may be exploited by adversaries to their advantage.