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ID PMID Title PublicationDate abstract
29196182 Peripheral 5-HT(3) mediates mirror-image pain by a cross-talk with acid-sensing ion channe 2018 Mar 1 Mirror-image pain (MIP), which occurs along with complex regional pain syndrome, rheumatoid arthritis and chronic migraine, is characterized by increased pain sensitivity of healthy body regions other than the actual injured or inflamed sites. A high level of peripheral inflammation may activate central or peripheral glia, triggering mirror-image pain. However, which receptors mediate inflammatory signals to contribute glial activation remains unclear. Intraplantarly injecting mice with 5-hydroxytryptamine (5-HT) or acidic buffer (proton) caused only unilateral hyperalgesia, but co-injection of 5-HT/acid induced bilateral hyperalgesia (MIP). Blocking 5-HT(3) or acid-sensing ion channel 3 (ASIC3) abolished satellite glial activation, inhibiting MIP. Interestingly, intraplantar administration of a 5-HT(3) agonist induced MIP, and 5-HT(3)-mediated MIP can be reversed by a 5-HT(3) antagonist or an ASIC3 blocker. Similar results were found using a ASIC3 agonist. Furthermore, 5-HT(3) was observed to co-localize with ASIC3 in DRG neurons; 5-HT(3) activation-induced an increase in intracellular calcium that was inhibited by an ASIC3 blocker and vice versa. A cross-talk between 5-HT(3) and ASIC3 mediates satellite glial activation, thereby triggering mirror-image pain.
29137646 The potential of interleukin-37 as an effective therapeutic agent in asthma. 2017 Nov 14 Interleukin (IL)-37 belongs to the IL-1 cytokine family. It binds to IL-18Rα and recruits the orphan decoy IL-1R8. Emerging evidence shows that IL-37 is a key player in the regulation of inflammation, cellular differentiation, and proliferation. Altered IL-37 expression has been demonstrated in many inflammatory disease conditions, including asthma. In rheumatoid arthritis, IL-37 is involved in the regulation of proliferation, production of inflammatory mediators, and activation of inflammatory cells. Furthermore, this cytokine acts as a negative regulator of inflammation in inflammatory bowel disease. Similarly, IL-37 also appears to suppress allergic inflammation in asthma. In a murine model of asthma, local administration of IL-37 markedly reduced the degree of inflammatory cell infiltration and airway hyper-responsiveness. IL-37 has also been shown to be involved in a number of aspects of allergic inflammation, such as eosinophil and neutrophil recruitment, as well as inhibition of Th1/Th2/Th17 inflammatory mediators. However, the exact molecular mechanisms underlying the function of IL-37 in human asthma have yet to be fully elucidated. This review describes the current evidence regarding the role of IL-37 in the pathophysiology of asthma and evaluates both the potential of IL-37 as a biomarker for airway inflammation and a therapeutic target for the treatment of asthma.
28988120 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-in 2017 Dec 1 Leflunomide, used for the treatment of rheumatoid arthritis, has been reported to cause severe liver problems and liver failure; however, the underlying mechanisms are not clear. In this study, we used multiple approaches including genomic analysis to investigate and characterize the possible molecular mechanisms of the cytotoxicity of leflunomide in hepatic cells. We found that leflunomide caused endoplasmic reticulum (ER) stress and activated an unfolded protein response, as evidenced by increased expression of related genes including CHOP and GADD34; and elevated protein levels of typical ER stress markers including CHOP, ATF-4, p-eIF2α, and spliced XBP1. The secretion of Gaussia luciferase was suppressed in cells treated with leflunomide in an ER stress reporter assay. Inhibition of ER stress with an ER stress inhibitor 4-phenylbutyrate, and knockdown of ATF-4 and CHOP genes partially protected cells upon leflunomide exposure. In addition, both genomic and biochemical analyses revealed that JNK and ERK1/2 of MAPK signaling pathways were activated, and both contributed to the leflunomide-induced cytotoxicity. Inhibiting JNK activation using a JNK inhibitor attenuated the ER stress and cytotoxicity of leflunomide, whereas inhibiting ERK1/2 using an ERK1/2 inhibitor or ERK1/2 siRNA increased the adverse effect caused by leflunomide, suggesting opposite roles for the two pathways. In summary, our data indicate that both ER stress and the activation of JNK and ERK1/2 contribute to leflunomide-induced cytotoxicity.
30920519 Cyclodextrin-Based Nanohydrogels Containing Polyamidoamine Units: A New Dexamethasone Deli 2017 Jun 8 Glucocorticoids are widely prescribed in treatment of rheumatoid arthritis, asthma, systemic lupus erythematosus, lymphoid neoplasia, skin and eye inflammations. However, well-documented adverse effects offset their therapeutic advantages. In this work, novel nano-hydrogels for the sustained delivery of dexamethasone were designed to increase both bioavailability and duration of the administered drug and reducing the therapeutic dose. Hydrogels are soft materials consisting of water-swollen cross-linked polymers to which the insertion of cyclodextrin (CD) moieties adds hydrophobic drug-complexing sites. Polyamidoamines (PAAs) are biocompatible and biodegradable polymers apt to create CD moieties in hydrogels. In this work, β or γ-CD/PAA nanogels have been developed. In vitro studies showed that a pretreatment for 24⁻48 h with dexamethasone-loaded, β-CD/PAA nanogel (nanodexa) inhibits adhesion of Jurkat cells to human umbilical vein endothelial cells (HUVEC) in conditions mimicking inflammation. This inhibitory effect was faster and higher than that displayed by free dexamethasone. Moreover, nanodexa inhibited COX-2 expression induced by PMA+A23187 in Jurkat cells after 24⁻48 h incubation in the 10(-8)⁻10(-5) M concentration range, while dexamethasone was effective only at 10(-5) M after 48 h treatment. Hence, the novel nanogel-dexamethasone formulation combines faster action with lower doses, suggesting the potential for being more manageable than the free drug, reducing its adverse side effects.
28413859 Meniscus, articular cartilage and nucleus pulposus: a comparative review of cartilage-like 2017 Oct The degradation of cartilage in the human body is impacted by aging, disease, genetic predisposition and continued insults resulting from daily activity. The burden of cartilage defects (osteoarthritis, rheumatoid arthritis, intervertebral disc damage, knee replacement surgeries, etc.) is daunting in light of substantial economic and social stresses. This review strives to broaden the scope of regenerative medicine and tissue engineering approaches used for cartilage repair by comparing and contrasting the anatomical and functional nature of the meniscus, articular cartilage (AC) and nucleus pulposus (NP). Many review papers have provided detailed evaluations of these cartilages and cartilage-like tissues individually but none have comprehensively examined the parallels and inconsistencies in signaling, genetic expression and extracellular matrix composition between tissues. For the first time, this review outlines the importance of understanding these three tissues as unique entities, providing a comparative analysis of anatomy, ultrastructure, biochemistry and function for each tissue. This novel approach highlights the similarities and differences between tissues, progressing research toward an understanding of what defines each tissue as distinctive. The goal of this paper is to provide researchers with the fundamental knowledge to correctly engineer the meniscus, AC and NP without inadvertently developing the wrong tissue function or biochemistry.
28349073 DEPTOR-mTOR Signaling Is Critical for Lipid Metabolism and Inflammation Homeostasis of Lym 2017 Abnormal immune response of the body against substances and tissues causes autoimmune diseases, such as polymyositis, dermatomyositis, and rheumatoid arthritis. Irregular lipid metabolism and inflammation may be a significant cause of autoimmune diseases. Although much progress has been made, mechanisms of initiation and proceeding of metabolic and inflammatory regulation in autoimmune disease have not been well-defined. And novel markers for the detection and therapy of autoimmune disease are urgent. mTOR signaling is a central regulator of extracellular metabolic and inflammatory processes, while DEP domain-containing mTOR-interacting protein (DEPTOR) is a natural inhibitor of mTOR. Here, we report that overexpression of DEPTOR reduces mTORC1 activity in lymphocytes of human peripheral blood mononuclear cells (PBMCs). Combination of DEPTOR overexpression and mTORC2/AKT inhibitors effectively inhibits lipogenesis and inflammation in lymphocytes of PBMC culture. Moreover, DEPTOR knockdown activates mTORC1 and increases lipogenesis and inflammations. Our findings provide a deep insight into the relationship between lipid metabolism and inflammations via DEPTOR-mTOR pathway and imply that DEPTOR-mTOR in lymphocytes of PBMC culture has the potential to be as biomarkers for the detection and therapies of autoimmune diseases.
29166574 Altered TNF-α response by Aconibal® and methotrexate in a lipopolysaccharide-induced set 2018 Mar 1 ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum carmichaelii (AC) is a common herbal medicine used as anti-inflammatory and analgesic agent in Eastern Asia. In Korea, a commercial processed AC (Aconibal®) is traditionally used to treat the symptoms of spondylosis deformans and rheumatic pain. AIM OF STUDY: Rheumatoid arthritis (RA) is systemic and autoimmune disease characterized by chronic inflammation. Methotrexate (MTX) is often the first-line therapy for RA. If MTX monotherapy is ineffective or RA is initially severe, adding a tumor necrosis factor alpha (TNF-α) inhibitor to the treatment can be beneficial. However, its inhibitory effects on RA when combined with MTX are unknown. Therefore, we investigated the stable modulation of and synergistic to additive effect on TNF-α using AC combined with MTX (AMC). MATERIALS AND METHODS: An inflammatory response mimicking RA was induced in the mouse macrophage cell line Raw 264.7 using interferon-γ or lipopolysaccharide (LPS). We predicted that AC and MTX at a 3:1 ratio would have synergistic therapeutic effects and this was determined using the Chou-Talalay method of median effect analysis and CalcuSyn software. We analyzed the profiles of various inflammatory cytokine-related proteins using Search tool for retrieval of interacting genes and Kyoto Encyclopedia of Genes and Genomes. RESULTS: The expression levels of selected inflammatory immune mediators such as interleukin (IL)-6, IL-1α, chemokine ligand 5, granulocyte-colony stimulating factor, nitric oxide synthase, and cyclooxygenase were reduced via regulation of the mitogen-activated protein kinase signaling pathway. AMC inhibited the levels of matrix metalloproteinases-1 and -3 in the human synovial cell line SW982. CONCLUSIONS: Our data show for the first time the potential beneficial effects of AMC in RA management.
29108826 Physical activity and autoimmune diseases: Get moving and manage the disease. 2018 Jan Physical activity, by definition, is any skeletal muscle body movement that results in energy expenditure. In the last few decades, a plethora of scientific evidences have accumulated and confirmed the beneficial role of physical activity as a modifiable risk factor for a wide variety of chronic diseases including cardiovascular diseases (CVDs), diabetes mellitus and cancer, among others. Autoimmune diseases are a heterogeneous group of chronic diseases, which occur secondary to loss of self-antigen tolerance. With the advent of biological therapies, better outcomes have recently been noted in the management of autoimmune diseases. Nonetheless, recent research highlights the salient role of modifiable behaviors such as physical inactivity on various aspects of the immune system and autoimmune diseases. Physical activity leads to a significant elevation in T-regulatory cells, decreased immunoglobulin secretion and produces a shift in the Th1/Th2 balance to a decreased Th1 cell production. Moreover, physical activity has been proven to promote the release of IL-6 from muscles. IL-6 released from muscles functions as a myokine and has been shown to induce an anti-inflammatory response through IL-10 secretion and IL-1β inhibition. Physical activity has been shown to be safe in most of autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel diseases (IBD), as well as others. Additionally, the incidence of RA, MS, IBD and psoriasis has been found to be higher in patients less engaged in physical activity. As a general trend, patients with autoimmune diseases tend to be less physically active as compared to the general population. Physically active RA patients were found to have a milder disease course, better cardiovascular disease (CVD) profile, and improved joint mobility. Physical activity decreases fatigue, enhances mood, cognitive abilities and mobility in patients with MS. In SLE patients, enhanced quality of life and better CVD profile were documented in more physically active patients. Physically active patients with type 1 diabetes mellitus have a decreased risk of autonomic neuropathy and CVD. Both fibromyalgia and systemic sclerosis patients report decreased disease severity, pain, as well as better quality of life with more physical activity. Further, SSc patients improve their grip strength, finger stretching and mouth opening with increased level of exercise. The purpose of this paper is to review the clinical evidence regarding the safety, barriers to engagement, and impact of physical activity on autoimmune diseases.
29027676 Toxicokinetics of strychnine and brucine after the oral administration of Biqi capsule to 2018 Mar Biqi capsule is a well-known traditional Chinese medicine formula that has been widely applied for the clinical treatment of such diseases as rheumatoid arthritis, scapulohumeral periarthritis and cervical spondylopathy. However, there is concern regarding the toxicity of Biqi capsule owing to its active ingredients, strychnine and brucine. To investigate the toxicokinetics of strychnine and brucine after oral administration of Biqi capsule to rats, a sensitive and simple rapid-resolution liquid chromatography/tandem mass spectrometry method was developed to determine the levels of strychnine and brucine in rat plasma. Chromatographic separation was performed on a Capcell Pak C(18) MG II (3.0 μm, 2.0 × 35 mm) column by gradient elution with acetonitrile and 0.2% formic acid as the mobile phase. The method was validated over the range of 0.25-250 ng/mL for strychnine and 0.025-25 ng/mL for brucine. The intra- and inter-day accuracies of strychnine and brucine in rat plasma were 100.3-106.6 and 90.75-106.1% respectively, and the precisions were within 14.2%. The established method was successfully applied to the toxicokinetic study of strychnine and brucine after single and multiple oral administration of Biqi capsule to male and female rats at 0.4, 0.8 and 1.6 g/kg doses. The results showed different toxicokinetic characteristics in the different groups.
28900017 Omega-3 fatty acids and inflammatory processes: from molecules to man. 2017 Oct 15 Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.
28746281 Corticosteroid Injections for Carpal Tunnel Syndrome: Long-Term Follow-Up in a Population- 2017 Aug BACKGROUND: Corticosteroid injection is a recommended treatment option for carpal tunnel syndrome, before considering surgery. Nevertheless, injections remain controversial because there is strong evidence of only short-term benefits. This study aimed to determine the reintervention rate and to identify prognostic indicators for subsequent treatment after corticosteroid injection for carpal tunnel syndrome. METHODS: This study evaluated residents of Olmsted County treated with a corticosteroid injection for carpal tunnel syndrome between 2001 and 2010. Treatment failure was the primary outcome of interest. Two definitions for failure were examined: (1) the patient receiving subsequent procedural intervention and (2) the patient undergoing carpal tunnel release. Survival was estimated using Kaplan-Meier methods, and association of covariates with increased failure was modeled using Cox proportional hazards regression. RESULTS: The study included 774 affected hands in 595 patients. The median follow-up period was 7.4 years. Reintervention was performed in 68 percent of cases, of which 63 percent resulted in eventual surgery. Injectate volume was significant for the outcome of any retreatment [hazard ratio, 0.879 (95 percent CI, 0.804 to 0.96)] and surgery [hazard ratio, 0.906 (95 percent CI, 0.827 to 0.99)]. Rheumatoid arthritis was also significant in both models, with a hazard ratio of 0.627 (95 percent CI, 0.404 to 0.97) for any retreatment and 0.493 (95 percent CI, 0.292 to 0.83) for surgery. CONCLUSIONS: In this cohort, 32 percent of patients did not receive subsequent treatment after a single injection, which indicates that there is a therapeutic role for corticosteroid injections in treating carpal tunnel syndrome. Further research is necessary to identify those patients who will benefit from an injection, to provide more individually tailored treatment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.
28688676 Predictors of readmissions after head and neck cancer surgery: A national perspective. 2017 Aug OBJECTIVES: Surgical oncology patients have multiple comorbidities and are at high risk of readmission. Prior studies are limited in their ability to capture readmissions outside of the index hospital that performed the surgery. Our goal is to evaluate risk factors for readmission for head and neck cancer patients on a national scale. MATERIAL AND METHODS: A retrospective cohort study of head and neck cancer patients in the Nationwide Readmissions Database (2013). Our main outcome was 30-day readmission. Statistical analysis included 2-sided t tests, χ(2), and multivariate logistic regression analysis. RESULTS: Within 30days, 16.1% of 11,832 patients were readmitted and 20% of readmissions were at non-index hospitals, costing $31million. Hypopharyngeal cancer patients had the highest readmission rate (29.6%), followed by laryngeal (21.8%), oropharyngeal (18.2%), and oral cavity (11.6%) cancers (P<0.001). Half of readmissions occurred within 10days and were often associated with infections (27%) or wound complications (12%). Patients from lower household income areas were more likely to be readmitted (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.16-2.05). Patients with valvular disease (OR, 2.07; 95% CI, 1.16-3.69), rheumatoid arthritis/collagen vascular disease (OR, 2.05; 95% CI, 1.27-3.31), liver disease (OR, 2.02, 95% CI, 1.37-2.99), and hypothyroidism (OR 1.30; 95% CI, 1.02-1.66) were at highest risk of readmission. CONCLUSION: The true rate of 30-day readmissions after head and neck cancer surgery is 16%, capturing non-index hospital readmissions which make up 20% of readmissions. Readmissions after head and neck cancer surgery are most commonly associated with infections and wound complications.
28509400 Glycyrrhetinic Acid Accelerates the Clearance of Triptolide through P-gp In Vitro. 2017 Jul Triptolide (TP) is an active ingredient isolated from Tripterygium wilfordii Hook. f. (TWHF), which is a traditional herbal medicine widely used for the treatment of rheumatoid arthritis and autoimmune disease in the clinic. However, its adverse reactions of hepatotoxicity and nephrotoxicity have been frequently reported which limited its clinical application. The aim of this study was to investigate the mechanism of glycyrrhetinic acid (GA) effecting on the elimination of TP in HK-2 cells and the role of the efflux transporters of P-gp and multidrug resistance-associated proteins (MRPs) in this process. An ultra performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS) analytical method was established to determine the intracellular concentration of TP. In order to study the role of efflux transporters of P-gp and MRPs in GA impacting on the accumulation of TP, the inhibitors of efflux transporters (P-gp: verapamil; MRPs: MK571) were used in this study. The results showed that GA could enhance the elimination of TP and reduce the TP accumulation in HK-2 cells. Verapamil and MK571 could increase the intracellular concentration of TP; in addition, GA co-incubation with verapamil significantly increased the TP cellular concentration compared with the control group. In conclusion, GA could reduce the accumulation of TP in HK-2 cells, which was related to P-gp. This is probably one of the mechanisms that TP combined with GA to detoxify its toxicity. Copyright © 2017 John Wiley & Sons, Ltd.
28507328 Pro-inflammatory Ca(++)-activated K(+) channels are inhibited by hydroxychloroquine. 2017 May 15 Antimalarials have demonstrated beneficial effects in Systemic Lupus Erithematosus and Rheumatoid Arthritis. However, the mechanisms and the molecular players targeted by these drugs remain obscure. Although hydroxychloroquine (HCQ) is a known ion channel inhibitor, this property has not been linked to its anti-inflammatory effects. We aimed to study whether HCQ inhibits pro-inflammatory ion channels. Electrophysiology experiments demonstrated that HCQ inhibited Ca(++)-activated K(+) conductance in THP-1 macrophages in a dose-dependent manner. In macrophages, ATP-induced K(+) efflux plays a key role in activating the NLRP3 inflammasome. ATP-induced IL-1beta secretion was controlled by the KCa1.1 inhibitor iberiotoxin. NS1619 and NS309 (KCa1.1 and KCa3.1 activators respectively) induced the secretion of IL-1beta. This effect was inhibited by HCQ and also by iberiotoxin and clotrimazol (KCa3.1 inhibitor), arguing against off-target effect. In vitro, HCQ inhibited IL-1beta and caspase 1 activation induced by ATP in a dose-dependent manner. HCQ impaired K(+) efflux induced by ATP. In vivo, HCQ inhibited caspase 1-dependent ATP-induced neutrophil recruitment. Our results show that HCQ inhibits Ca(++)-activated K(+) channels. This effect may lead to impaired inflammasome activation. These results are the basis for i) a novel anti-inflammatory mechanism for HCQ and ii) a new strategy to target pro-rheumatic Ca(++)-activated K(+) channels.
28500564 Calcium Signaling: From Normal B Cell Development to Tolerance Breakdown and Autoimmunity. 2017 Oct Maintenance of self-tolerance of auto-reactive lymphocytes is a fundamental mechanism to prevent the onset of autoimmune diseases. Deciphering the mechanisms involved in the deregulations leading to tolerance disruption and autoimmunity is still a major area of interest to identify new therapeutic targets and options. Ca(2+) signaling plays a major role in B cell normal development and is therefore finely tuned by B cell receptor (BCR)-dependent and independent pathways. Developmental changes in the characteristics of BCR-dependent Ca(2+) signals as well as the modulation of basal intracellular concentration ([Ca(2+)](i)) contribute strongly to self-tolerance maintaining mechanisms responsible for the physical or functional elimination of autoreactive B cells such as clonal deletion, receptor editing, and anergy. Implication of Ca(2+) signals in B tolerance mechanisms mainly occurs through the specific activation of transcriptional programs depending on the amplitude, shape, and duration of Ca(2+) signals. A large number of studies reported Ca(2+) signaling defects in autoimmune pathology such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and primary SjÓ§gren's syndrome (pSS). However, the precise nature of the molecular events responsible for these deregulations is not fully understood. Moreover, the demonstration of a direct correlation between Ca(2+) signaling defects and tolerance disruption is still lacking. The recent identification of proteins involved in B cell Ca(2+) signals such as ORAI, stromal interaction molecule and transient receptor potential is opening new horizons for understanding Ca(2+) signaling defects observed in autoimmune diseases and for proposing potentially new therapeutic solutions. This review aims to present an overview of the developmental evolution of BCR dependent Ca(2+) signaling and to place this signaling pathway in the context of mechanisms involved in tolerance maintenance and breakdown.
28416826 [Surgical technique and early clinical outcomes of direct anterior approach to total hip a 2017 Apr 18 OBJECTIVE: To describe the surgical technique of direct anterior approach to total hip arthroplasty and to report the early clinical outcomes. METHODS: A series of 100 consecutive, unselected patients who had 116 primary total hip arthroplasty surgeries (16 bilateral) done through direct anterior approach from March 11 2015 to June 21 2016 was reviewed. There were 50 male patients and 50 female patients. The average patient age was 51 years, and the average body mass index was 24.69 kg/m(2). The preoperative diagnosis included avascular necrosis of femoral head, hip osteoarthritis, osteoarthritis secondary to acetabular dysplasia, sequelae of hip old infection, ankylosing spondylitis, rheumatoid arthritis and avascular necrosis of femoral head after cannulated screws fixation of femoral neck fracture. There were 7 hips which had surgical history prior to the index hip arthroplasty, including 3 cases with bone graft treatment for avascular necrosis of femoral head through Smith-Peterson approach, 2 cases with acetabular shelf procedures for acetabular dysplasia through Smith-Peterson approach, and 2 cases with cannulated screws fixation for femoral neck fracture (internal fixation residual). All were uncemented hips. The stems used in this study included 67 Triloc stems (DePuy company, USA), 45 Corail stems (DePuy company, USA), 2 Accolade stems (Stryker company, USA), 1 Synergy stem (Smith-Nephew company, USA) and 1 Polarstem (Smith-Nephew company, USA). RESULTS: The average follow up period was 8.5 months, the average incision scar length was 10 cm, and the average postoperative Harris score was 93.62. There was 95% postoperative leg length discrepancy within 3 mm. The average cup inclination angle was 38.7° with 94.8% in the range of 30° to 50°. The average cup anteversion angle was 14.3° with 94.2% within the target range of 5° to 25°.The were 15 (12.9%) operative complications, including two femoral perforations (changing stem from Triloc to Corail), three calcar fractures (treated with cerclage wires), four greater trochanter fractures (2 were treated wire tension band, and 2 nondisplaced fractures untreated), one deep infection (debridement and retaining of the prothesis), one superficial infection (debridement), one hematoma and three wound healing complications (debridement). All the complications were successfully treated without any sequelae at the end of the latest follow-up. There was no postoperative dislocation. There was no major nerve and vascular injuries. There were 35 cases (30.2%) reporting symptoms of lateral femoral cutaneous nerve palsy. CONCLUSION: Direct anterior approach to total hip arthroplasty allows accurate and reproducible cup orientation positioning and leg length restoration and decreases the risk of postoperative dislocation, which is helpful for early rapid postoperative recovery.
28413313 Additional Risk Minimisation Measures for Medicinal Products in the European Union: A Revi 2017 INTRODUCTION: Additional risk minimisation measures (aRMMs) for medicinal products are necessary to address specific important safety issues which may not be practically achieved through routine risk management measures alone. The implementation and determination of effectiveness for aRMMs can be a challenge as it involves multiple stakeholders. It is therefore important to have concise objectives to avoid undue burden on patients, healthcare professionals and the healthcare system. AIM: The aim of this study was to examine how aRMMs are implemented and how effectiveness is assessed in the European Union (EU) using practical examples from Roche Products Limited in the United Kingdom (UK) (referred to as the 'Company'). METHODS: Three centrally authorised products were selected from the Company's portfolio, each of which had aRMMs to address important safety concerns; specifically, teratogenicity, medication error and infections. The implementation of EU aRMMs, effectiveness checks and specific UK activities were analysed. Hard copy folders and electronic sites for Company aRMMs were used to assess process indicators. Periodic benefit-risk evaluation reports for specified time intervals and the Company safety database was used in checking safety outcomes for the selected products. For each product, the effectiveness of aRMMs was analysed based on specific process indicators and the subsequent safety outcomes. Literature searches were performed on scientific databases for the purposes of the broader study. RESULTS: The main process indicators in measuring effectiveness of Company aRMMs were distribution metrics for educational materials, assessment of awareness and clinical actions among healthcare professionals (HCPs). Case reports of pregnancy, medication errors and progressive multifocal leukoencephalopathy (PML) were the outcome indicators for Erivedge(®)▼, Kadcyla(®)▼ and MabThera(®) (the latter specifically in autoimmune indications: rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis) respectively. No pregnancy, one medication error and 10 confirmed PML cases were reported for Erivedge(®)▼, Kadcyla(®)▼ and MabThera(®) respectively. CONCLUSIONS: For the chosen products, a reasonable awareness of aRMMs amongst HCPs is a positive indicator of success in the use of educational materials. However, low response rates from surveys indicate that voluntary feedback may not always achieve the desired level of response in measuring effectiveness. There is a challenge in determining overall effectiveness of aRMMs due to a lack of defined success thresholds. Further regulatory guidance to outline the elements and desired outcomes of aRMMs will be useful for consistency in achieving successful outcomes.
28167941 NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells. 2017 Dysregulation of inflammatory responses is a hallmark of multiple diseases such as atherosclerosis and rheumatoid arthritis. As constitutively active transcription factors, NR4A nuclear receptors function to control the magnitude of inflammatory responses and in chronic inflammatory disease can be protective or pathogenic. Within this study, we demonstrate that TLR4 stimulation using the endotoxin lipopolysaccharide (LPS) rapidly enhances NR4A1-3 expression in human and murine, primary and immortalized myeloid cells with concomitant gene transcription and protein secretion of MIP-3α, a central chemokine implicated in numerous pathologies. Deficiency of NR4A2 and NR4A3 in human and murine myeloid cells reveals that both receptors function as positive regulators of enhanced MIP-3α expression. In contrast, within the same cell types and conditions, altered NR4A activity leads to suppression of LPS-induced MCP-1 gene and protein expression. An equivalent pattern of inflammatory gene regulation is replicated in TNFα-treated myeloid cells. We show that NF-κB is the critical regulator of NR4A1-3, MIP-3α, and MCP-1 during TLR4 stimulation in myeloid cells and highlight a parallel mechanism whereby NR4A activity can repress or enhance NF-κB target gene expression simultaneously. Mechanistic insight reveals that NR4A2 does not require DNA-binding capacity in order to enhance or repress NF-κB target gene expression simultaneously and establishes a role for NF-κB family member Relb as a novel NR4A target gene involved in the positive regulation of MIP-3α. Thus, our data reveal a dynamic role for NR4A receptors concurrently enhancing and repressing NF-κB activity in myeloid cells leading to altered transcription of key inflammatory mediators.
28151883 Beyond bone mineral density, FRAX-based tailor-made intervention thresholds for therapeuti 2017 Feb Glucocorticoid-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis and confers a substantial risk for future fractures. Several recent guidelines for GIOP management have recommended the use of intervention thresholds to direct pharmacological therapy in those at high risk of fracture. The aim of this study was to analyze the characteristics of subjects on a glucocorticoid (GC) and to implement the Fracture Risk Assessment Tool (FRAX)-based intervention threshold for therapeutic decision-making.This was a cohort substudy of a nationwide osteoporosis screening program conducted in Taiwan from 2008 to 2011. All participants were requested to complete a questionnaire including FRAX elements, and antiosteoporosis medication (AOM) history was assessed before bone mineral density (BMD) measurement. GC users were recruited as the study group. Controls comprised randomly selected age- and sex-matched non-GC users. Individual intervention threshold (IIT) was set at individual-specific FRAX probability of a major osteoporotic fracture, relative to subjects with prior fractures. The characteristics and calculated IIT of all participants were analyzed.A total of 8704 participants were enrolled, including GC users (n = 807) and controls (n = 7897). There was no significant difference in BMD between GC users and controls. Clinical fracture risks, including previous fracture, parental hip fracture, rheumatoid arthritis, and secondary osteoporosis were higher in GC users than in controls. GC users had a higher 10-year probability of either major or hip fracture than controls. The proportion of GC users with a 10-year probability of major osteoporotic fracture above IIT was higher than in controls (75.0% vs 10.6%; P < 0.001). Only 20.3% of GC users and 30.5% of controls whose fracture risk was above IIT reported taking AOM.These findings suggest that more GC users should receive active intervention based on IIT, regardless of BMD. However, less than one-fourth of GC users whose fracture risk was above IIT received AOM, indicating that GIOP is markedly undertreated. We recommend commencing AOM for GIOP according to IIT, instead of BMD alone.
28051320 Correlation of Antibody Responses to a Peptide Antigen gp120-C5(501-512)/gp41(732-744) wit 2017 Jun Antibodies to the carboxy-terminal constant (C5) region 5 of the HIV-1 envelope glycoprotein gp120 have previously been associated with slow disease progression. This is one of the regions on gp120 that interact with the transmembrane glycoprotein, gp41, anchoring it to the viral and infected cell membrane. This study analyzed humoral responses to a novel heterodimeric peptide construct comprising the C5(501-512) region and a compatible region on gp41(732-744). Antibody levels to C5(501-512)/gp41(732-744) were associated with slow disease progression in a treatment naive historical longitudinal cohort from Norway (n = 32; p = .00001). Elevated anti-C5(501-512)/gp41(732-744) antibody levels correlated with moderate viral load (VL) (50-10,000 copies/ml) in a cohort, including natural viral suppressors (NVS) in the Unites States (n = 58; p = .002). Analysis of HIV-positive sera from treatment naive patients in Estonia (n = 300) showed an inverse correlation between anti-C5(501-512)/gp41(732-744) antibodies and VL when comparing VL 2,000-10,000 copies/ml with VL >10,000 (p = .050). Further mapping using peptide inhibition of antibody binding revealed that responses to the C5(501-506) subdomain correlated with preserved CD4 counts (n = 55; p = .0012) irrespective of VL in this cohort. The C5 region encompassing C5(501-506) shows sequence similarity to the shared epitope (SE) of certain HLA-DR associated with immune dysfunction. Partial antigenic cross-reactivity between SE and C5 is indicated by partial inhibition of NVS antibody binding using SE 15-mer peptide (median 65% inhibition), the C5(501-506) 6-mer peptide (79% inhibition), and binding of rheumatoid arthritis patient sera to both SE and C5 peptide sequences. The potential influence of these observations on HIV-1 pathogenesis remains to be determined.