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ID PMID Title PublicationDate abstract
24781619 Total knee arthroplasty with an oxidised zirconium femoral component: a 5-year follow-up s 2014 Apr PURPOSE: To report the early results of the Oxinium Genesis II prosthesis with an oxidised zirconium femoral component in 55 patients. METHODS: 71 knees in 21 men and 34 women aged 32 to 75 (mean, 55) years were evaluated; 16 of the patients had bilateral staged total knee replacements with a mean interval of 9 (range, 6-16) months between surgeries. The indications for surgery included osteoarthritis (n=57), rheumatoid arthritis (n=13) and revision from a unicompartmental knee replacement for osteoarthritis (n=1). Postoperatively, patients were evaluated using the Knee Society score (KSS), the modified Oxford Knee Score, and the SF-12 health survey, as were component position, leg and knee alignment, and prosthesis-bone interface or fixation on radiographs. RESULTS: The mean follow-up was 62 (range, 51-88) months. The mean KSS, Oxford Knee Score, and SF-12 physical component score improved significantly. Radiolucent lines (<2 mm) were noted in the tibial cement-bone interface in 17 knees (most commonly in zones 4 and 1) and in the femoral cement-bone interface in one knee. The alignment of the knees and positioning of the components were acceptable. There were no revisions for septic or aseptic loosening. CONCLUSION: Early results of the Oxinium Genesis II prosthesis are comparable to the standard total knee prostheses.
24694566 Chemical comparison of Tripterygium wilfordii and Tripterygium hypoglaucum based on quanti 2014 Jul Tripterygium wilfordii (T. wilfordii) and Tripterygium hypoglaucum (T. hypoglaucum), two commonly used Chinese herbal medicines derived from Tripterygium genus, have been widely used for the treatment of rheumatoid arthritis and other related inflammatory diseases in clinical therapy. In the present study, a rapid resolution liquid chromatography/electrospray ionization tandem mass spectrometry (RRLC-ESI-MS(n)) method has been developed and validated for simultaneous determination of 19 bioactive compounds including four catechins, three sesquiterpene alkaloids, four diterpenoids, and eight triterpenoids in these two similar herbs. The method validation results indicated that the developed method had desirable specificity, linearity, precision and accuracy. Quantitative analysis results showed that there were significant differences in the content of different types of compounds in T. wilfordii and T. hypoglaucum. Moreover, chemometrics methods such as one-way ANOVA, principal component analysis (PCA) and hierarchical clustering analysis (HCA) were performed to compare and discriminate the two Tripterygium herbs based on the quantitative data of analytes, and it was proven straightforward and reliable to differentiate T. wilfordii and T. hypoglaucum samples from different origins. In conclusion, simultaneous quantification of multiple-active component by RRLC-ESI-MS(n) coupled with chemometrics analysis could be a well-acceptable strategy to compare and evaluate the quality of T. wilfordii and T. hypoglaucum.
24654603 Therapeutic potential of tyrosine kinase 2 in autoimmunity. 2014 May INTRODUCTION: Tyrosine kinase 2 (Tyk2) is a Janus kinase family member that is crucial for signaling transduction in response to a wide variety of cytokines, including type I IFNs, IL-6, IL-10, IL-12 and IL-23. An appropriate expression of Tyk2-mediated signaling might be essential for maintaining normal immune responses. AREAS COVERED: This review summarizes that Tyk2 is essential for the differentiation and function of a wide variety of immune cells, including natural killer cells, B cells, as well as T helper cells. In addition, Tyk2-mediated signaling promoted the production of autoimmune-associated components, which is implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis. Aberrant expression of Tyk2 was observed in many autoimmune conditions. EXPERT OPINION: Until recently, no patent filings had claimed selective inhibitors of Tyk2. Both CP-690,500 and CMP6 failed to be used in clinical treatment due to the difficulties of finding suitable selective leads or due to detrimental toxicities. Although the result of Cmpd1 is promising, it remains to be seen how specific the Tyk2 inhibitor is and how they are working. Currently, structure-based drug design (SBDD) technology has provided us with a quite useful window for SBDD of Tyk2 inhibitors.
24599726 The AGRIculture and CANcer (AGRICAN) cohort study: enrollment and causes of death for the 2015 Jan OBJECTIVE: To elaborate and describe a large prospective agricultural cohort including males and females in France with various agricultural activities and to study causes of death. METHODS: To date, few large prospective cohorts have been conducted among agricultural population. AGRIculture and CANcer cohort is a large prospective cohort of subjects in agriculture studying cancer among active and retired males and females, farm owners and workers, living in eleven areas of France with a population-based cancer registry. RESULTS: Enrollment was conducted from 2005 to 2007 with a postal questionnaire. In January 2008, 180,060 individuals (54 % males, 54 % farm owners, 50 % retired) were enrolled. Mortality was studied until December 2009 (605,956 person-years with standardized mortality ratio (SMR) by comparison with the general population of the areas. Over this period, 11,450 deaths 6,741 in men and 4,709 in women were observed, including 3,405 cancer-related deaths. SMRs were significantly reduced for global mortality (SMR = 0.68, 95 % CI 0.67-0.70 in males and SMR = 0.71, 95 % CI 0.69-0.73 in females) and for death by cancer (SMR = 0.67, 95 % CI 0.65, 0.70 in males and SMR = 0.76, 95 % C: 0.71, 0.80 in females). These results were mainly explained by less frequent smoking-related causes of death (lung cancer, cardiovascular diseases). Nonsignificant excesses of death were observed only for rheumatoid arthritis and arthrosis, suicides (in females), death for event of undetermined intent (in males) and breast cancer in male agricultural workers. CONCLUSIONS: These first results are the first ones obtained in France based on a large prospective agricultural cohort showing that farmers would be in healthier condition than the general population.
24576203 Household members of persons with Alzheimer's disease: health conditions, healthcare resou 2014 Mar OBJECTIVES: To compare medical condition burden, healthcare resource use, and healthcare costs of household members (HHMs) of individuals diagnosed with Alzheimer's disease (AD) with those of HHMs of matched individuals without AD. DESIGN: Retrospective cohort study based on administrative claims data collected between January 1, 2007, and December 31, 2011. SETTING: Medicare Advantage Prescription Drug (MAPD) plan. PARTICIPANTS: MAPD plan members with a diagnosis of AD (International Classification of Disease Ninth Revision, Clinical Modification, code 331.0) were selected and linked to a HHM to form patient-HHM dyads. AD dyads were matched to non-AD dyads. MEASUREMENTS: Health-related endpoints, including medical condition burden, healthcare resource use, and direct healthcare costs, were measured during 36 months of continuous health plan enrollment. RESULTS: Individuals with AD (n = 1,861) were linked to HHMs (n = 1,861), and these AD dyads were matched to 1,861 non-AD patient-HHM dyads. AD HHMs had greater medical condition burden scores than non-AD HHMs, with mood disorders, anxiety disorders, insomnia, substance abuse or dependence, cardiovascular disease, and rheumatoid arthritis being more prevalent in AD HHMs. Emergency department and outpatient service use were more common in AD HHMs than in non-AD HHMs, and AD HHMs had greater healthcare costs. CONCLUSION: HHMs of individuals diagnosed with AD demonstrated greater medical condition burden, healthcare resource use, and direct healthcare costs than non-AD HHMs. These findings demonstrate the significant clinical and financial impact of AD on HHMs of individuals with AD.
24534550 Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel d 2014 Aug The Food and Drug Administration (FDA) is moving from the Crohn's Disease Activity Index to patient-reported outcomes (PROs) and objective measures of disease, such as findings from endoscopy. PROs will become an important aspect of assessing activity of inflammatory bowel disease (IBD) and for labeling specific drugs for this disease. PROs always have been considered in the management of patients with rheumatoid arthritis or multiple sclerosis, and have included measurements of quality of life, disability, or fatigue. Several disease-specific scales have been developed to assess these PROs and commonly are used in clinical trials. Outcomes reported by patients in clinical trials of IBD initially focused on quality of life, measured by the Short-Form 36 questionnaire or disease-specific scales such as the Inflammatory Bowel Disease Questionnaire or its shorter version. Recently considered factors include fatigue, depression and anxiety, and work productivity, as measured by the Functional Assessment Chronic Illness Therapy-Fatigue, the Hospital Anxiety Depression, and the Work Productivity Activity Impairment Questionnaire, respectively. However, few data are available on how treatment affects these factors in patients with IBD. Although disability generally is recognized in patients with IBD, it is not measured. The international IBD disability index currently is being validated. None of the PROs currently used in IBD were developed according to FDA guidance for PRO development. PROs will be a major primary end point of future trials. FDA guidance is needed to develop additional PROs for IBD that can be incorporated into trials, to better compare patients' experience with different therapies.
24516346 Stromal cell-derived factor-1 and its receptor CXCR4 are upregulated expression in degener 2014 BACKGROUND: Although chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 induce degradation of articular cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA), the association between the SDF-1/CXCR4 pathway and degradation of the cartilaginous endplate and nucleus pulposus has not been thoroughly clarified. We investigated the expression of SDF-1 and CXCR4 in intervertebral discs (IVDs). METHODS: SDF-1 and CXCR4 levels in human IVDs and the rat L5/6 motion segment were quantified by enzyme-linked immunosorbent assay. SDF-1 staining was quantified using a microscope and Image-Pro Plus software. Integrated optical density (IOD) served as the measurement parameter. The number of CXCR4 immunoreactive cells was expressed as a percentage of the total number of cells. RESULTS: SDF-1 and CXCR4 were both expressed in IVDs, and the levels of SDF-1 and CXCR4 were both significantly higher in the degeneration group than in the normal group of human (or rat) discs. Both nucleus pulposus cells and cartilaginous endplate cells expressed the CXCR4 protein. Furthermore, a positive correlation was observed between the SDF-1 IOD value and the percentage of CXCR4-positive disc cells in the nucleus pulposus and cartilaginous endplate. The SDF-1 IOD values were significantly higher in the outer annular fibrosus and bone/endplate junction region than in the nucleus pulposus and cartilaginous endplate in the rat specimens. CONCLUSIONS: Our findings suggest upregulated expression of SDF-1 and its receptor CXCR4 in degenerated IVD.
24450743 Cytokine networking of innate immunity cells: a potential target of therapy. 2014 May Innate immune cells, particularly macrophages and epithelial cells, play a key role in multiple layers of immune responses. Alarmins and pro-inflammatory cytokines from the IL (interleukin)-1 and TNF (tumour necrosis factor) families initiate the cascade of events by inducing chemokine release from bystander cells and by the up-regulation of adhesion molecules required for transendothelial trafficking of immune cells. Furthermore, innate cytokines produced by dendritic cells, macrophages, epithelial cells and innate lymphoid cells seem to play a critical role in polarization of helper T-cell cytokine profiles into specific subsets of Th1/Th2/Th17 effector cells or regulatory T-cells. Lastly, the innate immune system down-regulates effector mechanisms and restores homoeostasis in injured tissue via cytokines from the IL-10 and TGF (transforming growth factor) families mainly released from macrophages, preferentially the M2 subset, which have a capacity to induce regulatory T-cells, inhibit the production of pro-inflammatory cytokines and induce healing of the tissue by regulating extracellular matrix protein deposition and angiogenesis. Cytokines produced by innate immune cells represent an attractive target for therapeutic intervention, and multiple molecules are currently being tested clinically in patients with inflammatory bowel disease, rheumatoid arthritis, systemic diseases, autoinflammatory syndromes, fibrosing processes or malignancies. In addition to the already widely used blockers of TNFα and the tested inhibitors of IL-1 and IL-6, multiple therapeutic molecules are currently in clinical trials targeting TNF-related molecules [APRIL (a proliferation-inducing ligand) and BAFF (B-cell-activating factor belonging to the TNF family)], chemokine receptors, IL-17, TGFβ and other cytokines.
24395183 Norisoboldine attenuates inflammatory pain via the adenosine A1 receptor. 2014 Aug BACKGROUND: Norisoboldine (NOR) is a benzylisoquinoline alkaloid isolated from Radix Linderae, a traditional Chinese medicine. Our previous studies have demonstrated that it produces anti-inflammatory and anti-rheumatoid arthritis effects. METHODS: The present study was undertaken to explore the analgesic effects of NOR and its potential mechanism in the formalin test and the acetic acid writhing test. RESULTS: Oral administration of NOR dose dependently attenuated the formalin-induced pain responses in the second phase, and reduced formalin-induced paw oedema. It also diminished acetic acid-induced writhing responses but had no effect on acute thermal pain in the hotplate test. The mechanistic studies suggested that the adenosine system, but not the opioid receptor system, is involved in NOR-induced antinociception. Naloxone, a non-selective opioid receptor antagonist, had no effect on NOR-induced analgesic action. However, caffeine (a non-selective adenosine receptor antagonist) completely reversed the analgesic effect of NOR in formalin-induced nociceptive responses in the second phase, and 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, a selective adenosine A1 receptor antagonist) completely inhibited NOR-induced analgesia in both formalin-induced nociceptive responses and acetic acid-induced writhing responses. In addition, NOR reduced formalin-induced activation of extracellular signal-regulated kinase and calcium/calmodulin-dependent protein kinase II in the spinal cord, which is also blocked by DPCPX. Furthermore, NOR decreased forskolin-evoked cyclic adenosine monophosphate levels in mouse spinal cord neuronal cultures through the adenosine A1 receptor. CONCLUSION: Our data demonstrate that NOR produces the analgesic effect in inflammatory pain by a mechanism related to the adenosine system.
24122251 IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 p 2014 Jul It has been suggested that interleukin-6 (IL-6)plays a key role in the pathogenesis of rheumatoid arthritis(RA), including osteoporosis not only in inflamed joints but also in the whole body. However, previous in vitro studies regarding the effects of IL-6 on osteoblast differentiation are inconsistent. The aim of this study was to examine the effects and signal transduction of IL-6 on osteoblast differentiation in MC3T3-E1 cells and primary murine calvarial osteoblasts. IL-6 and its soluble receptor significantly reduced alkaline phosphatase (ALP) activity, the expression of osteoblastic genes (Runx2, osterix, and osteocalcin), and mineralization in a dose-dependent manner, which indicates negative effects of IL-6 on osteoblast differentiation. Signal transduction studies demonstrated that IL-6 activated not only two major signaling pathways, SHP2/MEK/ERK and JAK/STAT3, but also the SHP2/PI3K/Akt2 signaling pathway. The negative effect of IL-6 on osteoblast differentiation was restored by inhibition of MEK as well as PI3K, while it was enhanced by inhibition of STAT3. Knockdown of MEK2 and Akt2 transfected with siRNA enhanced ALP activity and gene expression of Runx2. These results indicate that IL-6 negatively regulates osteoblast differentiation through SHP2/MEK2/ERK and SHP2/PI3K/Akt2 pathways, while affecting it positively through JAK/STAT3. Inhibition of MEK2 and Akt2 signaling in osteoblasts might be of potential use in the treatment of osteoporosis in RA.
24101173 Higher circulating levels of OxLDL % of LDL are associated with subclinical atherosclerosi 2014 May Because systemic lupus erythematosus (SLE) is associated with a high risk of atherosclerosis, a process that involves low-density lipoprotein (LDL) oxidation, we examined the hypothesis that raised fraction of LDL that is converted to oxidized (Ox) LDL expressed in OxLDL % of LDL (OxLDL %) is associated with the subclinical atherosclerosis in SLE. A cohort of 60 SLE patients with no previous history of cardiovascular disease had carotid artery ultrasound to identify plaques and to measure intima-media thickness (IMT). Forty females with rheumatoid arthritis (RA) were also enrolled in the study to serve as a control group. Plasma OxLDL concentrations were measured, and the OxLDL % of LDL were calculated. Traditional and SLE-related risk factors for atherosclerosis were evaluated. OxLDL % were significantly higher in SLE patients compared to patients with RA (p = 0.0311). OxLDL % were significantly higher in SLE patients with plaques than in those without plaques (p < 0.001). SLE patients in the highest IMT quartile have higher OxLDL % than patients in the lower three quartiles (p < 0.001). The odd ratio (OR) for the OxLDL % in patients with plaques was 6.143 (p < 0.001) when compared to patient without plaques, while OR for the OxLDL % was 8.34 (p < 0.001) in the patients with highest IMT quartile as compared to patients in the lower three quartiles after adjustment for confounding factors in logistic regression analysis. Our data provide evidence of an association between the circulating levels of OxLDL % of LDL with the risk for developing atherosclerosis in patients with SLE.
24009135 Potential utility of rituximab for Graves' orbitopathy. 2013 Nov CONTEXT: B-Cell contribution to autoimmunity has been emphasized since the use of B-cell depleting therapies. B cells produce autoantibodies but also activate CD4+ T cells and inflammation and are important antigen-presenting cells. Several cell surface markers are targets on which B cell-depleting agents can act directly. EVIDENCE ACQUISITION: Targeting of CD20+ cells removes B lymphocytes in all intermediate stages of B-cell maturation, activated memory B, and short-lived plasma cells by depleting their immediate precursors. Rituximab (RTX) has been used off-label in various autoimmune disorders but is approved for clinical use only in non-Hodgkin's lymphoma and rheumatoid arthritis. The rationale of RTX use in Graves' disease is that blockade of pathogenic autoantibody generation might bring about Graves' hyperthyroidism remission. EVIDENCE SYNTHESIS: To date, RTX has been used in 43 patients with active Graves' orbitopathy (GO). Disease has become inactive in as many as 39 (91%), has not changed in three, and worsened in one patient. In most patients, proptosis and eye motility have been shown to improve. Side effects have been reported in about one-third of patients, usually infusion-related reactions. Because RTX does not seem to modify circulating TSH receptor antibodies, its effect may result from the blockade of antigen presentation by B cells after anti-CD20-induced lysis. CONCLUSIONS: Although evidence from controlled trials is needed before proposing RTX as a novel therapeutic tool in this disease, collected data suggest that RTX does significantly affect the activity and severity of GO. Controlled studies will also help decide whether RTX is to be used in any patients with active GO or only in those with otherwise unresponsive disease of a severe degree. The data reported on RTX therapy in GO suggest that B-cell depletion may be pursued shortly after diagnosis, and not only as a therapeutic option when standard immunosuppression has failed.
23711851 Interleukin-33 synergistically enhances immune complex-induced tumor necrosis factor alpha 2013 BACKGROUND: Substantial evidence suggests that human synovial mast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-33 is believed to play an important role in the pathogenesis of RA. We recently reported that FcγRI is responsible for producing abundant tumor necrosis factor alpha (TNF-α) from cultured synovium-derived MCs (SyMCs) in response to aggregated immunoglobulin G (IgG). However, whether or not IL-33 affects immune complex (IC)-induced synovial MC activation remains unknown. This study sought to evaluate the effect of IL-33 on IC-induced synovial MC activation. METHODS: Cultured SyMCs were generated by culturing synovial cells with stem cell factor. ST2 expression was analyzed using FACS and immunohistochemical techniques. Mediators released from the MCs were measured using EIAs or ELISAs. RESULTS: SyMCs obtained from patients with RA or osteoarthritis (OA) expressed ST2 on their surfaces. We confirmed the expression of ST2 in MCs using immunofluorescence staining in joint tissue obtained from RA patients. IC-triggered histamine release was not enhanced by IL-33. However, IL-33 synergistically enhanced IC-induced IL-8 and TNF-α production in SyMCs. CONCLUSIONS: ICs and IL-33 may exacerbate inflammation associated with RA by abundantly producing TNF-α and IL-8 from SyMCs.
23632741 Elevated miR-29a expression is not correlated with disease activity index in PBMCs of pati 2013 Apr 30 OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by new bone formation. Recent evidence suggests that new bone formation in AS may be due to upregulation of Wnt signaling in the osteoblastic pathway secondary to low serum Dickkopf homolog 1 (Dkk-1) levels. And miR-29a orchestrates osteoblast differentiation through direct targeting and negative regulation of Dkk-1. METHODS: We initially validated the expression levels of miR-29a in the peripheral blood mononuclear cells (PBMCs) of AS patients (n = 30), rheumatoid arthritis (RA) patients (n = 30) and healthy controls (n = 30) using real-time quantitative reverse transcription PCR (qRT-PCR). Correlation analysis was assessed between miR-29a level in PBMCs of AS patients and disease activity indexes, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis function index (BASFI) and modified Stoke ankylosing spondylitis spinal score (mSASSS). RESULTS: Significantly higher expression of miR-29a was observed in PBMCs of AS patients (Ct 9.18 ± 1.96) compared with that in RA patients (10.97 ± 0.70, p < 0.001) and healthy controls (Ct 11.45 ± 1.23, p < 0.001). There was no significant difference between RA patients and healthy controls in miR-29a expression (p > 0.05). Elevated miR-29a expression is not correlated with disease activity index (p > 0.05). A weak correlation was found between elevated miR-29a expression and mSASSS (r = -0.393, p = 0.032). CONCLUSIONS: We report for the first time elevated miR-29a expression in PBMCs of patients with ankylosing spondylitis, and miR-29a might be used as a useful diagnostic marker in new bone formation but cannot reflect disease activity.
23622762 Emotional modulation of pain and spinal nociception in fibromyalgia. 2013 Jul Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (eg, depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in 4 blocks; 2 blocks assessed only physiological-emotional reactions (ie, pleasure/arousal ratings, corrugator electromyography, startle modulation, skin conductance) in the absence of pain, and 2 blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (eg, reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all 3 groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes.
23620516 Characterization of pathogenic human monoclonal autoantibodies against GM-CSF. 2013 May 7 The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.
23582575 FEV1 over time in patients with connective tissue disease-related bronchiolitis. 2013 Jun BACKGROUND: Fibrosis or inflammation of the bronchioles is a well-known manifestation of connective tissue disease (CTD). However, the natural history of CTD-related bronchiolitis is largely unknown. METHODS: We analyzed consecutive patients evaluated at National Jewish Health (Denver, CO) from 1998 to 2008 with CTD and surgical lung biopsy-confirmed bronchiolitis. Linear mixed effects models were used to estimate the longitudinal postbronchodilator FEV1 %predicted (%pred) course and differences between subjects with or without constrictive bronchiolitis (CB). RESULTS: Of 28 subjects with a mean age of 53 ± 9 years, fourteen (50%) had CB. The most common CTD diagnosis was rheumatoid arthritis (n = 14; 50%). There were no significant differences in demographics, smoking status, underlying CTD diagnoses, 6-min walk distance, dyspnea score or drug therapy between subjects with CB and those with cellular bronchiolitis. Three subjects with CB (11%) and four with cellular bronchiolitis (14%) died. Compared with subjects with CB, those with cellular bronchiolitis had higher mean FEV1 %pred at all times. There were no significant differences in FEV1 %pred slope within- or between-groups (CB vs. cellular bronchiolitis) preceding surgical lung biopsy or afterward. CONCLUSION: Subjects with CTD-related CB had lower FEV1 %pred values than those with CTD-related cellular bronchiolitis at all time points, but FEV1 %pred remained stable over time in both groups regardless of therapy received.
23565673 Subsequent leukaemia in autoimmune disease patients. 2013 Jun Previous studies have shown that patients diagnosed with some autoimmune (AI) diseases are at an increased risk of leukaemia but limited data are available on survival. We systematically analysed the risks (standardized incidence ratio, SIR) and survival (hazard ratio, HR) in nine types of leukaemia among 402 462 patients hospitalized for any of 33 AI diseases and compared to persons not hospitalized for AI diseases. Risk for all leukaemia was increased after 13 AI diseases and survival was decreased after six AI diseases. SIRs were increased after all AI diseases for seven types of leukaemia, including SIR 1·69 (95% confidence interval (CI): 1·29-2·19) for acute lymphoblastic leukaemia (ALL), 1·85 (95% CI: 1·65-2·07) for acute myeloid leukaemia, 1·68 (95% CI: 1·37-2·04) for chronic myeloid leukaemia, 2·20 (95% CI: 1·69-2·81) for 'other myeloid leukaemia', 2·45 (95% 1·99-2·98) for 'other and unspecified leukaemia', 1·81 (95% CI: 1·11-2·81) for monocytic leukaemia, and 1·36 (95% CI: 1·08-1·69) for myelofibrosis. The HRs were increased for four types of leukaemia, most for myelofibrosis (1·74, 95% CI: 1·33-2·29) and ALL (1·42, 95% CI: 1·03-1·95). Some AI diseases, including rheumatoid arthritis, were associated with increased SIRs and HRs in many types of leukaemia. The present data showed increases in risk and decreases in survival for many types of leukaemia after various AI diseases. Leukaemia is a rare complication in AI disease but findings about this comorbidity at the time of leukaemia diagnosis may help to optimize the treatment and improve survival.
23833800 Optimization and characterization of a pan protein arginine deiminase (PAD) inhibitor. 2010 The protein arginine deiminases (PADs) are a family of Ca(2+)-dependent enzymes that catalyze the conversion of peptidyl-arginine to peptidyl-citrulline in numerous protein substrates. Disruption of normal PAD activity plays a role in the pathogenesis of multiple inflammatory diseases such as rheumatoid arthritis (RA), chronic obstructive pulmonary disease, ulcerative colitis, multiple sclerosis, psoriasis, Alzheimer’s disease, and in various cancers. PAD inhibitors described in the literature have been useful chemical tools to study the role of PAD enzymes in inflammatory diseases and cancer biology. Most published PAD inhibitors are mechanism-based inactivators belonging to the halogen-amidine chemotype. For emerging targets such as the PADs, it can be difficult to distinguish compound-specific effects from those truly resulting from enzyme inhibition. We therefore initiated a fluorescence polarization activity-based protein profiling (fluopol-ABPP) high throughput screening (HTS) campaign to identify a second PAD inhibitor chemotype. The PAD4 HTS campaign identified the natural product streptonigrin (SID 11532976) as an irreversible PAD4-specific inhibitor. We describe herein the medicinal chemistry optimization of streptonigrin to the pan PAD probe ML325 (SID 118043677). ML325 inhibits PAD1, 2, 3, and 4 in vitro with IC50 values of 70 nM, 200 nM 170 nM, and 240 nM respectively. In a kinetic assay of inhibition more appropriate for irreversible inhibitors, ML325 has k(inact)/K(I) values of 3500, 7300, 1900, and 5300 M(−1)min(−1) for PAD1, 2, 3 and 4 respectively; indicating it has less than 4-fold selectivity among the four family members. Despite its promiscuity within the PAD family, ML325 exhibits high selectivity vs. more than 20 cysteine-reactive proteins as assayed by activity-based protein profiling. ML325 was also demonstrated to inhibit all four PAD isozymes irreversibly and to be non-cytotoxic to NIH-3T3 cells. The complete properties, characterization, and synthesis of ML325 are detailed in this report.
23531543 Toll-like receptors as therapeutic targets for autoimmune connective tissue diseases. 2013 Jun Autoimmune connective tissue diseases (ACTDs) are a family of consistent systemic autoimmune inflammatory disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc) and Sjögren's syndrome (SS). IL-1R-like receptors (TLRs) are located on various cellular membranes and sense exogenous and endogenous danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), playing a critical role in innate immune responses. During the past decade, the investigation of TLRs in inflammatory autoimmune diseases has been fruitful. In this report, we review the significant biochemical, physiological and pathological studies of the key functions of TLRs in ACTDs. Several proteins in the TLR signaling pathways (e.g., IKK-2 and MyD88) have been identified as potential therapeutic targets for the treatment of ACTDs. Antibodies, oligodeoxyribonucleotides (ODNs) and small molecular inhibitors (SMIs) have been tested to modulate TLR signaling. Some drug-like SMIs of TLR signaling, such as RDP58, ST2825, ML120B and PHA-408, have demonstrated remarkable potential, with promising safety and efficacy profiles, which should warrant further clinical investigation. Nonetheless, one should bear in mind that all TLRs exert both protective and pathogenic functions; the function of TLR4 in inflammatory bowel disease represents such an example. Therefore, an important aspect of TLR modulator development involves the identification of a balance between the suppression of disease-inducing inflammation, while retaining the beneficiary host immune response.