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ID PMID Title PublicationDate abstract
23771531 Molecular structure and physicochemical properties of pepsin-solubilized type II collagen 2013 Jun BACKGROUND AND OBJECTIVES: Recently, type II collagen (CII) was found to be effective clinically for treatment of rheumatoid arthritis (RA). However, the molecular properties of CII could be changed during the preparation process. In the present study, we isolated CII from chick sternal cartilage and studied the structural characteristics of purified CII. MATERIALS AND METHODS: Pepsin-solubilized CII was purified from sternal cartilage of the chick using a combination of pepsin digestion, NaCl precipitation and DEAE-Sepharose CL 6B ion exchange chromatography. Then, the molecular structure and physicochemical properties of pepsin-solubilized CII were investigated. RESULTS: According to the electrophoretic patterns, the purified preparation consisted of a single band (α chain) and dimmers (β chains) with a subunit Mr of 110 kDa, were characterized to type II, and contained imino acid of 232 residues/1000 residues. The maximum transition temperature (Tmax) of the pepsin-solubilized CII measured by DSC was 45.60°C. Circular dichroism (CD) spectra analysis revealed that pepsin-solubilized CII retained more intermolecular crosslinks during the preparation process. Investigation results of atomic force microscope (AFM) indicated that the collagen fibrils from chick cartilage were about 146 nm in width and highly periodic with a banding pattern of -68.3 nm spacing. Analysis of physical properties indicated that pepsin-solubilized CII were highly solubilized in the pH range of 1-3.5 and the optimal NaCl concentration was 0.6 mol/L. CONCLUSIONS: Chick sternal cartilage can be used as an alternative CII source.
23771077 Disseminated granuloma annulare: study on eight cases. 2013 Granuloma annulare (GA) is classified as localized, generalized/disseminated, subcutaneous, and perforating types. The studies show connection with diabetes mellitus, lipidic metabolic disorders, malignant diseases, thyroid disorders, infections (HBV, HCV, HIV). We performed a retrospective study between 2010-2011, regarding disseminated GA (GAD), and the relationship between GAD and other comorbidities. We clinically and histologically diagnosed eight cases of GAD. The patients were also investigated for the diagnosis of associated diseases. The treatment included topical corticosteroids, antihistamines, Calcipotriol/Betamethasone, Tacrolimus 0.03%, Pentoxifylline, Hydroxychloroquine. Therapeutic response was assessed one month and three months after hospitalization. Our patients were five women and three men, aged 46-68 years, mean age 57.25 years, with a disease history of one year and a half (between three months and four years). The lesions occurred in the upper extremities (eight cases), distal extremities (three cases), cervical area (two cases), and trunk (five cases). In seven cases, we found annular appearance and one patient had disseminated small papules eruption. Associated pathology was diabetes mellitus type II (five cases), overweight and obesity (five cases), dyslipidemia (three cases), hypothyroidism (one case), rheumatoid arthritis (one case), external ear canal basal carcinoma (one case). Although there is controversy regarding the relationship between GAD and associated diseases, it is accepted that it is significantly associated with diabetes mellitus, also found in our study in five out of eight cases. We noticed obvious improvements after local and general treatment. It is confirmed that GAD is prevalent in women, over 40-year-old. GAD is often associated with diabetes and dyslipidemia, therefore it is necessary to investigate patients in this direction. The histopathological exam is essential for an accurate confirmation of GA.
23669873 Historic condition in a modern child with autism. 2013 May Haven is an 11-year-old primary care patient who you have followed since her birth. She was the 9 lb 6 oz product of a 38-week gestation complicated by maternal hypertension and seizure disorder treated with tegretol. Her delivery and neonatal course were uneventful. She was diagnosed with austistic disorder at age 2 years, at which time she used no functional language or gestures, had repetitive motor mannerisms, and limited eye contact. She had strong tactile sensory aversions. Her diet was very restricted including only banana yogurt and drinking milk and apple juice for the first several years of life. She was followed by a developmental-behavioral pediatrician approximately annually through age 8 years and then more frequently. She was healthy other than lead exposure (maximum serum level 18 at age 3 years) and multiple febrile seizures with other possible absence episodes. Her development remained very delayed with use of single words and short phrases. She developed multiple repetitive, anxious, obsessive behaviors (picking up lint, organizing, cleaning, and freezing in certain postures) that were treated with a selective serotonin reuptake inhibitors fluvoxamine. Sensory issues were ongoing, with restrictive eating (primarily peanut butter and jelly sandwiches, cereal bars, milk, and a kiwi-strawberry drink). She took a liquid multivitamin until age 8.At age 11 years, 3 weeks prior to admission, Haven developed acute loss of ambulation over the course of 1 day, initially dragging her right leg, and then refusing to walk and her parents brought her in to see you. She had fever, vomiting, and general weakness. She developed extensive bruising over her legs, especially in the popliteal fossae. She was also noted to have friability and dark discoloration of her gums. Initially, you suspected a post-viral syndrome and close monitoring. She was seen twice in the next 2 weeks in a local emergency room where her erythrocyte sedimentation rate was reported to be elevated and juvenile rheumatoid arthritis or a reaction to fluvoxamine were suspected. Antibiotics were also prescribed for gingivitis. She was seen by an orthopedist who felt it was not an orthopedic issue and leg films were unremarkable. With her second emergency room visit, she was transferred to a tertiary medical center and admitted for further evaluation. Where would you go from here?
23649812 Targeting potassium channels Kv1.3 and KC a 3.1: routes to selective immunomodulators in a 2013 May The Kv1.3 and KC a 3.1 potassium channels are promising targets for the treatment of autoimmune disorders. Many Kv1.3 and KC a 3.1 blockers have a more favorable adverse event profiles than existing immunosuppressants, suggesting the selectivity of Kv1.3 and KC a 3.1 blockade. The Kv1.3 and KC a 3.1 blockers exert differential effects in different autoimmune diseases. The Kv1.3 inhibitors or gene deletion have been shown to have benefits in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, and rapidly progressive glomerulonephritis. The KC a 3.1 blockers have demonstrated efficacy in human primary biliary cirrhosis and showed protective effects in animal models of severe colitis, allergic encephalomyelitis, inflammatory bowel disease, and multiple sclerosis. The KC a 3.1 blockers are not considered candidates for treatment of multiple sclerosis. The selective immunosuppressive effects of the Kv1.3 and KC a 3.1 blockers are due to the differences in their distribution on autoimmune-related immune cells and tissues and β1 integrin (very late activating antigen)-Kv1.3 channel cross-talk.
23641923 Use of folate-conjugated imaging agents to target alternatively activated macrophages in a 2013 May 6 Pro-inflammatory macrophages play a prominent role in such autoimmune diseases as rheumatoid arthritis, Crohn's disease, psoriasis, sarcoidosis, and atherosclerosis. Because pro-inflammatory macrophages have also been shown to overexpress a receptor for the vitamin folic acid (i.e., folate receptor beta; FR-β), folate-linked drugs have been explored for use in imaging and treatment of these same diseases. To determine whether allergic inflammatory disorders might be similarly targeted with folate-linked drugs, we have examined the characteristics of macrophages that are prominent in the pathogenesis of asthma. We report here that macrophages from the lungs of mice with experimental allergic asthma express FR-β. We further document that these FR-β(+) macrophages coexpress markers of alternatively activated (M2-type) macrophages, including the mannose receptor and arginase-1. Finally, we demonstrate that folate-conjugated fluorescent dyes and radioimaging agents can be specifically targeted to these asthmatic lung macrophages, with little uptake by macrophages present in healthy lung tissue. These data suggest strategies for the development of novel diagnostic agents for the imaging of asthma and other diseases involving alternatively activated macrophages.
23637551 RANTES and fibroblast growth factor 2 in jawbone cavitations: triggers for systemic diseas 2013 BACKGROUND: Jawbone cavitations (JC) are hollow dead spaces in jawbones with dying or dead bone marrow. These areas are defined as fatty degenerative osteonecrosis of the jawbone or neuralgia-inducing cavitational osteonecrosis and may produce facial pain. These afflictions have been linked to the immune system and chronic illnesses. Surgical debridement of JC is reported to lead to an improvement in immunological complaints, such as rheumatic, allergic, and other inflammatory diseases (ID). Little is known about the underlying cause/effect relationship. OBJECTIVES: JC bone samples were analyzed to assess the expression and quantification of immune modulators that can play a role in the pathogenesis of IDs. The study supports a potential mechanism where JC is a mediating link in IDs. MATERIALS AND METHODS: Samples of fatty softened bone taken from JCs were extracted from 31 patients. The specimens were analyzed by bead-based multiplex technology and tested for seven immune messengers. RESULTS: Regulated upon activation, normal T-cell expressed, and secreted (RANTES) and fibroblast growth factor (FGF)-2 were found at high levels in the JCs tested. Other cytokines could not be detected at excessive levels. DISCUSSION: The study confirms that JC is able to produce inflammatory messengers, primarily RANTES, and, secondarily, FGF-2. Both are implicated in many serious illnesses. The excessive levels of RANTES/FGF-2 in JC patients with amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, and breast cancer are compared to levels published in medical journals. Levels detected in JCs are higher than in the serum and cerebrospinal fluid of amyotrophic lateral sclerosis and multiple sclerosis patients and four-fold higher than in breast cancer tissue. CONCLUSION: This study suggests that JC might serve as a fundamental cause of IDs, through RANTES/FGF-2 production. Thus, JC and implicated immune messengers represent an integrative aspect of IDs and serve as a possible cause. Removing JCs may be a key to reversing IDs. There is a need to raise awareness about JC throughout medicine and dentistry.
23579459 Pharmacology of the sphingosine-1-phosphate signalling system. 2013 The recent success of FTY720 (Fingolimod, Gilenya(®)), which has been approved for the treatment of relapsing-remitting multiple sclerosis and is the first-in-class sphingosine-1-phosphate (S1P) receptor modulating drug, has boosted the interest in further drug development in this area. Several selective S1P1 receptor-modulating drugs are being investigated in clinical trials for the treatment of diverse autoimmune disorders. Sphingosine kinase inhibitors are under development for the treatment of cancer, aberrant angiogenesis and inflammatory diseases; an inhibitor of SK2 with relatively low affinity is being analysed in patients with advanced solid tumours. While an indirect S1P lyase inhibitor has just failed the proof of concept in patients with rheumatoid arthritis, S1P lyase is still a promising target for the treatment of inflammatory and autoimmune diseases. Another approach is the development of S1P-scavenging or -clearing agents, including a monoclonal S1P antibody that has successfully passed phase I clinical trials and will be further developed for age-related macular degeneration.
23546732 Anticardiolipin antibody and anti-beta 2 glycoprotein I antibody assays. 2013 Antiphospholipid syndrome (APS) is an autoimmune disease and is a risk factor for a number of clinical manifestations; the classic presentations include fetal death or thrombosis (arterial or venous thromboembolism), in the presence of persistently increased titers of antiphospholipid (aPL) antibodies. The actual cause of APS is unknown but thought to be multifactorial. The disease is characterized by the presence of a heterogenous population of autoantibodies against phospholipid-binding proteins. APS presents either in isolation with no evidence of an underlying disease or in concert with an autoimmune disease such as systemic lupus erythematosus or rheumatoid arthritis. The wide diversity in clinical presentation often causes difficulty in identifying and treating patients and therefore a concise laboratory report containing interpretative comments is required to provide needed guidance to the clinician. For a diagnosis of APS to be made both clinical and laboratory classification criteria must be met. Laboratory testing to identify aPL antibodies includes lupus anticoagulant (liquid-based clotting assays) and immunological solid-phase assays (usually enzyme-linked immunosorbent assay formats) for IgG and/or IgM anticardiolipin (aCL) antibodies and anti-beta 2 glycoprotein I (β2-GPI) antibodies. Other autoantibodies, such as those directed against anionic phospholipids, can also be assayed; however they are not of clinical significance. Participation in a quality assurance program and an in-depth technical and clinical understanding of testing for aPL antibodies are required, as methods are limited by poor robustness, reproducibility, specificity, and standardization. Testing is further complicated by the lack of a "gold standard" laboratory test to diagnose or classify a patient as having APS. This chapter discusses the clinical and laboratory theoretical and technical aspects of aCL and anti-β2GPI antibody assays.
23357309 Microfluidics assisted synthesis and bioevaluation of sinomenine derivatives as antiinflam 2013 Apr Sinomenine (1) is currently used for the treatment of rheumatoid arthritis (RA) in China and there is still room for the improvement of its efficacy. In present study, capillary based microfluidic system was effectively applied for the syntheses of two novel series of sinomenine derivatives. The Heck reactions in microreactor gave much higher conversions compared to the batch ones. The two-step synthesis of the isoxazoline in microreactor greatly shortened the reaction time without any isolation of intermediates. The inhibitory activity of synthesized compounds on the TNF-α-induced nuclear factor kappa B (NF-κB) activation was evaluated in vitro. Among the compounds, 3c and 3g showed the potent inhibitory activity. Furthermore, 3g exhibited the antiinflammatory effect in vivo.
23334563 Incidence of potential drug interactions in medication prescriptions for children and adol 2013 May Drug interactions are important potential causes of adverse drug reactions. However, studies of their occurrence in children are almost entirely lacking. This study evaluates the incidence of potential drug interactions (PDIs) in medication prescriptions for children. The study was performed at the University Hospital in Olomouc. PDIs in each patient's prescriptions were identified. Multivariate analysis was performed in order to assess the risk factors confounding the potential interactions. Univariate analysis was used to assess which diagnostic groups and medication groups significantly increase or lower the odds of a potential drug-drug interaction. A total of 6,078 patients meeting the inclusion criteria entered the study. They received 19,522 prescriptions. PDIs were identified in 3.83 % of patients (moderate-to-severe cases in 0.47 %). Patient age (p = 0.008), the average number of prescriptions per visit (p < 0.0001), and the number of visits per year (p < 0.0001) were found to increase the risk of drug interaction. The presence of epilepsy, leukemia, or rheumatoid arthritis and related disease diagnoses were discovered to increase the risk of PDIs significantly. CONCLUSION: The risk of PDIs in children is low, but it increases significantly with age and the number of drugs prescribed, particularly antiepileptics and immunosuppressants. The finding of a potential interaction in 0.47 % of all children in whom any medication was prescribed should not be underestimated since it means a significant risk for one child out of every 200, and it is also substantially higher in the chronically ill. Pediatricians should be aware of relevant interactions and should prevent them by therapeutic drug monitoring or appropriate clinical and laboratory monitoring.
23279749 The patient acceptable symptom state of chronic musculoskeletal pain measured on a visual 2013 Jan OBJECTIVES: The patient acceptable symptom state (PAccSS) is the value beyond which patients consider themselves well. Our aim was to determine the PAccSS of chronic pain in Moroccan outpatients suffering from chronic rheumatic diseases and to identify contributors to PAccSS. METHODS: A 4-week prospective study of 387 outpatients suffering from chronic rheumatic diseases was carried out. Pain level was evaluated using a 0-100 mm visual analog scale. An anchoring method based on patient's opinion was used. The PAccSS was defined as the 75th percentile of the score for patients who considered their state satisfactory. Pearson's chi-square and binary logistic regression were used to analyze the data. RESULTS: The underlying disease of the patients (mean age 50 ± 13 years; female sex 70%) was rheumatoid arthritis (N = 102), ankylosing spondylitis (N = 100), peripheral osteoarthritis (N = 100), and degenerative back pain (N = 85). The mean disease duration was 7.4 ± 6.7 years. At the time of the study, the level of pain was 44 ± 23 mm. One hundred ninety (49%) patients considered their state as satisfactory, and the PAccSS threshold was 50 mm. Significant contributors to PAccSS were high educational level, high socioeconomic status, higher functional status scores, and shorter term disease duration. CONCLUSION: Half of patients were satisfied of their disease state, while the PAccSS threshold of pain was unexpectedly high. This could be explained by an overestimation of the pain intensity or a Moroccan patients' high tolerance to pain. The main protective factors that contribute to achieving the PAccSS were high educational level, high socioeconomic status, higher functional status, and shorter term disease duration.
25258655 Accounting for linkage disequilibrium in genome-wide association studies: A penalized regr 2013 Jan 1 Penalized regression methods are becoming increasingly popular in genome-wide association studies (GWAS) for identifying genetic markers associated with disease. However, standard penalized methods such as LASSO do not take into account the possible linkage disequilibrium between adjacent markers. We propose a novel penalized approach for GWAS using a dense set of single nucleotide polymorphisms (SNPs). The proposed method uses the minimax concave penalty (MCP) for marker selection and incorporates linkage disequilibrium (LD) information by penalizing the difference of the genetic effects at adjacent SNPs with high correlation. A coordinate descent algorithm is derived to implement the proposed method. This algorithm is efficient in dealing with a large number of SNPs. A multi-split method is used to calculate the p-values of the selected SNPs for assessing their significance. We refer to the proposed penalty function as the smoothed MCP and the proposed approach as the SMCP method. Performance of the proposed SMCP method and its comparison with LASSO and MCP approaches are evaluated through simulation studies, which demonstrate that the proposed method is more accurate in selecting associated SNPs. Its applicability to real data is illustrated using heterogeneous stock mice data and a rheumatoid arthritis.
23147107 Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and media 2013 Jan In addition to the proinflammatory cytokines tumor necrosis factor-α, interleukin-6 and interleukin-1ß, the cytokine interleukin-17 (IL-17) is considered an important mediator of autoimmune diseases such as rheumatoid arthritis. Because tumor necrosis factor-α and interleukin-1ß have the potential to influence the expression of transduction molecules such as transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons and thus to contribute to pain we explored in the present study whether IL-17A activates DRG neurons and influences the expression of TRPV1. The IL-17A receptor was visualized in most neurons in dorsal root ganglion (DRG) sections as well as in cultured DRG neurons. Upon long-term exposure to IL-17A, isolated and cultured rat DRG neurons showed a significant upregulation of extracellular-regulated kinase (ERK) and nuclear factor κB (NFκB). Long-term exposure of neurons to IL-17A did not upregulate the expression of TRPV1. However, we found a pronounced upregulation of transient receptor potential vanilloid 4 (TRPV4) which is considered a candidate transduction molecule for mechanical hyperalgesia. Upon the injection of zymosan into the paw, IL-17A-deficient mice showed less mechanical hyperalgesia than wild type mice but thermal hyperalgesia was not attenuated in IL-17A-deficient mice. These data show, therefore, a particular role of IL-17 in mechanical hyperalgesia, and they suggest that this effect is linked to an activation and upregulation of TRPV4.
25043127 NF-κB-inducing kinase is a key regulator of inflammation-induced and tumour-associated an 2014 Nov Angiogenesis is essential during development and in pathological conditions such as chronic inflammation and cancer progression. Inhibition of angiogenesis by targeting vascular endothelial growth factor (VEGF) blocks disease progression, but most patients eventually develop resistance which may result from compensatory signalling pathways. In endothelial cells (ECs), expression of the pro-angiogenic chemokine CXCL12 is regulated by non-canonical nuclear factor (NF)-κB signalling. Here, we report that NF-κB-inducing kinase (NIK) and subsequent non-canonical NF-κB signalling regulate both inflammation-induced and tumour-associated angiogenesis. NIK is highly expressed in endothelial cells (ECs) in tumour tissues and inflamed rheumatoid arthritis synovial tissue. Furthermore, non-canonical NF-κB signalling in human microvascular ECs significantly enhanced vascular tube formation, which was completely blocked by siRNA targeting NIK. Interestingly, Nik(-/-) mice exhibited normal angiogenesis during development and unaltered TNFα- or VEGF-induced angiogenic responses, whereas angiogenesis induced by non-canonical NF-κB stimuli was significantly reduced. In addition, angiogenesis in experimental arthritis and a murine tumour model was severely impaired in these mice. These studies provide evidence for a role of non-canonical NF-κB signalling in pathological angiogenesis, and identify NIK as a potential therapeutic target in chronic inflammatory diseases and tumour neoangiogenesis.
23983073 A regulatory variant in CCR6 is associated with susceptibility to antitopoisomerase-positi 2013 Dec OBJECTIVE: Recognition of the well-known pleiotropism of autoimmune genes supports the concept of a shared pathogenesis across autoimmune diseases such as rheumatoid arthritis (RA) and systemic sclerosis (SSc). Studies have reproducibly demonstrated an association between susceptibility to RA and polymorphisms of the CCR6 gene, a surface marker for Th17 cells, and the causal variant was recently identified. The present study was thus undertaken to investigate whether CCR6 polymorphisms could also be associated with susceptibility to SSc. METHODS: Twelve tag single-nucleotide polymorphisms (SNPs) of CCR6, including the known RA-associated SNP rs3093023, were genotyped in a total of 2,411 SSc patients and 7,084 healthy individuals from 3 European populations (France, Italy, and Germany). Meta-analyses of the data were performed to assess whether an association exists between CCR6 polymorphisms and susceptibility to SSc or its main subtypes. Direct sequencing of DNA was performed to ascertain whether the functional dinucleotide polymorphism of CCR6 previously identified in RA (CCR6DNP) was also present in SSc. RESULTS: Combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility (odds ratio [OR] 1.13, 95% confidence interval [95% CI] 1.05-1.21, adjusted P [P(adj)] = 0.026). The rs3093023 A allele and rs10946216 T allele were in high linkage disequilibrium, and both were found to confer disease susceptibility in the antitopoisomerase-positive subset of SSc patients (OR 1.27, 95% CI 1.13-1.42, P(adj) = 1.5 × 10(-3) and OR 1.32, 95% CI 1.17-1.48, P(adj) = 9.0 × 10(-5), respectively, relative to healthy controls). Direct sequencing of the DNA of 78 individuals supported the hypothesis that the regulatory dinucleotide CCR6DNP could be the causal variant in SSc. CONCLUSION: The results of this study establish CCR6 as a new susceptibility factor for antitopoisomerase-positive SSc, as demonstrated in 3 European Caucasian populations, confirming the notion that SSc and RA could conceivably share autoimmune risk alleles. The results also suggest a potential role of the interleukin-17 pathway in SSc.
23692684 Water extract of Spatholobus suberectus inhibits osteoclast differentiation and bone resor 2013 May 21 BACKGROUND: Osteoclasts are primarily responsible for bone resorption. In many pathological bone diseases including osteoporosis and rheumatoid arthritis, osteoclasts are excessively activated. Thus, controlling of osteoclasts would be an effective therapeutic strategy for the treatment of excessive bone loss. The stem of Spatholobus suberectus has been widely used in traditional medicine to treat blood stasis syndrome and arthritis in Asia. In the present study, we investigated the effects and action mechanism of water extract of the stem of Spatholobus suberectus (WESS) on osteoclast differentiation and function. METHODS: The effect of WESS on osteoclast differentiation was evaluated by counting tartrate resistant acid phosphatase-positive multinucleated cells in bone marrow-derived macrophages system and murine bone marrow cell-osteoblast coculture system. Bone resorption activity of mature osteoclast was examined on a calcium phosphate-coated plate. Actin ring structure of osteoclasts was detected fluorescently by staining for F-actin. Activation of signaling pathways and induction of transcription factors required for osteoclastogenesis were investigated by real-time PCR and Western blotting. RESULTS: WESS effectively inhibited osteoclast differentiation from its precursors. The inhibitory effect of WESS on osteoclast differentiation was due to the suppression of osteoclastogenic transcription factors, c-Fos and nuclear factor of activated T cells cytoplasmic 1 expression, via preventing receptor activator of nuclear factor-κB ligand-induced early signaling pathways and decreasing c-Fos protein level in osteoclast precursors. Furthermore, WESS suppressed bone resorption activity of osteoclasts by disrupting actin ring structure. CONCLUSIONS: This study demonstrated that WESS inhibits osteoclast differentiation and function. These results suggest that WESS has a potential for treating pathological bone diseases caused by excessive bone resorption.
24265897 A rare presentation of Henoch-Schönlein purpura and myocardial infarction at the 5th deca 2013 Jun Henoch-Schönlein purpura is an IgA-mediated, autoimmune, hypersensitivity vasculitis of childhood that results in a triad of symptoms, including a purpuric rash occurring on the lower extremities, abdominal pain or renal involvement, and arthritis. However, any of the triad may be absent, which often leads to a confusion in diagnosing the condition. Although the cause is unknown, Henoch-Schönlein purpura (HSP) is often associated with infectious agents, such as group A streptococci and mycoplasma. It has also been associated with food reactions, exposure to cold, insect bites, and drug allergies. The treatment is supportive and needs close followup of renal status. This report describes a rare presentation of Henoch-Schönlein purpura with coronary vasculitis which leads to myocardial infarction at the age of 53. Henoch-Schönlein purpura was diagnosed on the basis of no infection, accelerated ESR (35 mm/h), normal platelet count, positive skin biopsy, proteinuria, and negative searches for rheumatoid factor (RF), antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies (ANCA), and anti-dsDNA.
25500708 An autoimmune myositis-overlap syndrome associated with autoantibodies to nuclear pore com 2014 Nov Autoimmune myositis encompasses various myositis-overlap syndromes, each being identified by the presence of serum marker autoantibodies. We describe a novel myositis-overlap syndrome in 4 patients characterized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes. The clinical phenotype was characterized by prominent myositis in association with erosive, anti-CCP, and rheumatoid factor-positive arthritis, trigeminal neuralgia, mild interstitial lung disease, Raynaud phenomenon, and weight loss. The myositis was typically chronic, relapsing, and refractory to corticosteroids alone, but remitted with the addition of a second immunomodulating drug. There was no clinical or laboratory evidence for liver disease. The prognosis was good with 100% long-term survival (mean follow-up 19.5 yr).By indirect immunofluorescence on HEp-2 cells, sera from all 4 patients displayed a high titer of antinuclear autoantibodies (ANA) with a distinct punctate peripheral (rim) fluorescent pattern of the nuclear envelope characteristic of nuclear pore complexes. Reactivity with nuclear pore complexes was confirmed by immunoelectron microscopy. In a cohort of 100 French Canadian patients with autoimmune myositis, the nuclear pore complex fluorescent ANA pattern was restricted to these 4 patients (4%). It was not observed in sera from 393 adult patients with systemic sclerosis (n = 112), mixed connective tissue disease (n = 35), systemic lupus (n = 94), rheumatoid arthritis (n = 45), or other rheumatic diseases (n = 107), nor was it observed in 62 normal adults.Autoantibodies to nuclear pore complexes were predominantly of IgG isotype. No other IgG autoantibody markers for defined connective tissue diseases or overlap syndromes were present, indicating a selective and highly focused immune response. In 3 patients, anti-nuclear pore complex autoantibody titers varied in parallel with myositis activity, suggesting a pathogenic link to pathophysiology. The nuclear pore complex proteins, that is, nucleoporins (nup), recognized by these sera were heterogeneous and included Nup358/RanBP2 (n = 2 patients), Nup90 (n = 1), Nup62 (n = 1), and gp210 (n = 1). Taken together the data suggest that nup autoantigens themselves drive the anti-nup autoimmune response. Immunogenetically, the 4 patients shared the DQA1*0501 allele associated with an increased risk for autoimmune myositis.In conclusion, we report an apparent novel subset of autoimmune myositis in our population of French Canadian patients with connective tissue diseases. This syndrome is recognized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes that react with nups, consistent with an "anti-nup syndrome."
24268386 Comparison of apparent diffusion coefficient in spondylarthritis axial active inflammatory 2014 Feb OBJECTIVE: The goal of this study was to evaluate whether the values of ADC in spondylarthritis axial active inflammatory lesions are different from ADC values in type 1 Modic changes. SUBJECTS AND METHODS: 95 patients with recent lumbar pain, including 46 patients with diagnosed or suspected spondylarthritis and 49 patients with purely degenerative history, underwent spine MRI. T1w, STIR, and diffusion-weighted images (DWI) were obtained. Two musculoskeletal radiologists interpreted the images. Axial active inflammatory lesions from the SpA group and type 1 Modic changes from the degenerative group were identified on T1w and STIR sequences. ADC values from these lesions and from healthy subchondral bone were compared. RESULTS: All axial active inflammatory lesions (n=27) and type 1 Modic changes (n=22) identified in T1w and STIR images were visible on DWI. ADC values were significantly higher (p<0.05) for axial active inflammatory lesions (median=0.788×10(-3)mm(2)/s, IQR 25-75 [0.7×10(-3)mm(2)/s; 0.9×10(-3)mm(2)/s]) than for type 1 Modic changes (median=0.585×10(-3)mm(2)/s, IQR 25-75 [0.55×10(-3)mm(2)/s; 0.60×10(-3)mm(2)/s]) and normal subchondral bone (median=0.443×10(-3)mm(2)/s, IQR 25-75 [0.40×10(-3)mm(2)/s; 0.50×10(-3)mm(2)/s]). Intra-class correlation coefficients for intra- and inter-reader ADC values comparison were excellent (0.89 and 0.98 respectively). CONCLUSION: DWI is a sensitive and fast sequence that offer the possibility of quantifying diffusion coefficients of the lesions, which could help to discriminate between spondylarthritis axial active inflammatory and type 1 Modic changes.
25354400 Specific targeting of the IL-23 receptor, using a novel small peptide noncompetitive antag 2014 Nov 15 IL-23 is part of the IL-12 family of cytokines and is composed of the p19 subunit specific to IL-23 and the p40 subunit shared with IL-12. IL-23 specifically contributes to the inflammatory process of multiple chronic inflammatory autoimmune disorders, including psoriasis, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. So far, one antibody targeting the shared p40 subunit of IL-12 and IL-23, Ustekinumab, is approved clinically to treat psoriasis. However, there are no treatments inhibiting specifically the IL-23 proinflammatory response. We have developed small IL-23R-specific antagonists by designing all D-peptides arising from flexible regions of IL-23R. Of these peptides, we selected 2305 (teeeqqly), since in addition to its soluble properties, it inhibited IL-23-induced STAT3 phosphorylation in spleen cells. Peptide 2305 specifically binds to IL-23R/IL-12Rβ1-expressing HEK-293 cells and not to cells devoid of the receptor. Peptide 2305 showed functional selectivity by modulating IL-23-induced gene expression in IL-23R/IL-12Rβ1-expressing cells and in Jurkat cells; 2305 does not inhibit IL-12-induced cytokine expression in IL-12Rβ-IL-12Rβ2-HEK-293 cells. Finally, compared with anti-p40 treatment, 2305 effectively and selectively inhibits IL-23-induced inflammation in three in vivo mouse models: IL-23-induced ear inflammation, anti-CD40-induced systemic inflammatory response, and collagen-induced arthritis. We, hereby, describe the discovery and characterization of a potent IL-23R small-peptide modulator, 2305 (teeeqqly), that is effective in vivo. 2305 may be more convenient, less cumbersome, less costly, and most importantly, more specific than current biologics for the treatment of inflammatory conditions, and conceivably complement the actual therapies for these chronic and debilitating inflammatory diseases.