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ID PMID Title PublicationDate abstract
26132273 Structure-Based Development of a Protein-Protein Interaction Inhibitor Targeting Tumor Nec 2015 Jul 23 The interactions between tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF superfamily receptors (TNFRSFs) are promising targets for rheumatoid arthritis (RA) treatment. However, due to the challenging nature of protein-protein interactions (PPIs), a potent inhibitor that surpasses the affinity of the TRAF6-TNFRSF interactions has not been developed. We developed a small-molecule PPI inhibitor of TRAF6-TNFRSF interactions using NMR and in silico techniques. The most potent compound, TRI4, exhibited an affinity higher than those of TNFRSFs and competitively inhibited a TRAF6-TNFRSF interaction. Structural characterization of the TRAF6-TRI4 complex revealed that TRI4 supplants key interactions in the TRAF6-TNFRSF interfaces. In addition, some TRAF6-TRI4 interactions extend beyond the TRAF6-TNFRSF interfaces and increase the binding affinity. Our successful development of TRI4 provides a new opportunity for RA treatment and implications for structure-guided development of PPI inhibitors.
26026701 Tumor necrosis factor inhibition increases the revascularization of ischemic hind-limbs in 2015 Oct Tumor necrosis factor (TNF) is first identified as a mediator of lethal endotoxin poisoning. The anti-TNF therapy in the treatment of rheumatoid arthritis is based on the recognition of the role of TNF as the master regulator. Type II diabetes is characterized with altered stem cells and reduced vasculogenesis. Therefore, we aimed to determine if TNF inhibitor would improve vasculogenesis in ischemic hind-limbs of diabetic mice. Fifty male type 2 diabetic and their control (8-10 weeks old mice) were used, and ischemia was induced in the hind-limbs of all mice for 28 days. Vessel density was assessed by high-definition microangiography at the end of the treatment period. After 4 weeks, vessel density displayed no difference between the ischemic and the non-ischemic legs in control mice. However, in diabetic mice, the ischemic hind-limb vessel density was significantly decreased. Interestingly, diabetic mice displayed a significant improved vasculogenesis when treated with TNF inhibitor. Moreover, this data was confirmed by capillary density determined by immunostaining. TNF inhibitors are able to improve the formation of microvessels in response to ischemia in type 2 diabetes.
25980533 Heat shock protein 90: a pathophysiological factor and novel treatment target in autoimmun 2015 Aug The chaperone heat shock protein 90 (Hsp90), a cell stress-inducible molecule that regulates activity of many client proteins responsible for cellular growth, differentiation and apoptosis, has been proposed as an important therapeutic target in patients with malignancies. More recently, its active participation in (auto)immune processes has been recognized as evidenced by amelioration of inflammatory disease pathways through pharmacological inhibition of Hsp90 in rodent models of autoimmune encephalomyelitis, rheumatoid arthritis and systemic lupus erythematosus. Based on own current research results, this viewpoint essay provides important insights that Hsp90 is also involved as a notable pathophysiological factor in autoimmune blistering dermatoses including epidermolysis bullosa acquisita, bullous pemphigoid and possibly dermatitis herpetiformis. The observed in vitro, ex vivo and in vivo efficacy of anti-Hsp90 treatment in experimental models of autoimmune bullous diseases and its underlying multimodal anti-inflammatory mechanisms of interference with key contributors to autoimmune-mediated blister formation supports the introduction of selective non-toxic Hsp90 inhibitors into the clinical setting for the treatment of patients with these disorders.
25973486 Evaluation of the anti-inflammatory and antioxidative potential of four fern species from 2015 Apr Inflammation plays a major role in many diseases, for instance in arteriosclerosis, rheumatoid arthritis, autoimmune disorders and cancer. Since many plants contain compounds with anti-inflammatory activity, their consumption may be able to prevent the development of inflammatory-based diseases. Edible ferns are some of the most important wild vegetables in China and have traditionally been used both for dietary and therapeutic purposes. In this study we investigated the anti-inflammatory and antioxidant potential of fern extracts from Matteuccia struthiopteris, Osmundajaponica, Matteuccia orientalis and Pteridium aquilinum intended for use as nutraceuticals. Two modes of action were investigated: the inhibition of the pro-inflammatory gene expression of interleukin-1 beta (IL1-β) and interleukin-6 (IL6), and the gene expression of iNOS by LPS-elicited macrophages. The results showed a decrease of IL1-β gene expression for the five fern extracts. This effect was more pronounced for the extracts prepared from the roots of O. japonica (IC50 of 17.8 µg/mL) and the young fronds of M orientalis (50.0 µg/mL). Regarding the indirect measurement of NO, via iNOS gene expression, an interesting decrease of 50% was obtained with the extract of M. orientalis fronds at a low concentration (20 µg/mL) compared with P. aquilinum fronds (160 µg/mL) and leaves of O. japonica. The latter showed a higher decrease but at a high concentration of extract (160 µg/mL). The five fern extracts were also evaluated for their ability to scavenge 2,2-diphenyl-l-picrylhydrazyl (DPPH) radicals and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). All fern extracts exhibited antioxidant effects but the roots of O. japonica and the fronds of M orientalis were most efficient. The HPLC-MS analysis of the constituents of the fern extracts confirmed the presence of chlorogenic acid, caffeic acid, p-coumaric acid, ferulic acid, kaempferol and apigenin, molecules known to exhibit antiinflammatory and/or antioxidant properties.
25949746 Two-stage revision total knee arthroplasty in cases of periprosthetic joint infection: an 2015 OBJECTIVES: A periprosthetic joint infection (PJI) is a significant complication after total knee arthroplasty (TKA). Still there is no agreement on a perfect diagnosis and treatment algorithm. The aim of this study was to evaluate the success and revision rates after two-stage revision total knee arthroplasty (TKA) and factors that affect the success rate. MATERIAL AND METHODS: 50 consecutive two-stage revision TKAs were performed between January 2011 and December 2012. We retrospectively reviewed study patient's charts including demographics, prior surgeries, comorbidities, incidence of persistent infection and revisions. At the final follow-up examination the patient's satisfaction, pain level and disorders were evaluated. A successful clinical outcome was defined as a functioning prosthesis without wound healing disorders, no sinuses tracts or other clinical evidence of a persistent infection. Results : Re-implantation of prosthesis was performed in 47 cases; three patients received a septic arthrodesis. Twelve patients had a persistent infection despite two-stage re-implantation resulting in a success rate of 76.0%. In eight of these twelve patients an infecting germ was isolated during second-stage procedure. Three patients received another two-stage revision arthroplasty and one patient an above knee amputation. A revision was performed in 23 of 50 patients (46.0%). Factors that diminish the success rate were further operations after primary TKA (p = 0.048), prior revision arthroplasties after TKA (p = 0.045), nicotine abuse (p = 0.048), Charlson comorbidity index above a score of 2 (p = 0.031) and a mixed flora during first-stage procedure (p < 0.001). Age, sex, immune status, chronic anticoagulant use, rheumatoid arthritis, body mass index and the presence of multidrug resistant germs showed no significant effect on success rate (p > 0.05). Conclusion : We found that patients who required surgery after the primary TKA, had a higher Charlson comorbidity index or were found to have mixed flora during explantation. The treatment of PJI remains difficult, both for the patient and for the treating surgeons.
25918157 The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain F 2015 Jun 12 Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune diseases such as rheumatoid arthritis. Cancer Osaka thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a serine-threonine (ST) kinase and is a key regulator in the production of pro-inflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective, and potent inhibitors for the treatment of autoimmune disorders and cancer. The production of monomeric, recombinant COT kinase has proven to be very difficult, and issues with solubility and stability of the enzyme have hampered the discovery and optimization of potent and selective inhibitors. We developed a protocol for the production of recombinant human COT kinase that yields pure and highly active enzyme in sufficient yields for biochemical and structural studies. The quality of the enzyme allowed us to establish a robust in vitro phosphorylation assay for the efficient biochemical characterization of COT kinase inhibitors and to determine the x-ray co-crystal structures of the COT kinase domain in complex with two ATP-binding site inhibitors. The structures presented in this study reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The structurally versatile active site significantly impacts the design of potent, low molecular weight COT kinase inhibitors.
25908025 Secretion, blood levels and cutaneous expression of TL1A in psoriasis patients. 2015 Jul TL1A is a TNF-like cytokine which has been shown to co-stimulate TH1 and TH17 responses during chronic inflammation. The expression of this novel cytokine has been investigated in inflammatory disorders like rheumatoid arthritis and inflammatory bowel disease, but little is known about expression and induction in psoriasis. Indeed, the pathogenesis in psoriasis is still not fully understood and it is speculated that cytokines other than TNF-α are important in subsets of patients. Also, for patients with severe disease that are treated with systemic anti-TNF-α blockade, novel candidates to be used as disease and response biomarkers are of high interest. Here, we demonstrate TL1A expression in biopsies from psoriatic lesions. Also, we investigated spontaneous and induced TL1A secretion from PBMCs and blood levels from a cohort of psoriasis patients. Here, increased spontaneous secretion from PBMCs was observed as compared to healthy controls and a small subset of patients had highly elevated TL1A in the blood. Interestingly, activation of PBMCs with various cytokines showed a decreased sensitivity for TL1A activation in psoriasis patients compared to healthy controls.TL1A levels in blood and biopsies could not be correlated with disease activity with this patient cohort. Thus, additional large-scale studies are warranted to investigate TL1A as a biomarker.
25839236 Reactivity of Cys4 zinc finger domains with gold(III) complexes: insights into the formati 2015 Apr 20 Gold(I) complexes such as auranofin or aurothiomalate have been used as therapeutic agents for the treatment of rheumatoid arthritis for several decades. Several gold(I) and gold(III) complexes have also shown in vitro anticancer properties against human cancer cell lines, including cell lines resistant to cisplatin. Because of the thiophilicity of gold, cysteine-containing proteins appear as likely targets for gold complexes. Among them, zinc finger proteins have attracted attention and, recently, gold(I) and gold(III) complexes have been shown to inhibit poly(adenosine diphosphate ribose)polymerase-1 (PARP-1), which is an essential protein involved in DNA repair and in cancer resistance to chemotherapies. In this Article, we characterize the reactivity of the gold(III) complex [Au(III)(terpy)Cl]Cl2 (Auterpy) with a model of Zn(Cys)4 "zinc ribbon" zinc finger by a combination of absorption spectroscopy, circular dichroism, mass spectrometry, high-performance liquid chromatography analysis, and X-ray absorption spectroscopy. We show that the Zn(Cys)4 site of Zn·LZR is rapidly oxidized by Auterpy to form a disulfide bond. The Zn(2+) ion is released, and the two remaining cysteines coordinate the Au(+) ion that is produced during the redox reaction. Subsequent oxidation of these cysteines can take place in conditions of excess gold(III) complex. In the presence of excess free thiols mimicking the presence of glutathione in cells, mixing of the zinc finger model and gold(III) complex yields a different product: complex (Au(I))2·LZR with two Au(+) ions bound to cysteines is formed. Thus, on the basis of detailed speciation and kinetic measurements, we demonstrate herein that the destruction of Zn(Cys)4 zinc fingers by gold(III) complexes to achieve the formation of "gold fingers" is worth consideration, either directly or mediated by reducing agents.
25559347 Design, synthesis, and biological evaluation of tetrazole analogs of Cl-amidine as protein 2015 Feb 12 Protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of arginine residues to form citrulline. This once obscure modification is now known to play a key role in the etiology of multiple autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, lupus, and ulcerative colitis) and in some forms of cancer. Among the five human PADs (PAD1, -2, -3, -4, and -6), it is unclear which isozyme contributes to disease pathogenesis. Toward the identification of potent, selective, and bioavailable PAD inhibitors that can be used to elucidate the specific roles of each isozyme, we describe tetrazole analogs as suitable backbone amide bond bioisosteres for the parent pan PAD inhibitor Cl-amidine. These tetrazole based analogs are highly potent and show selectivity toward particular isozymes. Importantly, one of the compounds, biphenyl tetrazole tert-butyl Cl-amidine (compound 13), exhibits enhanced cell killing in a PAD4 expressing osteosarcoma bone marrow (U2OS) cell line and can also block the formation of neutrophil extracellular traps. These bioisosteres represent an important step in our efforts to develop stable, bioavailable, and selective inhibitors for the PADs.
24333456 Revision surgery after cervical laminoplasty: report of five cases and literature review. 2015 Jun 1 BACKGROUND CONTEXT: Revision surgery after laminoplasty is rarely performed, and there are few reports of this procedure in the English literature. PURPOSE: To evaluate the reasons why patients underwent revision surgery after laminoplasty and to discuss methods of preventing the need for revision surgery. A literature review with a comparative analysis between previous reports and present cases was also performed. STUDY DESIGN: Case report and literature review. PATIENT SAMPLE: Five patients who underwent revision surgery after laminoplasty. OUTCOME MEASURES: Diagnosis was based on the preoperative computed tomography and magnetic resonance imaging findings. Neurologic findings were evaluated using the Japanese Orthopedic Association score. METHODS: A total of 237 patients who underwent cervical laminoplasty for cervical spondylotic myelopathy from 1990 to 2010 were reviewed. Patients with ossification of the posterior longitudinal ligament, renal dialysis, infection, tumor, or rheumatoid arthritis were excluded. Five patients who underwent revision surgery for symptoms of recurrent myelopathy or radiculopathy were identified, and the clinical courses and radiological findings of these patients were retrospectively reviewed. RESULTS: The average interval from the initial surgery to revision surgery was 15.0 (range 9-19) years. The patients were four men and one woman with an average age at the time of the initial operation of 49.8 (range 34-65) years. Four patients developed symptoms of recurrent myelopathy after their initial surgery, for the following reasons: adjacent segment canal stenosis, restenosis after inadequate opening of the lamina with degenerative changes, and trauma after inadequate opening of the lamina. One patient developed new radiculopathy symptoms because of foraminal stenosis secondary to osteoarthritis at the Luschka and zygapophyseal joints. All patients experienced resolution of their symptoms after revision surgery. CONCLUSIONS: Revision surgery after laminoplasty is rare. Inadequate opening of the lamina is one of the important reasons for needing revision surgery. Degenerative changes after laminoplasty may also result in a need for revision surgery. Surgeons should be aware of the degenerative changes that can cause neurologic deterioration after laminoplasty.
26255211 Interleukin-6 inhibits apoptosis of exocrine gland tissues under inflammatory conditions. 2015 Dec Interleukin (IL)-6 is a multi-functional cytokine that can either promote or suppress tissue inflammation depending on the specific disease context. IL-6 is elevated in the exocrine glands and serum of patients with Sjögren's syndrome (SS), but the specific role of IL-6 in the pathogenesis of this disease has not been defined. In this study, we showed that IL-6 expression levels were increased with age in C56BL/6.NOD-Aec1Aec2 mice, a primary SS model, and higher than the control C57BL/6 mice. To assess the role of IL-6 during the immunological phase of SS development, a neutralizing anti-IL-6 antibody was administered into 16 week-old female C56BL/6.NOD-Aec1Aec2 mice, 3 times weekly for a consecutive 8 weeks. Neutralization of endogenous IL-6 throughout the immunological phase of SS development led to increased apoptosis, caspase-3 activation, leukocytic infiltration, and IFN-γ- and TNF-α production in the salivary gland. To further determine the effect of IL-6 on the apoptosis of exocrine gland cells, recombinant human IL-6 or the neutralizing anti-IL-6 antibody was injected into female C57BL/6 mice that received concurrent injection of anti-CD3 antibody to induce the apoptosis of exocrine gland tissues. Neutralization of IL-6 enhanced, whereas administration of IL-6 inhibited apoptosis and caspase-3 activation in salivary and lacrimal glands in this model. The apoptosis-suppressing effect of IL-6 was associated with up-regulation of Bcl-xL and Mcl-1 in both glands. Moreover, IL-6 treatment induced activation of STAT3 and up-regulated Bcl-xL and Mcl-1 gene expression in a human salivary gland epithelial cell line. In conclusion, IL-6 inhibits the apoptosis of exocrine gland tissues and exerts a tissue-protective effect under inflammatory conditions including SS. These findings suggest the possibility of using this property of IL-6 to preserve exocrine gland tissue integrity and function under autoimmune and inflammatory conditions.
27227345 Genetics of systemic lupus erythematosus and Sjögren's syndrome: an update. 2016 Sep PURPOSE OF REVIEW: To describe the recent studies on the genetics of systemic lupus erythematosus (SLE) and Sjögren's syndrome. RECENT FINDINGS: We overview the most recent findings on the genetic susceptibility of the diseases and provide information on their genetic similarities and differences. SUMMARY: SLE and Sjögren's syndrome are two closely related systemic autoimmune diseases that share multiple clinical and molecular aspects, including a significant number of susceptibility genes. Several genome-wide association studies were recently published in different populations that provide a better picture of their molecular mechanisms. It is becoming clear that their genetic architecture is quite well established, but more information is required on expression quantitative trait loci, epigenetic genome-wide analyses, gene × gene interactions and the role of rare variants.
25268749 Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic 2015 OBJECTIVES: To determine the clinical and laboratory differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome (pSS), in a large Italian multicentre cohort. METHOD: Patients were selected according to the following criteria: fulfilling the American-European classification criteria for pSS, serum cryoglobulin and gammaglobulin levels evaluated, and lack of hepatitis C virus (HCV) infection. Multinomial analyses were performed by distinguishing three groups of pSS: (i) purpura associated with cryoglobulinaemic vasculitis (CV), (ii) purpura associated with hypergammaglobulinaemic vasculitis (HGV), and (iii) pSS patients without purpura (pSS controls). Patients with purpura but without cryoglobulins or hypergammaglobulinaemia were excluded. RESULTS: A total of 652 patients were enrolled in this study. Group 1/CV comprised 23/652 patients (3.53%), group 2/HGV 40/652 patients (6.13%), and group 3/pSS controls 589/652 (90.34%). The three groups were found to be significantly different from each other (post-estimation test: group 1/CV vs. group 3/pSS controls: p < 0.0001; group 1/CV vs. group 2/HGV: p = 0.0001; group 2/HGV vs. group 3/pSS controls: p = 0.0003), thus confirming the different phenotypes of purpura in pSS.Multivariate analyses revealed that peripheral neuropathy (p < 0.001), low C4 (p < 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.02), and the presence of anti-SSB/La antibodies (p = 0.02) characterized CV whereas rheumatoid factor (p = 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.01), and anti-SSA/Ro antibodies (p = 0.049) were significantly associated with HGV. Lymphoma was associated only with CV. CONCLUSIONS: HGV is a cutaneous vasculitis, related to a benign B-cell proliferation, whereas CV is a systemic immune complex-mediated vasculitis with complement activation and a higher risk of lymphoma, thus confirming CV but not HGV as a prelymphomatous condition in pSS.
24952418 Neuromyelitis optica spectrum disorders associated with other autoimmune diseases. 2015 Feb Neuromyelitis optica (NMO) is an inflammatory demyelinating autoimmune disease with severe, tremendously incapacitating, consequences in the patient's health and wellbeing. Until 2004, NMO was considered a restricted type of multiple sclerosis but in the same year an auto-antibody reacting against aquaporin-4 (NMO-IgG) was found to be related with NMO and it was considered the main etiologic agent of this disease. Its detection is very sensitive and specific allowing an early diagnosis and a better treatment and prognosis. With this tool, a spectrum of diseases including other autoimmune diseases was found to have NMO-IgG antibodies and a new classification named NMO spectrum disorders was created. In this review, we sum up the developments in this field associated with other autoimmune diseases. We approach the latest discoveries in the diagnosis like the new biomarkers that will possibly be used in the close future or the developments in the neuroimaging techniques. We reviewed the literature and synthesized case reports of NMO patients with concurrent autoimmune diseases and the information from useful larger studies. Finally, we summarize the commonly used treatments in NMO and we try to specify the best treatment for NMO with simultaneous autoimmune disease. This review updates the information about this issue and raises the awareness of rheumatologists for these severe diseases.
27803305 Clinical relevance of RORγ positive and negative subsets of CD161+CD4+ T cells in primary 2017 Feb OBJECTIVE: The relevance of the Th17 pathway in primary SS (pSS) is unclear. Published studies have relied on restimulating circulating CD161(+) T cells in vitro for quantitation of IL-17-producing cells. While CD161 marks all IL-17(+) T cells, it is also expressed by other Th subsets. The aim of this study was to directly analyse retinoic acid receptor-related orphan nuclear receptor (ROR)-γ expressing and non-expressing subsets of CD161(+) T cells to determine the relevance of the Th17 pathway in pSS. METHODS: We quantitated the frequencies of both CD161(-) and RORγ-expressing T cells by comparative flow cytometry in peripheral blood mononuclear cells from a well-stratified cohort of pSS patients and control subjects. We also analysed the expression of antigen D-related HLA (HLA-DR) and CD161 in labial salivary glands from nine subjects undergoing a diagnostic biopsy. RESULTS: While the frequencies of both RORγ(+) and RORγ(-) subsets of CD161(+) CD4(+) T cells were increased in peripheral blood from pSS patients, the increase in the RORγ(+) subset positively correlated with humoral manifestations of the disease (anti-SSA/SSB autoantibodies and hypergammaglobulinaemia), but not with disease activity, and vice versa for the RORγ(-) subset. An increased frequency of HLA-DR(+) CD161(+)CD4(+) T cells was observed in labial salivary gland biopsies from pSS patients, suggesting chronic activation of CD161(+)CD4(+) T cells in the target tissue of the disease. CONCLUSION: In addition to pointing to CD161 as a marker of a pathogenic subset of CD4(+) T cells in pSS patients, our data indicate that even though the RORγ(+) (Th17) CD161(+) subset might contribute to humoral manifestations of the disease, the RORγ(-) (non-Th17) CD161(+) subset is the one associated with disease activity in pSS patients.
24834925 Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopath 2015 Jun OBJECTIVE: To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). METHODS: This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. RESULTS: In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: -0.21; 95% CI -0.35 to -0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). CONCLUSIONS: Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. TRIAL REGISTRATION NUMBER: NCT00988221.
25681337 Estradiol promotes M1-like macrophage activation through cadherin-11 to aggravate temporom 2015 Mar 15 Macrophages play a major role in joint inflammation. Estrogen is involved in rheumatoid arthritis and temporomandibular disorders. However, the underlying mechanism is still unclear. This study was done to verify and test how estrogen affects M1/M2-like macrophage polarization and then contributes to joint inflammation. Female rats were ovariectomized and treated with increasing doses of 17β-estradiol for 10 d and then intra-articularly injected with CFA to induce temporomandibular joint (TMJ) inflammation. The polarization of macrophages and expression of cadherin-11 was evaluated at 24 h after the induction of TMJ inflammation and after blocking cadherin-11 or estrogen receptors. NR8383 macrophages were treated with estradiol and TNF-α, with or without blocking cadherin-11 or estrogen receptors, to evaluate the expression of the M1/M2-like macrophage-associated genes. We found that estradiol increased the infiltration of macrophages with a proinflammatory M1-like predominant profile in the synovium of inflamed TMJ. In addition, estradiol dose-dependently upregulated the expressions of the M1-associated proinflammatory factor inducible NO synthase (iNOS) but repressed the expressions of the M2-associated genes IL-10 and arginase in NR8383 macrophages. Furthermore, estradiol mainly promoted cadherin-11 expression in M1-like macrophages of inflamed TMJ. By contrast, blockage of cadherin-11 concurrently reversed estradiol-potentiated M1-like macrophage activation and TMJ inflammation, as well as reversed TNF-α-induced induction of inducible NO synthase and NO in NR8383 macrophages. The blocking of estrogen receptors reversed estradiol-potentiated M1-like macrophage activation and cadherin-11 expression. These results suggested that estradiol could promote M1-like macrophage activation through cadherin-11 to aggravate the acute inflammation of TMJs.
27228635 Chikungunya Fever Presenting as a Systemic Disease with Fever. Arthritis and Rash: Our Exp 2016 Mar Chikungunya fever (CHIK-F) has been increasingly documented among Western travelers returning from areas with chikungunya virus transmission, which are also popular tourist sites. We present three Israeli travelers who developed fever, maculopapular rash and long-standing arthralgias while visiting northern Indian states not known to be involved in the chikungunya fever epidemic. We also present an epidemiological review of the chikungunya epidemic over the past decades. Rare systemic manifestations of this disorder, like catastrophic antiphospholipid syndrome (CAPS) and adult-onset Still's syndrome, are discussed. The present era of international travel poses a new diagnostic and epidemiologic challenge that demands increased awareness to the possibility of an exotic tropical infectious disease.
26521900 Use of Coils and a Pulmonary Vasodilator to Reduce Pulmonary Hypertension in a Patient wit 2015 Fistulas between systemic and pulmonary arteries are associated with various underlying etiologies and cause pulmonary hypertension (PH). Diagnosis of this condition requires several imaging studies and the exclusion of other possible causes of PH. We herein report a case of a patient with interstitial pneumonia and scleroderma. The imaging revealed multiple fistulas involving the inferior phrenic and left lower pulmonary arteries. The fistulas were closed using coils, but the PH remained presumably due to other undiagnosed fistulas. The improvement of symptoms following use of a supplementary pulmonary vasodilator provides the hope that the chosen treatment could be a viable alternative approach for other similar cases.
25715242 Clinical-laboratory characteristics of ANA-positive chronic idiopathic urticaria. 2015 Mar Despite the established association between chronic idiopathic/spontaneous urticaria (CIU) and presence of antinuclear antibodies (ANAs), the prevalence of autoimmune comorbidities in this population has not been analyzed. Here, we aim to identify clinical and laboratory manifestations associated with ANA-positive CIU. ANA-positive patients were identified via electronic data capture from the electronic patient record database of Leumit Health care Services (LHS) of Israel. Patient characteristics, medical histories, and details of diagnostic workup, medical treatment, and follow-up were retrieved by performing a chart review of electronic patient records (EPRs). The prevalence of target diseases among ANA(+) CIU(+), ANA(+) CIU(-), and ANA(-) CIU(+) patients was calculated. A total of 91 ANA(+) CIU(+), 3131 ANA(+) CIU(-), and 478 ANA(-) CIU(+) patients were identified. The ANA(+) CIU(+) group was characterized by higher prevalence of Sjögren's syndrome (SS)-A 52 antibodies (Ab) (7.7% versus 2.4%; p = 0.008), SS-A 60 Ab (11% versus 2.8%; p = < 0.001), and SS-B Ab (14.3% versus 3.2%; p < 0.001), compared with ANA(-) CIU(+) group. Additionally, ANA(+) CIU(+) patients were more likely to be diagnosed with thyroid autoimmune diseases, higher C-reactive protein (6.4 ± 10.3 versus 4.1 ± 8.8 mg/L; p = 0.027), and more profound basopenia (0.04 ± 0.09 versus 0.15 ± 0.11 cell/mm(3); p < 0.001) than ANA(-) CIU patients. More ANA(+) CIU(+) patients were resistant to four-fold standard licensed doses of antihistamines than ANA(-) CIU(+) patients [11 (12.1%) versus 29 (6.1%); p = 0.046]. ANA-positive CIU is characterized by higher prevalence of SS-A 52, SS-A 60, and SS-B antibodies and poorer clinical response to antihistamine medications.