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ID PMID Title PublicationDate abstract
25136784 IL-6 biology: implications for clinical targeting in rheumatic disease. 2014 Dec IL-6 has been linked to numerous diseases associated with inflammation, including rheumatoid arthritis, inflammatory bowel disease, vasculitis and several types of cancer. Moreover, IL-6 is important in the induction of hepatic acute-phase proteins for the trafficking of acute and chronic inflammatory cells, the differentiation of adaptive T-cell responses, and tissue regeneration and homeostatic regulation. Studies have investigated IL-6 biology using cell-bound IL-6 receptors expressed predominantly on hepatocytes and certain haematopoietic cells versus activation mediated by IL-6 and soluble IL-6 receptors via a second protein, gp130, which is expressed throughout the body. Advances in this research elucidating the differential effects of IL-6 activation provide important insights into the role of IL-6 in health and disease, as well as its potential as a therapeutic target. Knowledge of the basic biology of IL-6 and its signalling pathways can better inform both the research agenda for IL-6-based targeted therapies as well as the clinical use of strategies affecting IL-6-mediated inflammation. This Review covers novel, emerging aspects of the biology of IL-6, which might lead to more specific blockade of IL-6 signalling without compromising the protective function of this cytokine in the body's defence against infections.
25043266 Nondisseminated histoplasmosis of the trachea. 2016 Mar Histoplasma capsulatum can rarely affect the trachea. We report the case of a 68-year-old woman with rheumatoid arthritis on immunosuppressive therapy who presented with fevers, worsening shortness of breath, nonproductive cough and subjective throat hoarseness and fullness. Chest computed tomography demonstrated no tracheal findings. Bronchoscopy found mucosal irregularity, nodularity and vesicular regions in the proximal trachea extending seven centimeters distal to the vocal cords. Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion. Silver staining and culture and wash of the tracheal biopsy revealed Histoplasma capsulatum. She was treated with oral itraconazole then briefly on intravenous amphotericin for rising Histoplasma urinary antigen levels. She continued treatment 24 months following diagnosis with minimal dyspnea. Histoplasma tracheitis has been proposed as an indicator of disseminated infection. However, our patient did not demonstrate other organ manifestations. Histoplasma tracheitis should be considered in a differential diagnosis of tracheal lesions even in the absence of systemic involvement.
25037271 Multiple correlations of mRNA expression and protein abundance in human cytokine profile. 2014 Oct With the development of genomic study, researchers found that it is insufficient to predict protein expression from quantitative mRNA data in large scale, which is contrary to the traditional opinion that mRNA expression correlates with protein abundance at the single gene level. To try to solve the apparent conflicting views, here we set up a series of research models and chose soluble cytokines as targets. First, human peripheral blood mononuclear cell (PBMC) from one health donor was treated with 16 continuously changing conditions, the protein and mRNA profile were analyzed by multiplex Luminex and genomic microarray, respectively. Among the tested genes, around half mRNA correlated well with their corresponding proteins (ρ > 0.8), however if we put all the genes together, the correlation coefficient for the 16 conditions varied from 0.29 to 0.71. Second, PBMC from 14 healthy donors were stimulated with the same condition and it was found that the correlation coefficient went down (ρ < 0.6). Third, 28 rheumatoid arthritis (RA) patients were tested for their response to the same external stimuli and it turned out different individual displayed different protein expression pattern as expect. Lastly, autoimmune disease cohorts (8 diseases including RA, 103 patients in total) were assayed on the whole view. It was observed that there was still some similarity in the protein profile among patients from the single disease type although completely different patterns were displayed across different disease categories. This study built a good bridge between single gene analysis and the whole genome study and may give a reasonable explanation for the two conflicting views in current biological science.
25035841 Primary total elbow arthroplasty in complex fractures of the distal humerus. 2014 Jul 18 AIM: To evaluate short- to medium term outcome of total elbow arthroplasty (TEA) in complex fractures of the distal humerus. METHODS: A consecutive series of 24 complex distal humerus fractures operated with TEA in the period 2006-2012 was evaluated with the Mayo Elbow Performance score (MEPS), plain radiographs, complications and overall satisfaction. The indications for surgery were 1: AO type B3 or C3 or Sheffield type 3 fracture and age above 65 or 2: fracture and severe rheumatoid arthritis. Mean follow-up time was 21 mo. RESULTS: Twenty patients were followed up. Four patients, of which 3 had died, were lost to follow up. According to the AO classification there were 17 C3, 1 B2 and 2 A2 fractures. Mean follow-up was 21 months (range 4-54). Mean MEPS was 94 (range 65-100). Mean flexion was 114 degrees (range 80-140). According to MEPS there were 15 excellent, 4 good and 1 fair result. Patient satisfaction: 8 excellent, 10 good, 2 fair and 1 poor. There were two revisions due to infection treated successfully with revision and three months of antibiotics. In two patients the locking split had loosened. One was referred to re-insertion and one chose yearly controls. Two patients had persistent dysaesthesia of their 5th finger, but were able to discriminate between sharp and blunt. CONCLUSION: Our study suggests that TEA in complex fractures of the distal humerus in elderly patients can result in acceptable short- to medium term outcome.
24981042 Helminth therapy or elimination: epidemiological, immunological, and clinical consideratio 2014 Nov Deworming is rightly advocated to prevent helminth-induced morbidity. Nevertheless, in affluent countries, the deliberate infection of patients with worms is being explored as a possible treatment for inflammatory diseases. Several clinical trials are currently registered, for example, to assess the safety or efficacy of Trichuris suis ova in allergies, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, and autism, and the Necator americanus larvae for allergic rhinitis, asthma, coeliac disease, and multiple sclerosis. Studies in animals provide strong evidence that helminths can not only downregulate parasite-specific immune responses, but also modulate autoimmune and allergic inflammatory responses and improve metabolic homoeostasis. This finding suggests that deworming could lead to the emergence of inflammatory and metabolic conditions in countries that are not prepared for these new epidemics. Further studies in endemic countries are needed to assess this risk and to enhance understanding of how helminths modulate inflammatory and metabolic pathways. Studies are similarly needed in non-endemic countries to move helminth-related interventions that show promise in animals, and in phase 1 and 2 studies in human beings, into the therapeutic development pipeline.
24964172 The efficiency of granulocyte colony-stimulating factor in hemorrhagic mucositis and febri 2015 Methotrexate (MTX) remains one of the most frequently used anti-metabolite agents in dermatology. MTX is an analog of folate that competitively and irreversibly inhibits dihydrofolate reductase. Oral mucositis is a common side effect of chemotherapy drugs and is characterized by erythema, pain, poor oral intake, pseudomembranous destruction, open ulceration and hemorrhage of the oral mucosa. In this paper, we report a 32-year-old female with a case of mucositis due to MTX intoxication that resulted from an overdose for rheumatoid arthritis. The patient had abdominal pain, vomiting, and nausea. During follow-up, the patient's white blood cell count was found to be 0.9 × 10(9)/L (4-10 × 10(9)/L). The patient developed fever exceeding 40 °C. The patient was consulted to the hematology service. They suggested using granulocyte colony-stimulating factor for febrile neutropenia. On the fifth day of treatment, the white blood cell count reached 5.3 × 10(9)/L and the patient's fever and mucositis started to resolve. Here, we presented a case of hemorrhagic mucositis and febrile neutropenia resulted from high-dose MTX that responded very well to granulocyte colony-stimulating factor treatment and we reviewed the literature.
24897390 Need for CT-based bone density modelling in finite element analysis of a shoulder arthropl 2014 Oct Treatment of common pathologies of the shoulder complex, such as rheumatoid arthritis and osteoporosis, is usually performed by total shoulder arthroplasty (TSA). Survival of the glenoid component is still a problem in TSA, whereas the humeral component is rarely subject to failure. To set up a finite element analysis (FEA) for simulation of a TSA in order to gain insight into the mechanical behaviour of a glenoid implant, the modelling procedure and the application of boundary conditions are of major importance because the computed result strongly depends upon the accuracy and sense of realism of the model. The goal of this study was to show the influence on glenoid stress distribution of a patient-specific bone density distribution compared with a homogenous bone density distribution for the purpose of generating a valid model in future FEA studies of the shoulder complex. Detailed information on the integration of bone density properties using existing numerical models as well as the applied boundary conditions is provided. A novel approach involving statistical analysis of values derived from an FEA is demonstrated using a cumulative distribution function. The results show well the mechanically superior behaviour of a realistic bone density distribution and therefore emphasise the necessity for patient-specific simulations in biomechanical and medical simulations.
24874539 Jak2 inhibitor--a jackpot for pharmaceutical industries: a comprehensive computational met 2014 Aug A potent Jak2 inhibitor could solve numerous diseases including hypertension and cardiovascular diseases, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, psoriasis and rheumatoid arthritis. So, identifying potent Jak2 inhibitors is of great interest to researchers and pharmaceutical companies. Virtual screening and molecular docking are important tools for structure based drug discovery but selecting an appropriate method to calculate the electrostatic potential is critical. In this study, four semi empirical (AM1, RM1, PM3, and MNDO) and two empirical (DFT, HF) charges were investigated for their performance on the prediction of docking pose using Glide XP. The result shows that AM1 has the best charge model for our study. Further, we performed a 3D-quantitative structure-activity relationship (3D-QSAR) study of 76 decaene derivatives. Since 3D-QSAR methods are known to be highly sensitive to ligand conformation and alignment method, we did a comparative 3D-QSAR study of AM1 charge docked pose alignment based QSAR (structure based) and pharmacophore based QSAR. We found a better QSAR model in the structure based method. Hence, the results clearly demonstrate that selecting an appropriate method to calculate the electrostatic potential for docking studies and a good alignment of the ligand for 3D-QSAR is critical. Finally, extensive pharmacophore and e-pharmacophore based virtual screening followed by subsequent docking studies identified 27 lead molecules which could be potent Jak2 inhibitors.
24839444 The relationship of antibodies to modified citrullinated vimentin and markers of bone and 2014 Objective. To make individualised decisions regarding treatment is one of the most important challenges in clinical practise, and identification of sensitive and specific markers of prognosis is an important research question. The main objective of this study was to evaluate relationships between the level of autoantibodies, radiographic changes and laboratory markers of bone, and cartilage destruction. Methods. A total of 114 RA patients were examined. The serum concentration of IgM RF, antibodies to cyclic citrullinated peptide (anti-CCP), modified citrullinated vimentin (anti-MCV), matrix metalloproteinase 3 (MMP-3), and cartilage oligomeric matrix protein (COMP, ng/mL) were measured. The van der Heijde-modified Sharp Score was used to quantify the radiologic changes. Results. Among the patients who were high-positive for anti-MCV, the value of total modified Sharp score (mTSS) (96.5; 66-120) was higher as well as the joint space narrowing (82; 60.5-105.5), and a higher level of MMP-3 was recorded more frequently (56%) in comparison with negative/low-positive patients (57; 31-88, 50; 29-82, 31% resp., P < 0.05). The level of COMP was also higher among patients high-positive for anti-MCV (9.7; 8.1-13.1 and 6.8; 5.4-10.7, resp., P = 0.02). Conclusion. A high positive level of anti-MCV as contrasted with anti-CCP and IgM RF is associated with more pronounced destructive changes in the joints.
24811356 [Metabolic bone disease osteomalacia]. 2014 May Osteomalacia is a rare disorder of bone metabolism leading to reduced bone mineralization. Underlying vitamin D deficiency and a disturbed phosphate metabolism (so-called hypophosphatemic osteomalacia) can cause the disease. Leading symptoms are dull localized or generalized bone pain, muscle weakness and cramps as well as increased incidence of falls. Rheumatic diseases, such as polymyalgia rheumatica, rheumatoid arthritis, myositis and fibromyalgia must be considered in the differential diagnosis. Alkaline phosphatase (AP) is typically elevated in osteomalacia while serum phosphate and/or 25-OH vitamin D3 levels are reduced. The diagnosis of osteomalacia can be confirmed by an iliac crest bone biopsy. Histological correlate is reduced or deficient mineralization of the newly synthesized extracellular matrix. Treatment strategies comprise supplementation of vitamin D and calcium and for patients with intestinal malabsorption syndromes vitamin D and calcium are also given parenterally. In renal phosphate wasting syndromes substitution of phosphate is the treatment of choice, except for tumor-induced osteomalacia when removal of the tumor leads to a cure in most cases.
24713224 Psoriasis and risk of venous thromboembolism: a systematic review and meta-analysis. 2014 Oct BACKGROUND: Several chronic inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus, have been shown to increase venous thromboembolism (VTE) risk but the data on psoriasis is unclear. METHODS: We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing VTE risk in patients with psoriasis vs. non-psoriasis participants. Pooled risk ratio and 95% confidence intervals were calculated using a random effect, generic inverse variance method. RESULT: Four studies were identified and included in our data analysis. The pooled risk ratio of VTE in patients with psoriasis was 1.46 (95% CI, 1.29-1.66). The statistical heterogeneity of this meta-analysis was high with an I(2) of 86%. CONCLUSION: Our study demonstrated a statistically significant increased VTE risk among patients with psoriasis.
24698572 Closed reduction and internal fixation versus total hip arthroplasty for displaced femoral 2014 Apr 1 OBJECTIVE: To compare the clinical effects between closed reduction and internal fixation (CRIF) and total hip arthroplasty (THA) for displaced femoral neck fracture. METHODS: In this prospective randomized study, 285 patients aged above 65 years with hip fractures (Garden III or IV) were included from January 2001 to December 2005. The cases were randomly allocated to either the CRIF group or THA group. Patients with pathological fractures (bone tumors or metabolic bone disease), preoperative avascular necrosis of the femoral head, osteoarthritis, rheumatoid arthritis, hemiplegia, long-term bed rest and complications affecting hip functions were excluded. RESULTS: During the 5-year follow-up, CRIF group had significantly higher rates of complication in hip joint, general complication and reoperation than THA group (38.3% vs. 12.7%, P<0.01; 45.3% vs. 21.7%, P<0.01; 33.6% vs. 10.2%, P<0.05 respectively). There was no difference in mortality between the two groups. Postoperative function of the hip joint in THA group recovered favorably with higher Harris scores. CONCLUSION: For displaced fractures of the femoral neck in elderly patients, THA can achieve a lower rate of complication and reoperation, as well as better postoperative recovery of hip joint function compared with CRIF.
24646942 Sphingolipids in human synovial fluid--a lipidomic study. 2014 Articular synovial fluid (SF) is a complex mixture of components that regulate nutrition, communication, shock absorption, and lubrication. Alterations in its composition can be pathogenic. This lipidomic investigation aims to quantify the composition of sphingolipids (sphingomyelins, ceramides, and hexosyl- and dihexosylceramides) and minor glycerophospholipid species, including (lyso)phosphatidic acid, (lyso)phosphatidylglycerol, and bis(monoacylglycero)phosphate species, in the SF of knee joints from unaffected controls and from patients with early (eOA) and late (lOA) stages of osteoarthritis (OA), and rheumatoid arthritis (RA). SF without cells and cellular debris from 9 postmortem donors (control), 18 RA, 17 eOA, and 13 lOA patients were extracted to measure lipid species using electrospray ionization tandem mass spectrometry--directly or coupled with hydrophilic interaction liquid chromatography. We provide a novel, detailed overview of sphingolipid and minor glycerophospholipid species in human SF. A total of 41, 48, and 50 lipid species were significantly increased in eOA, lOA, and RA SF, respectively when compared with normal SF. The level of 21 lipid species differed in eOA SF versus SF from lOA, an observation that can be used to develop biomarkers. Sphingolipids can alter synovial inflammation and the repair responses of damaged joints. Thus, our lipidomic study provides the foundation for studying the biosynthesis and function of lipid species in health and most prevalent joint diseases.
24520947 Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specif 2014 Mar 27 Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.
24440516 Determination of chitinases family during osteoclastogenesis. 2014 Apr Mammalian chitinases consisting of CHIA, CHIT1, CHI3L1, CHI3L2 and CHID1 exert important biological roles in the monocyte lineage and chronic inflammatory diseases. Pathological bone resorption is a cause of significant morbidity in diseases affecting the skeleton such as rheumatoid arthritis, osteoporosis, periodontitis and cancer metastasis. The biologic role of chitinases in bone resorption is poorly understood. In this study, we evaluated the expression of the chitinases family during osteoclast differentiation. The expression of CHIA, CHI3L2 and CHID1 resulted unchanged during osteoclast differentiation, whereas CHIT1 and CHI3L1 increased significantly. We also observed that CHIT1 and CHI3L1 are involved in osteoclast function. Indeed, silencing CHIT1 and CHI3L1 with siRNA resulted in a significant decrease in bone resorption activity. In addition, transfection with CHIT1 or CHI3L1 siRNA and co-transfection with both decreased the levels of the pro-differentiative marker MMP9. Overall, these discoveries reveal a novel and crucial role for both CHIT1 and CHI3L1 in promoting bone resorption and identifying new potential candidate markers for therapeutic targeting.
24432340 Development of novel cellular model for affinity studies of histamine H(4) receptor ligand 2013 The G protein-coupled histamine H4 receptor (H4R) is the last member of histamine receptors family discovered so far. Its expression pattern, together with postulated involvement in a wide variety of immunological and inflammatory processes make histamine H4 receptor an interesting target for drug development. Potential H4R ligands may provide an innovative therapies for different immuno-based diseases, including allergy, asthma, pruritus associated with allergy or autoimmune skin conditions, rheumatoid arthritis and pain. However, none of successfully developed selective and potent histamine H4 receptor ligands have been introduced to the market up to date. For that reason there is still a strong demand for pharmacological models to be used in studies on potent H4R ligands. In current work we present the development of novel mammalian cell line, stably expressing human histamine H4 receptor, with use of retroviral transduction approach. Obtained cell line was pharmacologically characterized in radioligand binding studies and its utility for affinity testing of potent receptor ligands was confirmed in comparative studies with the use of relevant insect cells expression model. Obtained results allow for statement that developed cellular model may be successfully employed in search for new compounds active at histamine H4 receptor.
24394208 [Biologics and infections in rheumatic diseases]. 2014 Jan The successful use of a chimeric monoclonal antibody targeting TNF alpha (infliximab) to treat rheumatoid arthritis (RA) two decades ago, ushered in a new era of therapy with the so-called biopharmaceuticals, commonly referred to as "biologics". Their use rapidly spread to other indications such as Crohns disease, and their commercial success led to rapid extension of the concept using other forms of monoclonal antibodies and receptor recombinant molecules with specificities to other cytokines, growth factors and immune cell subsets. Soon after their introduction into the clinic, the first indications of increased risk of infection appeared in the form of reactivation of tuberculosis, mostly in the first months after treatment and often extrapulmonary. It was later recognised that an overall increased risk of bacterial infection under TNF-alpha blockade exists with a relative increased risk of around 2 - 3, and that classical symptoms of infection may be masked by cytokine blockade. Biologics against other cytokines such as IL-6, co-stimulatory molecules, and anti B cells seem less associated with infection, though this may be in part related to more careful patient monitoring. Increasing experience led to guidelines concerning pre-treatment screening, vaccination and perioperative advice, as well as the use of biologics in the presence of chronic viral infection, e. g. HIV, hepatitis B and C. Biologics have changed the outcome for patients with RA and other autoimmune diseases, but this success should not lead to complacency when assessing potential infectious complications of treatment in individual patients.
24329131 Effects of sulfasalazine and tofacitinib on the protein profile of articular chondrocytes. 2014 Sep OBJECTIVE: Sulfasalazine (SSZ) and tofacitinib are effective for treating rheumatoid arthritis, however, their effects on chondrocytes have not been fully understood. We here tried to elucidate their effects on chondrocyte proteins. METHODS: We treated chondrocytes from five osteoarthritis patients with IL-1β, IL-1β+ SSZ, IL-1β+ tofacitinib, SSZ alone, and tofacitinib alone. Then, we compared protein profiles of the chondrocytes using two-dimensional differential gel electrophoresis. Further, we identified altered proteins by mass spectrometry. RESULTS: Out of 892 detected protein spots, the IL-1β stimulation changed intensity of 43 spots more than 1.3-fold or less than 1/1.3-fold significantly. SSZ suppressed the IL-1β-induced intensity alteration in 16 (37%) out of the 43 protein spots. Tofacitinib suppressed the IL-1β-induced alteration in 4 (9.3%) out of the 43 spots. The production of AMP deaminase 2 and procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 were increased by IL-1β and the increase was suppressed by SSZ and by tofacitinib. SSZ alone altered intensity of 273 (31%) out of the 852 spots significantly, whereas tofacitinib alone altered intensity of only 24 (2.7%) out of them. CONCLUSION: SSZ and, to lesser extent, tofacitinib suppress the effects of IL-1β on the protein profiles of chondrocytes. Our data would promote understanding of effects of the drugs on chondrocytes.
24229049 Risk of subarachnoid haemorrhage in people admitted to hospital with selected immune-media 2013 Nov 14 BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating cause of stroke, occurring in relatively young people. It has been suggested that some immune-mediated diseases may be associated with an increased risk of SAH. METHODS: We analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999-2011). Rate ratios for SAH were determined, comparing immune-mediated disease cohorts with comparison cohorts. RESULTS: There were significantly elevated risks of SAH after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune haemolytic anaemia, Crohn's disease, diabetes mellitus, idiopathic thrombocytopenia purpura, myxoedema, pernicious anaemia, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, SLE and thyrotoxicosis. Elevated risks that were greater than 2-fold were found for Addison's disease (rate ratio (RR) = 2.01, 95% confidence interval 1.3-2.97), idiopathic thrombocytopenia purpura (RR = 2.42, 1.86-3.11), primary biliary cirrhosis (RR = 2.21, 1.43-3.16) and SLE (RR = 3.76, 3.08-4.55). CONCLUSIONS: Our findings strongly support the suggestion that patients with some immune-mediated diseases have an increased risk of SAH. Further studies of the mechanisms behind this association are warranted.
24189557 [Hepatocyte growth factor regulates immune reactions caused by transplantation and autoimm 2013 Hepatocyte growth factor (HGF) was first identified and cloned as a mitogenic protein for hepatocytes, and subsequent studies revealed that HGF has multiple biological effects on a wide variety of cells, including mitogenic, motogenic, morphogenic, anti-apoptotic, and angiogenic activities. It plays roles in organizing tissues during development and regeneration. HGF may be applied for the treatment of acute onset diseases such as fulminant hepatitis, myocardial infarction, acute renal failure, cerebral infarction, and chronic diseases like liver cirrhosis, chronic renal failure, pulmonary fibrosis, cardiomyopathy, and arteriosclerosis obliterans. HGF also has immunomodulatory activities and we previously demonstrated that its administration inhibited acute graft-versus-host disease (GVHD) after treatment with hematopoietic stem cell transplantation. We also demonstrated that HGF inhibited lupus nephritis induced by chronic GVHD and dermal sclerosis in systemic sclerosis using model mice. More than 7 hundred thousand patients suffer from rheumatoid arthritis (RA) in Japan. Although the prognosis of these patients has improved by the treatment of biological agents such as TNF-α and IL-6 blockers, there remain many for whom these agents have not proved beneficial. Recently, using RA model mice, we demonstrated that the HGF antagonist, NK4, can block disease progression of RA through its anti-angiogenic and immunomodulatory actions. In this review article, we discuss the possible roles of HGF signaling for the treatment of immunological reactions in transplantation and autoimmune diseases.