Inflammatory Connective Tissue Research Articles

Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFα.

IntroductionThe advent of anti-tumor necrosis factor alpha (anti-TNFα) drugs has considerably improved medical management in rheumatoid arthritis (RA) patients, although it has been reported to be ineffective in a fraction of them. MicroRNAs (miRNAs) are small, non-coding RNAs that act as fine-tuning regulators of gene expression. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various disease models. The aim of this study was to investigate serum miRNA levels as predictive biomarkers of response to anti-TNFα therapy in RA patients.MethodsIn total, 95 RA patients undergoing anti-TNFα/disease-modifying antirheumatic drugs (anti-TNFα/DMARDs) combined treatments were enrolled. Serum samples were obtained at 0 and 6 months and therapeutic efficacy was assessed. miRNAs were isolated from the serum of 10 patients before and after anti-TNFα/DMARDs combination therapy, cDNA transcribed and pooled, and human serum miRNA polymerase chain reaction (PCR) arrays were performed. Subsequently, selected miRNAs were analyzed in a validation cohort consisting of 85 RA patients. Correlation studies with clinical and serological variables were also performed.ResultsNinety percent of RA patients responded to anti-TNFα/DMARDs combination therapy according to European League Against Rheumatism (EULAR) criteria. Array analysis showed that 91% of miRNAS were overexpressed and 9% downregulated after therapy. Functional classification revealed a preponderance of target mRNAs involved in reduction of cells maturation - especially on chondrocytes - as well as in immune and inflammatory response, cardiovascular disease, connective tissue and musculoskeletal system. Six out of ten miRNAs selected for validation were found significantly upregulated by anti-TNFα/DMARDs combination therapy (miR-16-5p, miR-23-3p, miR125b-5p, miR-126-3p, miRN-146a-5p, miR-223-3p). Only responder patients showed an increase in those miRNAs after therapy, and paralleled the reduction of TNFα, interleukin (IL)-6, IL-17, rheumatoid factor (RF), and C-reactive protein (CRP). Correlation studies demonstrated associations between validated miRNAs and clinical and inflammatory parameters. Further, we identified a specific plasma miRNA signature (miR-23 and miR-223) that may serve both as predictor and biomarker of response to anti-TNFα/DMARDs combination therapy.ConclusionsmiRNA levels in the serum of RA patients before and after anti-TNFα/DMARDs combination therapy are potential novel biomarkers for predicting and monitoring therapy outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0555-z) contains supplementary material, which is available to authorized users.

The gouty tophus: a review.

The tophus is the cardinal feature of advanced gout. This review summarises recent research into the biology, impact and treatment of tophaceous gout. Microscopically, tophi are chronic foreign body granuloma-like structures containing collections of monosodium urate (MSU) crystals surrounded by inflammatory cells and connective tissue. Extracellular trap formation mediated by neutrophil interactions with MSU crystals may be a central checkpoint in tophus formation. Gouty tophi impact on many aspects of health-related quality of life. Tophi are also implicated in the development of structural joint damage and increased mortality risk in people with gout. Effective treatment of tophaceous gout requires long-term urate-lowering therapy, ideally to achieve a serum urate concentration of <5mg/dL (300μmol/L). Recent advances in gout therapeutics have expanded urate-lowering therapy options for patients with severe tophaceous disease to allow faster regression of tophi, improved health-related quality of life and, potentially, improved structural outcomes.

Angiofibroma in a Cockatiel (Nymphicus hollandicus)

Human angiofibromas are rare and arise typically in the nasopharynx. In veterinary medicine they have only been described in the dog. Microscopically, angiofibromas consist of irregular groups of blood vessels within a stroma of connective tissue, with oedema and secondary inflammation often present. A cockatiel (Nymphicus hollandicus) was presented with an oral mass that consisted of aggregates of blood vessels surrounded by a connective tissue stroma, with the presence of oedema and secondary inflammation. Tumours of the oral cavity are uncommon in birds and to the authors' knowledge this is the first case of avian angiofibroma.

A Case of Relapsing Polychondritis Successfully Treated with Combination of a Glucocorticoid and Cyclosporine

Relapsing polychondritis is a rare cartilaginous inflammatory disease affecting the external ear, nose, peripheral joints and tracheobronchial tree. It is characterized by recurrent inflammation and degeneration of cartilage and connective tissue. A 72-year-old man complained of dyspnea, cough and wheezing for 2 months. Diffuse wall thickening and narrowing from the trachea to segmental bronchus were seen on chest CT. Tracheostomy was performed in order to avoid as-phyxia, and he was diagnosed as relapsing polychondritis on the basis of pathology evaluation of a tracheal biopsy specimen. He was treated with high doses of a glucocorticoid, with which his symptoms improved. However, the cough and wheezing recurred after tapering of the glucocorticoid. His symptoms thereafter were improved by combination of the glucocorticoid with cyclosporine. The immunosuppressive agent provided effective treatment for glucocorticoid-resistant relapsing polychondritis.

Mesh implants: An overview of crucial mesh parameters.

Hernia repair is one of the most frequently performed surgical interventions that use mesh implants. This article evaluates crucial mesh parameters to facilitate selection of the most appropriate mesh implant, considering raw materials, mesh composition, structure parameters and mechanical parameters. A literature review was performed using the PubMed database. The most important mesh parameters in the selection of a mesh implant are the raw material, structural parameters and mechanical parameters, which should match the physiological conditions. The structural parameters, especially the porosity, are the most important predictors of the biocompatibility performance of synthetic meshes. Meshes with large pores exhibit less inflammatory infiltrate, connective tissue and scar bridging, which allows increased soft tissue ingrowth. The raw material and combination of raw materials of the used mesh, including potential coatings and textile design, strongly impact the inflammatory reaction to the mesh. Synthetic meshes made from innovative polymers combined with surface coating have been demonstrated to exhibit advantageous behavior in specialized fields. Monofilament, large-pore synthetic meshes exhibit advantages. The value of mesh classification based on mesh weight seems to be overestimated. Mechanical properties of meshes, such as anisotropy/isotropy, elasticity and tensile strength, are crucial parameters for predicting mesh performance after implantation.

Взаємозв’язок паталогічного ожиріння і хронічного запальної реакції тонкої кишки

Researched biopsy of the small intestine in control person (derived from the injuries of the small intestine) and in the conditions Islands surgical treatment of morbid obesity. In pathological obesity, compared with normal weight, a decrease in villus height, increasing their thickness and deformation. Was noted increase in connective tissue, expand and overflow blood vessels, changes in muscle membrane; also found changing spectrum of white blood cells in the lamina propria of the mucous membrane of the small intestine, increase the relative number of T-lymphocytes and reduction – B-lymphocytes, a significant increase in the number of cells macrophage number and the number of T-helper cells, and more than twice the reduction in the number of T-suppressors. The data is morphological confirmation of negative changes in morbid obesity. That is, the general tendency to enhance inflammatory responses in the body has its manifestations in the small intestine. Thus, the development of pathological obesity accompanied by the development of inflammatory infiltration and connective tissue changes in the state framework and muscular elements in the wall of the small intestine, which in turn is likely to cause breach of the regulation of secretion, absorption and motility of the small intestine.

Hydroxyapatite Microsphere Production by Plasma Spray

Hydroxyapatite is Ca5(PO4)3(OH) (HA) is a material used as a bone filler and dermal or therapeutic drug vehicles, due to their biocompatibility, bioactivity and relative reabsorption in hard or soft tissue. In particular, applications of facial fillers and cements formulated with HA require that this is available in the form of spheroidal particles, with size greater than 40 microns, with the purpose of reducing the in situ inflammation of connective tissue. Chemical synthesis techniques are limited to produce smaller particles, in micro or nanometric size. This paper proposes the reprocessing of the natural HA particles, obtained from fresh bovine bone, which is subjected to chemical and thermal treatments (pyrolysis in an oxidizing atmosphere at 900C for 2h), grinding and sieving (particles less than 200μm). These particles are atomized into plasma spray equipment that draws in a N2 flow, and projects them in distilled water. This material is observed by electron microscopy, which revealed the formation of spherical particles with smooth surfaces and with a size distribution of 20-70μm. X-ray diffraction analysis revealed the partial decomposition of the HA in other calcium phosphates: α-Ca3(PO4)2 and Ca4(PO4)2O, essential phases of the formulation of bone cements, which accelerate the absorption of the biological particles in the biological medium, requirement searched in facial fillers. The process would increase the size of the spherical particles.

Macrophage activation syndrome in a child with systemic onset of juvenile idiopathic arthritis

Macrophage activation syndrome (MAS) is a serious and potentially fatal complica-tion of various diseases, mainly systemic in-flammatory connective tissue disorders, the most frequent being systemic juvenile idi-opathic arthritis (sJIA). Its most important clinical and laboratory manifestations are non-remitting fever, hepatosplenomegaly, impaired liver function, cytopenia, hypoal-buminemia, hypertriglyceridemia, hypofi-brinogenemia and hyperferritinemia. The prognosis for the syndrome is often poor, so a prompt diagnosis and the appropriate medical treatment are critical for survival. We report a case of an 8-year-old boy who developed MAS as a complication of sJIA. The boy presented with liver insufficiency, impaired coagulation, encephalopathy and respiratory failure and was treated in in-tensive care unit (ICU). He has achieved complete remission of the disease after ther-apy with pulse doses of corticosteroids and ciclosporin.

Experimental rationale for colocolonic anastomosis formation by a compression suturing device

Aim. To experimentally compare the durability and biological integrity of compressional and manually made anastomoses, and to find out morphological features of their regeneration. Methods. Experimental studies were performed on 54 non-pedigree dogs of both gender and on autopsied specimens in prosectorium. Colocolonic anastomoses were formed by compression suturing device, Ziganshin-Gunter device, compression anastomosis device, and manually. Results. Compression anastomoses had higher durability compared to manual sutures (р 0.05). A test for microbial penetration showed only minimal signs of bacterial contamination of colocolonic anastomoses made by compression suturing device. Bacterial contamination of colocolonic anastomoses performed by compression anastomosis device and compression suturing device, was significantly less common compared to anastomoses formed by Ziganshin-Gunter device and manually (р 0.05). Examination of compression anastomoses morphogenesis revealed that healing of colocolonic anastomoses is accompanied by homogenous standard morphologic pattern. No scarring occurs due to absence of inflammation and low amount of connective tissue at the anastomosis region. Study of colocolonic anastomoses formation by compression devices on an autopsied specimens confirmed the opportunity for anastomosis formation on any part of colon. Conclusion. Compression colocolonic anastomosis formed by compression suturing device is characterized by low bacterial permeability, provides good durability and does not cause scarring in the anastomosis region. Revealed advantages of compression colonic suture allow recommending it for clinical use.

Abstract 15920: The Prevalence of Atherosclerotic Disease in Those With Connective Tissue Disease as a Function of Age, Race, and Traditional Risk Factors

Background: Atherosclerosis is a multifactorial disease with an intrinsic inflammatory component, but it may also be influenced by systemic inflammation. There is cardiovascular risk associated with rheumatoid arthritis (RA), but there is still a need to clarify the contributions of traditional risk factors in those with inflammatory connective tissue diseases (CTD, which includes RA) in the development of atherosclerotic cardiovascular disease (ASCVD). It would also be useful to identify particular groups of patients that are at disproportionately greater conferred risk for ASCVD owing to their CTD. For these reasons, a cross-sectional analysis of a diverse patient population could help develop finer ASCVD risk estimations in those with and without CTD. Results: A systematically queried warehouse of de-identified data from over a quarter-million adult patients at our urban medical center over the past six years showed that prevalence of ASCVD steadily increases with age, consistent with rates found in other large cohorts, in both white and African-American patients. Amongst the ~9,000 patients with CTD (RA, other inflammatory polyarthropathy, lupus, Sjögren’s syndrome, systemic sclerosis, dermatomyositis, polymyositis), the overall prevalence of ASCVD was higher than amongst those without CTD with a rate ratio of 1.9 [95% CI 1.8-2.1] for white patients and 3.3 [95% CI 3.1-3.5] for African-American patients. Subgroup analysis revealed that the rate ratio was particularly high for young adults, and especially young African-American patients (ages 18-44; rate ratio for women: 10.7 [95% CI 8.5-13.5], for men: 9.9 [95% CI 6.8-14.5]). Rate ratios of ASCVD in those with vs. without CTD declined with age as traditional risk factors became more prevalent. Importantly, in those without any documented traditional risk factors (smoking, hypertension, diabetes, dyslipidemia), a diagnosis of ASCVD was found nearly three times more frequently in those with CTD than without [rate ratio 2.9, 95% CI 2.4-3.5]. Conclusions: CTD is associated with increased ASCVD rates, and major traditional risk factors do not fully account for these increased rates. African-Americans and young adults have a disproportionately strengthened association between CTD and ASCVD.

Molecular signaling of the HMGB1/RAGE axis contributes to cholesteatoma pathogenesis.

Cholesteatoma represents progressive expansion of the keratinizing squamous epithelium in the middle ear with subsequent chronic inflammation in subepithelial connective tissues. The hypothesis was tested that receptor for advanced glycation endproduct (RAGE) and its ligand, high-mobility box 1 (HMGB1), are overexpressed in cholesteatoma, and the RAGE/HMGB1 axis might contribute to its pathogenesis. Cholesteatoma samples (n = 36) and 27 normal skin specimens were studied by immunohistochemistry (IHC) for HMGB1 and RAGE expression. Effects of HMGB1 signaling on proliferation, migration, cytokine production, and apoptosis of human immortalized keratinocytes (HaCaTs) and normal keratinocytes were studied by quantitative reverse transcription (qRT)-PCR, IHC, Western blots, and flow cytometry after cell co-incubation with HMGB1. While all studied tissues expressed HMGB1, its expression was higher in cholesteatoma than in normal skin (p < 0.0001). All cases of cholesteatoma also showed elevated RAGE expression levels, and only 7/27 (26 %) of normal skin specimens were weakly positive for RAGE. Proliferation and migration of HaCaT cells incubated with HMGB1 were up-regulated (p < 0.05). HMGB1 also prevented HaCaT cell apoptosis and induced activation of several molecular signaling pathways in keratinocytes. The data suggest that in cholesteatoma, HMGB1 released from stressed or necrotic epithelial cells and binding to RAGE overexpressed in keratinocytes initiates molecular signaling that culminates in pro-inflammatory cytokine release and chronic inflammation.Key message HMGB1 signaling engages multiple activation pathways in RAGE-positive keratinocytes.HMGB1 protects RAGE-positive keratinocytes from drug-induced apoptosis.Keratinocyte proliferation is controlled via RAGE and HMGB1 molecular signaling.Molecular signaling of the HMGB1/RAGE axis contributes to cholesteatoma pathogenesis. Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-014-1217-3) contains supplementary material, which is available to authorized users.

Biocompatibility of new nanostructural materials based on active silicate systems and hydroxyapatite: in vitro and in vivo study.

To evaluate in vitro cytotoxicity and in vivo inflammatory response to new nanostructural materials based on active calcium silicate systems (CS) and hydroxyapatite (HA-CS). Cytotoxicity of eluates of new nanostructural noncommercial materials CS and HA-CS, and MTA (White MTA, Angelus(®) Soluções Odontológicas, Londrina, Brazil) as a control, were tested using the MTT assay on MRC-5 cells. Eluates of set materials were tested in 100% and 50% concentrations, 24 h, 7 days and 21 days post-elution. The pH values were determined for undiluted eluates of set materials. Polyethylene tubes containing the test materials (CS, HA-CS, MTA) were implanted in subcutaneous tissue of Wistar rats. Histopathological examinations were conducted at 7, 15, 30 and 60 days after the implantation. Data were statistically analyzed using three-way and one-way anova Tukey's post hoc test as well as Kruskall-Wallis test with Dunn's post hoc test at α = 0.05. All materials significantly reduced cell viability; especially when undiluted eluates were used (P < 0.001). After 24 h elution, cell viability was 10 ± 1.8%, 49.5 ± 4.2% and 61 ± 7.4%, for MTA, and HA-CS, respectively. However, CS and HA-CS were significantly less toxic than the control material MTA (P < 0.05). Cytotoxicity could be at least partially attributed to pH kinetics over time. Dilution of eluates of all tested materials resulted in better cell survival. Histopathological examination indicated similar inflammatory reaction, vascular congestion and connective tissue integrity associated with CS, HA-CS and MTA at each observation period (P > 0.05). The only significant difference was found for capsule thickness, that is thicker capsule was associated with HA-CS compared to MTA at 60 days (P = 0.0039). HA-CS induced moderately thick capsules (median score 3, score range 2-3), whereas MTA resulted in thin capsule formation (median score 2, score range 1-3). Evaluation of cytotoxicity and inflammatory response indicated better biocompatibility of CS and HA-CS, in comparison with MTA (White MTA, Angelus(®) Soluções Odontológicas, Londrina, Brazil).

Ga-68-DOTA-TATE PET/CT for Discrimination of Tumors of the Optic Pathway

Purpose: Symptomatic tumors of the optic nerve pathway may endanger vision. They are difficult to classify by imaging alone and biopsy may damage visual function. Tumor pathology influences treatment decision and a diagnostic tool with a high sensitivity and specificity would therefore be invaluable. We hypothesized that Ga-68-DOTA-TATE PET/CT may help in discriminating optic nerve tumors as uptake of somatostatin is elevated in meningiomas.Material and Methods: Ga-68-DOTA-TATE PET/CT was used to examine 13 patients with ambiguous, symptomatic lesions of the optic pathway for treatment planning. The presence or absence of meningioma was validated by histopathology or supplementary diagnostic work-up.Results: Ga-68-DOTA-TATE PET/CT identified 10 meningiomas (en plaque = 1, optic nerve sheath = 4, sphenoidal = 5) correctly via increased SSTR (somatostatin receptor) expression (mean SUVmax (maximum standardized uptake value) = 14.3 ± 15.4). 3 tumors did not show elevated Ga-68-DOTA-TATE uptake (SUVmax = 2.1 ± 1.0). Subsumizing all clinical-radiological follow-up tools available, these lesions were classified as an intracerebral metastasis of an advanced gastric carcinoma, histologically proven inflammatory collagenous connective tissue and presumed leukemic infiltration of a newly diagnosed chronic lymphocytic leukemia. In this case series, Ga-68-DOTA-TATE PET/CT demonstrated both a sensitivity and specificity of 100%. Yet, the golden standard of histopathology was only available in a subset of patients included.Conclusion: Ga-68-DOTA-TATE PET/CT proved to be a valuable diagnostic tool for the correct classification of equivocal, symptomatic tumors of the anterior optic pathway requiring therapy. PET/CT results influenced therapy decision essentially in all cases.

A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases

IntroductionWe performed a meta-analysis to investigate the risk of deep vein thrombosis (DVT) and/or pulmonary embolisms (PEs) in patients with inflammatory arthritis, vasculitis and connective tissue diseases (CTDs) (systemic lupus erythematosus (SLE), Sjögren’s syndrome, inflammatory myositis and systemic sclerosis (SSc)).MethodsPubMed, Embase, the Cochrane databases and MEDLINE were searched to identify full-text English-language publications about adult patients with rheumatologic inflammatory diseases and venous thromboembolisms (VTEs). Data regarding rates of DVTs and PEs were extracted. Using random-effects models, pooled estimates for VTEs in individual and pooled diseases were compared with matched populations where possible. Studies were excluded if VTEs were described in the setting of pregnancy, postoperative outcomes or solely antiphospholipid antibody syndrome.ResultsMost of the 5,206 studies were excluded because they did not state the rate or incidence of VTEs. In total, 25 studies remained for analysis. Ten studies that included rheumatoid arthritis comprised an aggregate of 5,273,942 patients and 891,530,181 controls with a cumulative VTE incidence of 2.18% (95% confidence interval (CI): 1.82% to 2.54%) and an odds ratio of 2.23 (95% CI: 2.02 to 2.47) compared to age- and sex-matched populations. Ten studies comprised an aggregate of 54,697 SLE patients with a cumulative VTE incidence of 7.29% (95% CI: 5.82% to 8.75%). Four Sjögren’s syndrome studies comprising an aggregate of 25,100 patients demonstrated a cumulative VTE incidence of 2.18% (95% CI: 0.79% to 3.57%). Four studies of inflammatory myositis comprising an aggregate of 8,245 patients yielded a cumulative VTE incidence of 4.03% (95% CI: 2.38% to 5.67%). The SSc- and antineutrophil cytoplasmic antibody vasculitis–related cumulative VTE rates (four studies each) were 3.13% and 7.97%, respectively.ConclusionsThe inflammatory rheumatologic diseases studied were all associated with high rates of VTEs—more than three times higher than in the general population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0435-y) contains supplementary material, which is available to authorized users.

The risk of ischemic stroke in major rheumatic disorders.

Rheumatic disorders (RD) are a range of conditions associated with inflammation of joints and connective tissue. They can manifest beyond the musculoskeletal system. Recent focus has been placed on the association of ischemic stroke with these conditions. Traditional vascular risk factors seem to be more prevalent in patients with certain types of RD than in the general population, but these factors do not fully explain the enhanced vascular risk in this population. Four major RD will be discussed in terms of their relationship with ischemic stroke: rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and psoriatic arthritis.

Cushing syndrome.

Cushing syndrome.

Safety of less frequent monitoring of liver transaminases levels in rheumatic patients treated with low-dose methotrexate.

Consideration of the safety of liver transaminases monitoring every 12weeks in patients with inflammatory connective tissue disorders who are treated with methotrexate (MTX). In a retrospective study, the data from rheumatic patients receiving MTX were analyzed. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured every 12weeks. Based on the physician's final decision about the continuation of MTX, the patients were classified into one of the following groups: continuation of MTX without MTX dose reduction, MTX dose reduction, MTX discontinuation due to liver complication and MTX discontinuation due to other reasons. A total of 809 patients who were on MTX were included in the study. The mean follow-up duration and the mean duration of treatment with MTX were 31.22 and 19.76months, respectively. The mean accumulation dose of MTX was 865.85mg. Due to the increase in the level of transaminases in 3.2% of the patients, MTX dose was reduced; and in 1.1% of the cases it was temporarily discontinued. In the follow-up of the patients with elevated transaminases, they returned to normal limits in 99.5% of patients; and only in four cases (0.5%) they remained elevated and MTX was discontinued. The probability of the patients remaining on MTX for 5years without discontinuation for liver complications was 98.5% Liver transaminase monitoring every 12weeks for MTX-treated patients is safe.

Морфологические особенности поведения гемостатического препарата «Серджисел Фибрилляр» при лечении сквозных ран печени

The experiment was carried out on 21 mongrel dogs. The authors studied the morphological changes in the liver after introduction of a pass-through stab wound hemostatic preparation new generation &amp;#34; Sergisel Fibrillar &amp;#34; and cryo-application the mouth of the wound channel to secure the preparation and amplification hemostatic effect. During observation from 1 to 30 days it is established gradually wound healing and formation of liver damage in the area of fine connective tissue scar. After the use of the &amp;#34;Sergisel fibrillar&amp;#34; as a foreign object, standard morphological response in the form of a purulent inflammation and proliferation of connective tissue are developed. These processes are broken off and around the fibers don’t develop abscess, because resorption of fiber hemostatic agents occurs in a short time. The results of the end of the experimental observation were the followings: regenerative processes in liver parenchyma increasing, particularly in the area of damage and are shown restoration of the girder structure of the liver, the disappearance of oedema and plethora. It indicates the recovery of liver tissue after applying the proposed method.

AB1081 Results of A Walk-In Bone and Joint Screening CAMPAIGN to AID in the Diagnosis of Rheumatic Diseases

BackgroundRheumatic diseases are underdiagnosed in the Middle East. Screening and awareness campaigns can be used in conjunction with peripheral ultrasound machines used to screen for low bone mass are a...

THU0300 Septic Arthritis in the Central Part of Denmark

BackgroundSeptic arthritis (SA) is a serious condition which can lead to rapid cartilage destruction and irreversible joint damage and is asociated with a significant mortality. SA is an uncommon condition...