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ID PMID Title PublicationDate abstract
21678460 Biselyngbyaside, isolated from marine cyanobacteria, inhibits osteoclastogenesis and induc 2012 Feb The mass and function of bones depend on the maintenance of a complicated balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. An inhibitor of osteoclast differentiation and/or function is expected to be useful for treatment of bone lytic diseases such as osteoporosis, rheumatoid arthritis, and tumor metastasis into bone. Biselyngbyaside is a recently isolated macrolide compound from marine cyanobacteria Lyngbya sp. that shows wide-spectrum cytotoxicity toward human tumor cell lines. In this study, we investigated the effects of biselyngbyaside on osteoclast differentiation and function. Biselyngbyaside inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in mouse monocytic RAW264 cells and primary bone marrow-derived macrophages at a low concentration. Similarly, biselyngbyaside suppressed osteoblastic cell-mediated osteoclast differentiation in cocultures. In the RANKL-induced signaling pathway, biselyngbyaside inhibited the expression of c-Fos and NFATc1, which are important transcription factors in osteoclast differentiation. In mature osteoclasts, biselyngbyaside decreased resorption-pit formation. Biselyngbyaside also induced apoptosis accompanied by the induction of caspase-3 activation and nuclear condensation, and these effects were negated by the pancaspase inhibitor z-VAD-FMK. Taken together, the present findings indicate that biselyngbyaside suppresses bone resorption via inhibition of osteoclastogenesis and induction of apoptosis. Thus, biselyngbyaside may be useful for the prevention of bone lytic diseases.
21587110 Major complications in revision adult deformity surgery: risk factors and clinical outcome 2012 Mar 15 STUDY DESIGN: Retrospective cohort comparative study. OBJECTIVE: To determine the prevalence of major complications, identify risk factors, and assess long-term clinical benefit after revision adult spinal deformity surgery. SUMMARY OF BACKGROUND DATA: No study has analyzed risk factors for major complications in long revision fusion surgery and whether or not occurrence of a major complication affects ultimate clinical outcome. METHODS: Analysis of consecutive adult patients who underwent multilevel revision surgery for spinal deformity with a minimum 2-year follow-up was performed. All complications were classified as either major or minor. Outcome analysis was conducted with the Scoliosis Research Society and Oswestry Disability Index scores. RESULTS: A total of 166 patients (mean age = 53.8 years) were identified with a mean follow-up of 3.5 years (range: 2-7). Primary diagnoses included idiopathic/de novo scoliosis (107), degenerative (35), trauma (7), neuromuscular scoliosis (6), congenital deformity (5), ankylosing spondylitis (2), tumor (2), Scheuermann kyphosis (1), and rheumatoid arthritis (1). Most common secondary diagnoses that necessitated revision surgery were adjacent segment disease, fixed sagittal imbalance, and pseudarthrosis. Overall, 34.3% of patients developed major complications (19.3% perioperative; 18.7% follow-up). Associated risk factors for perioperative complications were patient- (age > 60 years, medical comorbidities, obesity) and surgery-related (pedicle subtraction osteotomy). Performance of a 3-column osteotomy and postoperative radiographic changes that suggested progressive loss of sagittal correction were recognized as risk factors for follow-up complications. Equivalent outcome scores were reported by patients preoperatively, but those experiencing follow-up complications reported lower scores at the final follow-up. CONCLUSION: Overall, 34.4% of patients experienced major complications after long revision fusion surgery. Different risk factors were identified for perioperative versus follow-up complications. The occurrence of a follow-up, not but perioperative, major complication seemed to have a negative impact on ultimate clinical outcome.
21499414 Probing the mechanical properties of TNF-α stimulated endothelial cell with atomic force 2011 TNF-α (tumor necrosis factor-α) is a potent pro-inflammatory cytokine that regulates the permeability of blood and lymphatic vessels. The plasma concentration of TNF-α is elevated (> 1 pg/mL) in several pathologies, including rheumatoid arthritis, atherosclerosis, cancer, pre-eclampsia; in obese individuals; and in trauma patients. To test whether circulating TNF-α could induce similar alterations in different districts along the vascular system, three endothelial cell lines, namely HUVEC, HPMEC, and HCAEC, were characterized in terms of 1) mechanical properties, employing atomic force microscopy; 2) cytoskeletal organization, through fluorescence microscopy; and 3) membrane overexpression of adhesion molecules, employing ELISA and immunostaining. Upon stimulation with TNF-α (10 ng/mL for 20 h), for all three endothelial cells, the mechanical stiffness increased by about 50% with a mean apparent elastic modulus of E ~5 ± 0.5 kPa (~3.3 ± 0.35 kPa for the control cells); the density of F-actin filaments increased in the apical and median planes; and the ICAM-1 receptors were overexpressed compared with controls. Collectively, these results demonstrate that sufficiently high levels of circulating TNF-α have similar effects on different endothelial districts, and provide additional information for unraveling the possible correlations between circulating pro-inflammatory cytokines and systemic vascular dysfunction.
21422868 Pregnancy in women with physical disabilities. 2011 Apr The Eunice Kennedy Shriver National Institute of Child Health and Human Development sponsored a 2-day workshop to assess the body of evidence on pregnancy in women with physical disabilities, identify gaps in knowledge, and formulate recommendations for further research. A multidisciplinary group of experts discussed available data on pregnancy outcomes among women with varying physically disabling conditions, medical and psychosocial risks for mothers and children, and barriers to prenatal care and parenting for women with physical disabilities. Existing evidence is limited by a preponderance of retrospective single-site studies of small sample sizes. For most women, pregnancy outcomes are favorable. However, increased rates of certain adverse outcomes, such as low birth weight (related to preterm birth or growth restriction) and cesarean delivery, have been reported in women with spinal cord injuries, rheumatoid arthritis, multiple sclerosis, or other conditions. Common morbidities across conditions may include urinary tract infections, decreased mobility and independence, skin ulceration, respiratory compromise, interpersonal abuse, stress, and mood disorders. Socioeconomic, physical, and attitudinal barriers to antenatal care and independent parenting can be problematic. Current evidence, although limited, indicates that most women with physical disabilities will have good pregnancy outcomes; however, some data suggest that rates of a range of complications may be more common among women with physical disabilities, depending on the nature and severity of the underlying condition. Many questions remain unanswered. Establishment of a systematic and comprehensive registry of pregnancy course and outcomes among women with physical disabilities is of high priority for addressing persistent gaps in knowledge.
21396998 Cortex Dictamni extract induces apoptosis of activated hepatic stellate cells via STAT1 an 2011 Apr 26 ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicines, Cortex Dictamni is prescribed for the treatment of a variety of inflammatory diseases such as acute rheumatoid arthritis, skin inflammation and jaundice. AIM OF THE STUDY: This study was designed to investigate the effect of ethanol extract of Cortex Dictamni on treatment of hepatic fibrosis and its possible mechanisms. MATERIALS AND METHODS: The in vivo effect of Cortex Dictamni extract (CDE) was evaluated by measuring histological changes and collagen content in CCl(4)-indcued hepatic fibrosis mice. Viability, apoptosis and protein expression of hepatic stellate cells (HSC) were analyzed by MTT, Annexin V staining and Western blot respectively. RESULTS: CDE alleviated CCl(4)-induced hepatic fibrosis in mice and showed a much stronger inhibition of cell viability in activated HSC cell line HSC-T6 than that in normal hepatocyte L02 cells. Furthermore, CDE induced apoptosis of HSC-T6 cells associated with increased expressions of cleaved PARP and cleaved caspase-3. Interestingly, CDE activated STAT1 in HSC-T6 cells and the effect of CDE on apoptosis of HSC-T6 cells could be neutralized using JAK/STAT1 signaling inhibitor AG490. CONCLUSIONS: These findings suggest that CDE possesses anti-fibrosis activity with selectively induction of activated HSC apoptosis via activating STAT1, which might be a novel strategy for hepatic fibrosis therapy.
21362236 [Clinic-pathologic characteristics of autoimmune diseases combined with non-Hodgkin's lymp 2011 Feb This study was aimed to investigate the clinical characteristics and treatment of patients with autoimmune disease combined with non-Hodgkin lymphoma (NHL). The clinical characteristics and pathologic patterns of 6 patients with NHL who concurrently suffered from autoimmune diseases were analysed retrospectively from aspects of clinical course, pathologic features, and therapy. Treatment outcomes for autoimmune diseases and NHL were observed. The results showed that 6 patients included 4 females and 2 males, range in age from 28 to 65 years with a median age of 56 years. The autoimmune diseases are Sjogren's syndrome (SS, 2 cases), rheumatoid arthritis (RA, 2 cases), ulcerative colitis (UC, 1 case) and Crohn's disease (CD, 1 case). The NHL diseases located not only in the lymph node (n = 3) but also in extranodal sites (n = 3). Histologically, 3 cases were diffuse large B cell lymphoma (DLBCL), 2 cases were extranodal nasal NK/T lymphoma (ENKL) and 1 case was peripheral T cell lymphoma, not otherwise specified. Based on CD10, Bcl-6 and MUM1 expression patterns, all 3 DLBCL were classified as non-GC subtype. EBER positive tumor cells were detected in 2 case of ENKL. 5 patients achieved a complete remission (83%) and 1 patient was primary drug-resistant after CHOP chemotherapy or involved radiotherapy. Median survival from the time of lymphoma diagnosis was 3 years. 1 patient showed clinical improvement of the SS symptoms, 2 patients (CD and UC) showed stable state of disease and 2 patients with RA and 1 patient with SS needed continuing treatment for their autoimmune diseases after chemotherapy for NHL. It is concluded that the development of NHL is one of the most serious complications in patients with autoimmune diseases. There is an increased frequency of non-GC subtype DLBCL. CHOP combined with or without radiotherapy proves to be effective for autoimmune disease patients with aggressive NHL but ineffective for concurrent autoimmune diseases.
21167838 Lactobacillus casei enhances type II collagen/glucosamine-mediated suppression of inflamma 2011 Feb 14 AIMS: We previously reported that Lactobacillus casei (L. casei) has beneficial effects in experimental rheumatoid arthritis (RA) by suppressing inflammatory immune responses. The major purpose of this study was to evaluate therapeutic effects of L. casei on pathological responses in experimental rodent model of osteoarthritis (OA). MAIN METHODS: Experimental OA was induced by intra-articular injection of monosodium iodoacetate (MIA) in Wistar rats. L. casei alone or together with type II collagen (CII) and glucosamine (Gln) was orally administered into OA rats. The pathophysiological aspects of OA were investigated by analyzing mechanical hyperalgesia and histology of articular tissues. Expression of inflammatory molecules was analyzed in CD4(+) T cells, synovial fibroblasts, and chondrocytes by quantitative real-time PCR. KEY FINDINGS: Oral administration of L. casei together with CII and Gln more effectively reduced pain, cartilage destruction, and lymphocyte infiltration than the treatment of Gln or L. casei alone. This co-administration also decreased expression of various pro-inflammatory cytokines (interleukin-1β (IL-1β), IL-2, IL-6, IL-12, IL-17, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ)) and matrix metalloproteinases (MMP1, MMP3, and MMP13), while up-regulating anti-inflammatory cytokines (IL-4 and IL-10). These results are concomitant with reduced translocation of NF-κB into the nucleus and increased expression of the tissue inhibitor of MMP1 (TIMP1) and CII in chondrocytes. SIGNIFICANCE: Our study provides evidence that L. casei could act as a potent nutraceutical modulator for OA treatment by reducing pain, inflammatory responses, and articular cartilage degradation.
21070482 Ultrasound detects joint damage and bleeding in haemophilic arthropathy: a proposal of a s 2011 Jan Haemarthrosis triggers haemophilic arthropathy (HA) because bleeding starts synovitis immediately, damages cartilage and leads to loss of function and disability. The aim of our study was to investigate the capacity of ultrasonography (US) in detecting bleeding and joint damage in HA. The joints of 62 patients (pts) with haemophilia A or haemophilia B were consecutively evaluated and scored (score ranging from 0 to 21) for effusion (E), bone remodelling (BR), cartilage damage (CD), synovial hypertrophy (SH), haemosiderin (H), osteophytes (O), haemarthrosis (Hae), erosion (Er) and fibrotic septa (FS) with US. X-rays [Pettersson Score (PXS)] were performed in 61 patients and clinical evaluation [World Federation Haemophiliac orthopaedic score (WFHO)] was performed in all patients. A total of 20 healthy subjects and 20 patients affected by Rheumatoid Arthritis (RA) were used as controls. Power Doppler US (PDUS) was performed in all patients on the knee, ankle and elbow joints. A total of 83 joints were studied (50 knees; 12 elbows and 21 ankles). US showed effusion in 57 joint, bone remodelling in 62, cartilage damage in 64, synovial hypertrophy in 45, haemosiderin in 39, osteophytes in 30, haemarthrosis in 24, erosion in 5 and fibrotic septa in 3. The X-rays score showed remodelling in 47 joints, narrowing joint space in 44, displacement/angulation in 39, osteoporosis in 42, subchondral irregularity in 44, subchondral cyst formation in 37, osteophytes in 36 and erosions in 25. The US score in healthy subjects was always ≤ 5 (range 0 to 4). In haemophiliacs, 34 of 83 joints showed US score ≤ 5, and 49 US score > 5. Joints with US score ≤ 5 had a low PXS (SRCC = 0.375, P < 0.01) and joints with US score > 5 showed a high PXS (SRCC = 0.440, P < 0.01). A significant correlation between US score and PXS for bone remodelling [Spearman's rho Correlation Coefficient (SRCC) = 0.429, P < 0.01] and for osteophytes (SRCC = 0.308, P < 0.05) was found. The correlation between the US score and number of bleedings in 83 joints was very significant (SRCC = 0.375, P < 0.01). A total of 24 bleeding joints were identified and verified with aspiration of haematic fluid. US may detect bone and cartilage alterations and synovitis. Indeed, PDUS identified bleeding also in asymptomatic joints and was able to show different entity of haemarthrosis. US may be a feasible and reliable tool to evaluate joint modifications in HA.
21040744 Allograft inflammatory factor-1 is overexpressed and induces fibroblast chemotaxis in the 2011 Mar 30 Allograft inflammatory factor (AIF)-1 has been identified in chronic rejection of rat cardiac allografts and is thought to be involved in the immune response. We previously showed that AIF-1 was strongly expressed in synovial tissues in rheumatoid arthritis and that rAIF-1 increased the IL-6 production of synoviocytes and peripheral blood mononuclear cells. Recently, the expression of AIF-1 has been reported in systemic sclerosis (SSc) tissues, whose clinical features and histopathology are similar to those of chronic graft-vs-host disease (GVHD). To clarify the pathogenic mechanism of fibrosis, we examined the expression and function of AIF in sclerodermatous (Scl) GVHD mice. We demonstrated that immunoreactive AIF-1 and IL-6 were significantly expressed in infiltrating mononuclear cells and fibroblasts in thickened skin of Scl GVHD mice compared with control. The immunohistochemical findings were confirmed by Western blot analysis. Wound healing assay also revealed that rAIF-1 increased the migration of normal human dermal fibroblasts (NHDF) directly, but cell growth assay did not show that rAIF-1 increased the proliferation of them. These findings suggest that AIF-1, which can induce the migration of fibroblasts and the production of IL-6 in affected skin tissues, is an important molecule promoting fibrosis in GVHD. Although the biological function of AIF-1 has not been completely elucidated, AIF-1 can induce IL-6 secretion on mononuclear cells and fibroblast chemotaxis. AIF-1 may accordingly provide an attractive new target for antifibrotic therapy in SSc as well as Scl GVHD.
20661687 Oral glutamine attenuates cyclophosphamide-induced oxidative stress in the bladder but doe 2011 Jun Cyclophosphamide (CP) is widely used in the treatment of cancer and non-malignant disease states such as rheumatoid arthritis. Hemorrhagic cystitis is a major dose-limiting side effect of CP. The incidence of this side effect is related to the dosage and can be as high as 75%. Elimination of the side effects of CP can lead to better tolerance of the drug, and a more efficient therapy can be achieved for patients in need of CP treatment. Several studies have demonstrated that oxidative stress and neutrophil infiltration play important roles in CP-induced bladder damage. Glutamine is utilized under clinical conditions for preventing chemotherapeutic drug-induced side effects, based on its ability to attenuate oxidative stress. The aim of the study is to verify whether glutamine prevents CP-induced oxidative stress and bladder damage using a rat model. Adult male rats were administered 150 mg/kg body weight of CP intraperitoneally. Glutamine pretreated rats were administered 1 g/kg body weight of glutamine orally 2 h before the administration of CP. Vehicle/glutamine-treated rats served as controls. All the rats were killed 16 h after the dose of CP/vehicle. The urinary bladders were removed and used for light microscopic and biochemical studies. The markers of oxidative stress including malondialdehyde content, protein carbonyl content, protein thiol, and myeloperoxidase activity, a marker of neutrophil infiltration, were measured in bladder homogenates. CP treatment induced hemorrhagic cystitis in the rats. Pretreatment with glutamine significantly reduced CP-induced lipid peroxidation (p < 0.01), protein oxidation (p < 0.01), and increase in myeloperoxidase activity (p < 0.05). However, it did not prevent CP-induced bladder damage. The results of the present study show that glutamine pretreatment does not attenuate CP-induced hemorrhagic cystitis, although it prevents CP-induced oxidative stress and neutrophil infiltration significantly. It is therefore necessary to clarify the utility of glutamine as a chemoprotective agent before it is recommended in the market as a nutrient supplement.
20444206 ELPylated anti-human TNF therapeutic single-domain antibodies for prevention of lethal sep 2011 Jan Tumour necrosis factor (TNF) is a major pro-inflammatory cytokine involved in multiple inflammatory diseases. The detrimental activity of TNF can be blocked by various antagonists, and commercial therapeutics based upon this principle have been approved for treatment of diseases including rheumatoid arthritis, Crohn's disease and psoriasis. In a search for new, improved anti-inflammatory therapeutics we have designed a single-domain monoclonal antibody (V(H) H), which recognizes TNF. The antibody component (TNF-V(H) H) is based upon an anti-human TNF Camelidae heavy-chain monoclonal antibody, which was linked to an elastin-like polypeptide (ELP). We demonstrate that ELP fusion to the TNF-V(H) H enhances accumulation of the fusion protein during biomanufacturing in transgenic tobacco plants. With this study, we show for the first time that this plant-derived anti-human TNF-V(H) H antibody was biologically active in vivo. Therefore, therapeutic application of TNF-V(H) H-ELP fusion protein was tested in humanized TNF mice and was shown to be effective in preventing death caused by septic shock. The in vivo persistence of the ELPylated antibody was ∼24 fold longer than that of non-ELPylated TNF-V(H) H.
23363939 Determination of subclinical atherosclerosis in plaque type psoriasis patients without tra 2012 Oct OBJECTIVES: Systemic inflammation plays an important role in the pathogenesis of atherosclerosis in psoriasis patients. Therefore, persistent skin inflammation in psoriasis patients may contribute to the development of premature atherosclerosis, as it occurs in rheumatoid arthritis and systemic lupus erythematosus. We aimed to evaluate the relationship between subclinical atherosclerosis and psoriasis by using pulse wave velocity (PWV) and the measurement of carotid intima media thickness (CIMT) in psoriatic patients. STUDY DESIGN: Fifty-seven plaque-type psoriasis patients (31 males, 26 females; mean age 41±10.8 years) and 60 healthy individuals (32 males, 28 females; mean age 40±9.4 years) were included. Atherosclerotic risk factors were excluded in both of the groups. Demographic, bio-chemical data, psoriasis area and severity index (PASI) score of the psoriasis group, and disease duration were recorded. Carotid-femoral artery PWV and CIMT values were compared. RESULTS: PWV, and the maximum and average CIMT values of psoriasis patients were higher than those of the healthy group (PWV: 7.04±1.1 m/sn vs. 6.03±0.61 m/sn, p<0.001; maximum CIMT: 0.86±0.09 mm vs. 0.77±0.06 mm, p<0.001; mean CIMT: 0.73±0.09 mm vs. 0.66±0.06 mm p<0.001, respectively). Although there was no difference in the lipid levels of the groups, total/HDL cholesterol (4.40±1.26 vs. 3.88±1.18, p=0.02, respectively), and LDL/HDL cholesterol ratios (2.78±0.98 vs. 2.32±0.92, p=0.01, respectively) of the psoriasis group were higher than those of the healthy group. A positive correlation was observed between PASI and the PWV (r=0.417, p=0.001). CONCLUSION: Despite the nonexistence of atherosclerotic risk factors, the risk of development of atherosclerosis is higher in psoriasis patients compared to healthy individuals. In addition to damage of the artery wall caused by systemic inflammation, lipid metabolism disorders may contribute to the development of atherosclerosis in these patients.
22701612 Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro. 2012 BACKGROUND: Osteoclasts are the body's sole bone resorbing cells. Cytokines produced by pro-inflammatory effector T-cells (T(EFF)) increase bone resorption by osteoclasts. Prolonged exposure to the T(EFF) produced cytokines leads to bone erosion diseases such as osteoporosis and rheumatoid arthritis. The crosstalk between T-cells and osteoclasts has been termed osteoimmunology. We have previously shown that under non-inflammatory conditions, murine osteoclasts can recruit naïve CD8 T-cells and activate these T-cells to induce CD25 and FoxP3 (Tc(REG)). The activation of CD8 T-cells by osteoclasts also induced the cytokines IL-2, IL-6, IL-10 and IFN-γ. Individually, these cytokines can activate or suppress osteoclast resorption. PRINCIPAL FINDINGS: To determine the net effect of Tc(REG) on osteoclast activity we used a number of in vitro assays. We found that Tc(REG) can potently and directly suppress bone resorption by osteoclasts. Tc(REG) could suppress osteoclast differentiation and resorption by mature osteoclasts, but did not affect their survival. Additionally, we showed that Tc(REG) suppress cytoskeletal reorganization in mature osteoclasts. Whereas induction of Tc(REG) by osteoclasts is antigen-dependent, suppression of osteoclasts by Tc(REG) does not require antigen or re-stimulation. We demonstrated that antibody blockade of IL-6, IL-10 or IFN-γ relieved suppression. The suppression did not require direct contact between the Tc(REG) and osteoclasts. SIGNIFICANCE: We have determined that osteoclast-induced Tc(REG) can suppress osteoclast activity, forming a negative feedback system. As the CD8 T-cells are activated in the absence of inflammatory signals, these observations suggest that this regulatory loop may play a role in regulating skeletal homeostasis. Our results provide the first documentation of suppression of osteoclast activity by CD8 regulatory T-cells and thus, extend the purview of osteoimmunology.
22658165 [Prevalence and diagnostic value of antinuclear antibodies without identified antigenic ta 2012 Sep PURPOSE: The objective of this study was to determine the clinical relevance and the diagnostic significance of positive antinuclear antibodies (ANA) without identified antigenic target by the usual characterization technique. PATIENTS AND METHODS: Retrospective study conducted in the Laboratory of Immunology of Habib Bourguiba Hospital (Sfax, Tunisia) during 18 months. The inclusion criteria were the presence of an ANA titer greater or equal to 1/320 with negative characterization result. ANA screening was performed by indirect immunofluorescence (IIF) on Hep2 cells. Each positive serum was tested by IIF on Crithidia luciliae (anti-native DNA) and by immunodot (anti-nucleosome, anti-histone, anti-Sm, anti-RNP, anti-SSA, anti-SSB, anti-Scl 70, anti-PM-Scl, anti-Jo1, anti-PCNA and anti-ribosomal protein). Sera of systemic lupus erythematosus (SLE), myositis, and scleroderma patients were tested for anti-Ku, anti-PL7, anti-PL12 and anti-Ro-52 using dot myositis. RESULTS: Sera of 90 patients were studied: 18 men and 72 women (average age: 44 years). Drug-induced ANA was found in eight patients. The most frequent clinical symptoms were joint (56.7%), cutaneous (54.4%) and constitutional symptoms (45.6%). The diagnosis of an autoimmune disease was suspected in 49 patients (54.5%) and confirmed in 30 (33.3%) including 20 cases of connective tissue disease: myositis (n=6), scleroderma (n=5), Sjögren's syndrome (n=3), SLE (n=4), rheumatoid arthritis (n=6) and antiphospholipid syndrome (n=4). Other autoimmune diseases were less frequent. The anti-Ku antibody was detected in the majority of patients with connective tissue disease. The diagnosis of non-autoimmune diseases was established in 25.5% of patients. Eighteen patients (20%) had no diagnosis orientation. CONCLUSION: Our study demonstrated the diagnostic value of the presence of ANA even in the absence of known antigenic target, confirmed the role of the IIF as "gold standard" test for ANA screening, and suggested the usefulness of the addition of Ku antigen in the immunodot classic profile.
22560840 Neuronal PAD4 expression and protein citrullination: possible role in production of autoan 2012 Jun Peptidyl arginine deiminases (PADs) catalyze a post-translational protein modification reaction called citrullination, where arginine is converted to citrulline. This modification has been linked to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). More recently, several studies have suggested that Alzheimer's disease (AD), a devastating neurodegenerative disorder, may have an autoimmune component. In the present study, we have investigated the possibility that expression of PADs and protein citrullination plays a role in the production of brain-reactive autoantibodies that may contribute to Alzheimer's-related brain pathology. Here, we report the selective expression of the PAD isoforms, PAD2 and PAD4, in astrocytes and neurons, respectively, and the concomitant accumulation of citrullinated proteins within PAD4-expressing cells, including neurons of the hippocampus and cerebral cortex. Expression of PADs and citrullinated proteins is prominent in brain regions engaged in neurodegenerative changes typical for AD pathology. Furthermore, we also demonstrate that the pentatricopeptide repeat domain2 (PTCD2) protein, an antigen target of a prominent AD diagnostic autoantibody, is present in a citrullinated form in AD brains. Our results suggest that disease-associated neuronal loss results in the release of cellular contents, including citrullinated proteins, into the brain interstitium. We propose that these citrullinated proteins and their degradation fragments enter into the blood and lymphatic circulation, and some are capable of eliciting an immune response that results in the production of autoantibodies. The long-term and progressive nature of AD and other neurodegenerative diseases results in chronic exposure of the immune system to these citrullinated products and may drive the continual production of autoantibodies.
22485170 Modulation of Wnt5a expression by periodontopathic bacteria. 2012 Wingless proteins, termed Wnt, are involved in embryonic development, blood cell differentiation, and tumorigenesis. In mammalian hematopoiesis, Wnt signaling is essential for stem-cell homeostasis and lymphocyte differentiation. Recent studies have suggested that these molecules are associated with cardiovascular diseases, rheumatoid arthritis, and osteoarthritis. Furthermore, Wnt5a signaling is essential for the general inflammatory response of human macrophages. Periodontitis is a chronic inflammatory disease caused by gram-negative periodontopathic bacteria and the resultant host immune response. Periodontitis is characterized by loss of tooth-supporting structures and alveolar bone resorption. There have been no previous reports on Wnt5a expression in periodontitis tissue, and only few study reported the molecular mechanisms of Wnt5a expression in LPS-stimulated monocytic cells. Using RT-PCR, we demonstrated that Wnt5a mRNA expression was up-regulated in chronic periodontitis tissue as compared to healthy control tissue. P. gingivalis LPS induced Wnt5a mRNA in the human monocytic cell line THP-1 with a peak at 4 hrs after stimulation. P. gingivalis LPS induced higher up-regulation of Wnt5a mRNA than E. coli LPS. The LPS receptors TLR2 and TLR4 were equally expressed on the surface of THP-1 cells. P. gingivalis LPS induced IκBα degradation and was able to increase the NF-κB binding activity to DNA. P. gingivalis LPS-induced Wnt5a expression was inhibited by NF-κB inhibitors, suggesting NF-κB involvement. Furthermore, IFN-γ synergistically enhanced the P. gingivalis LPS-induced production of Wnt5a. Pharmacological investigation and siRNA experiments showed that STAT1 was important for P. gingivalis LPS-induced Wnt5a expression. These results suggest that the modulation of Wnt5a expression by P. gingivalis may play an important role in the periodontal inflammatory process and serve a target for the development of new therapies.
22327458 Health-related quality of life in people with hereditary multiple exostoses. 2012 Mar BACKGROUND: Hereditary multiple exostoses (HME) is a rare genetic disorder, which can be associated with severe complications that may significantly affect the health-related quality of life (HRQL). Our primary objective was to describe the baseline HRQL in HME individuals at the British Columbia's Children's Hospital HME clinic and the Multiple Hereditary Exostoses Coalition compared with relevant Canadian and US population norms. This is the first study to explore the HRQL among adults and children with HME. METHODS: Previously validated instruments Short Form-36 version 2, Short form-6D, and Child Health Questionnaire Parent Form 50 were used to assess the HRQL of individuals with HME. The scores from these instruments were compared with the relevant population norms. The British Columbia's Children's Hospital and Multiple Hereditary Exostoses coalition populations were also compared with each other. RESULTS: The study sample consisted of 100 participants including 57 adults and 43 children. The mean age for Short Form 36 version 2 survey was 40.10±13.01 years and for Child Health Questionnaire Parent Form 50 was 9.93±3.48 years. Adult HME population had lower scores than both the US and Canadian general population in all domains except for emotional role limitations. Short Form -6D utility scores (0.65) indicates the quality of life for some individuals is near death and for others it is comparable or better than individuals with rheumatoid arthritis. Children with HME scored less than the US general population; particularly lower scores were seen in bodily pain (51.2 vs. 81.7) and emotional self-esteem (52.0 vs. 79.8). CONCLUSIONS: HME population has lower HRQL than the general population. These data provide a benchmark for individuals with HME. From such data, future research on HME disease progression and effectiveness of treatments/interventions can be tracked over time. LEVEL OF EVIDENCE: Level II, This is a prognostic, prospective study with participants enrolled at different points in their disease.
22153659 Nonunion rate of first metatarsal-phalangeal joint arthrodesis with crossed titanium flexi 2012 Mar Myriad forms of fixation have been proposed for arthrodesis of the first metatarsal-phalangeal joint (MTPJ). Regardless of fixation type, nonunion of the arthrodesis site has been purported as a common complication. We performed a retrospective review of all patients undergoing arthrodesis of the first MTPJ with crossed flexible titanium intramedullary nails and a dorsal static staple followed by immediate protected weight bearing. The subjects were included if they had undergone the exact internal fixation technique described; surgery had been performed only by 1 of us; and they had not undergone bilateral surgery in the same setting. Also, the indication for surgery was required to be pathology of the first MTPJ other than rheumatoid arthritis. Weight bearing preoperative radiographs and weight bearing radiographs at least 6 weeks postoperatively were required. Also, the patients had to have initiated weight bearing on the operative foot immediately postoperatively in a protective shoe. Finally, documentation of any complications was required. A total of 83 patients (95 feet) met the inclusion criteria and were included. Of the 83 patients, 77 (92.7%) were female and 6 (7.3%) were male. Their mean age ± standard deviation was 69.7 ± 16.7 years. Of the 95 feet, 55 (57.9%) were right and 40 (42.1%) were left feet. The indications included 61 (64.2%) with severe hallux valgus deformity, 24 (25.3%) with hallux rigidus, and 10 (9.5%) with failed first MTPJ surgery. Complications related to technical error during insertion of the crossed titanium flexible intramedullary nails occurred in 16 feet (16.8%) but none led to nonunion or revision surgery. A total of 3 asymptomatic nonunions (3.2%) occurred, all in female patients with severe hallux valgus that did not require revision surgery. The incidence of nonunion after arthrodesis of the first MTPJ consisting of crossed flexible titanium intramedullary nails and a dorsal static staple for predominantly severe hallux valgus and hallux rigidus was lower than the historic mean for most other fixation techniques. However, methodologically sound prospective cohort studies are still needed that focus on the use of isolated arthrodesis of the first MTPJ for purely severe hallux valgus or hallux rigidus and a comparison of the technique we have presented with other modern osteosynthesis techniques.
21946862 Chemopreventive effect of different ratios of fish oil and corn oil on prognostic markers, 2012 Mar Fish oil (FO) rich in n-3 polyunsaturated fatty acids (PUFAs) have a protective role in autoimmune disorders, type 2 diabetes, rheumatoid arthritis, and cancer, whereas corn oil (CO) rich in n-6 PUFAs has a proinflammatory and procarcinogenic effect. A balanced n-3/n-6 PUFA ratio in diet rather than absolute intake of either may be responsible for decreasing cancer incidence. This study was designed to evaluate the chemopreventive effect of different ratios of FO and CO on prognostic markers, DNA damage, and cell cycle distribution in colon carcinogenesis. Male Wistar rats were divided into control, N,N'-dimethylhydrazine dihydrochloride (DMH) treated, FO+CO(1 : 1)+DMH, and FO+CO(2.5 : 1)+DMH. All the groups, except control, received a weekly injection of DMH for 4 weeks. The animals were given modified AIN-76A diets and killed either 48 h later (initiation phase) or kept for 16 weeks (postinitiation phase). The animals treated with DMH in both the phases showed an increase in multiple plaque lesions, total sialic acid, lipid associated sialic acid, DNA damage and cell proliferation. However, levels of p53 in the postinitiation and cyclin D1 in both the phases were significantly elevated. FO+CO(2.5 : 1)+DMH treatment in both the phases led to a decrease in multiple plaque lesions, DNA damage, total sialic acid, lipid associated sialic acid as compared with the DMH treated group. There was a G1 arrest with a decrease in p53 and cyclin D1 levels in FO+CO(2.5 : 1) in both the phases whereas treatment with FO+CO(1 : 1)+DMH led to same results in the postinitiation phase only. This study suggests that FO+CO(2.5 : 1) is more effective in chemoprevention of experimental colon carcinogenesis.
23054487 Tricin 4'-O-(erythro-β-guaiacylglyceryl) ether and tricin 4'-O-(threo-β-guaiacylglyceryl 2013 Jul Njavara is an important medicinal rice variety of Kerala, India widely used in Ayurveda for the treatment of rheumatoid arthritis, paralysis, neurodegenerative diseases and in rejuvenation therapy. The study evaluated, for the first time, antitumor effects of the two rare flavonolignans, tricin 4'-O-(erythro-β-guaiacylglyceryl) ether (compound 1) and tricin 4'-O-(threo-β-guaiacylglyceryl) ether (compound 2), isolated from 'Njavara' black. Both the compounds induced apoptosis in three cancer cell lines colon adenocarcinoma cell line HCT 116, ovarian cancer cell line SKOV3 and breast cancer cell line MCF-7. Chromatin condensation in the three cancer cell lines by Hoechst staining showed >50 % of apoptosis by compounds 1 and 2 at concentration 40 and 30 μg/ml, respectively after 48 h. Further studies substantiated that both the compounds targeted cancer cells through mitochondrial membrane potential loss and subsequent chromatin condensation. Both compounds significantly increased the Annexin V binding thus confirming compounds 1 and 2 to be potential apoptotic agents.