An irregular performance of a mechanical-type constant power regulator is considered. In order to find the cause of an irregular discharge flow at the cut-off pressure area, modeling and numerical simulations are performed to observe dynamic behavior of internal parts of the constant power regulator system for a swashplate-type axial piston pump. The commercial numerical simulation software AMESim is applied to model the mechanical-type regulator with hydraulic pump and simulate the performance of it. The validity of the simulation model of the constant power regulator system is verified by comparing simulation results with experiments. In order to find the cause of the irregular performance of the mechanical-type constant power regulator system, the behavior of main components such as the spool, sleeve, and counterbalance piston is investigated using computer simulation. The shape modification of the counterbalance piston is proposed to improve the undesirable performance of the mechanical-type constant power regulator. The performance improvement is verified by computer simulation using AMESim software.
Cryptococcal meningitis is a rare complication of systemic lupus erythematosus (SLE). The nonspecific neurologic findings associated with this infection delays accurate diagnosis because initial neuropsychiatric manifestations of SLE are in instances indistinguishable from that of crytococcal meningitis. We report a case of cryptococcal meningitis presenting with unilateral sixth cranial nerve palsy in a male patient with SLE, which was successfully treated with antifungal agents.
Lupus Erythematosus, Systemic; Meningitis, Cryptococcal; Abducens Nerve Palsy
Cryptococcal infection is a rare, yet well recognized complication of systemic lupus erythematosus (SLE). We present a case of mesenteric and retroperitoneal cryptococcal lymphadenitis resulting in the obstruction of the stomach and proximal duodenum in a patient suffering from SLE, while recently she did not receive any immunosuppressive treatment. A 42-yr-old woman was admitted due to high fever and diffuse abdominal pain for three weeks. Abdominal computed tomography (CT) scan showed multiple conglomerated lymphadenopathies in the retroperitoneum and the mesentery resulting in luminal narrowing of the third portion of the duodenum. Cryptococcal lymphadenitis was proven by needle biopsy and she was treated with intravenous liposomal amphotericin B, followed by oral fluconazole. After fourteen-month antifungal therapies, the clinical symptoms and follow-up images improved. This case emphasize that the intrinsic immunological defects of SLE may be directly responsible for the predisposition to fungal infections.
Mesenteric Lymphadenitis; Cryptococcus neoformans; Lupus Erythematosus, Systemic
Interleukin-1β (IL-1β) is a potent proinflammatory and immunoregulatory cytokine playing an important role in the progression of rheumatoid arthritis (RA). However, the signaling network of IL-1β in synoviocytes from RA patients is still poorly understood. Here, we show for the first time that phospholipase D1 (PLD1), but not PLD2, is selectively upregulated in IL-1β-stimulated synoviocytes, as well as synovium, from RA patients. IL-1β enhanced the binding of NF-κB and ATF-2 to the PLD1 promoter, thereby enhancing PLD1 expression. PLD1 inhibition abolished the IL-1β-induced expression of proinflammatory mediators and angiogenic factors by suppressing the binding of NF-κB or hypoxia-inducible factor 1α to the promoter of its target genes, as well as IL-1β-induced proliferation or migration. However, suppression of PLD1 activity promoted cell cycle arrest via transactivation of FoxO3a. Furthermore, PLD1 inhibitor significantly suppressed joint inflammation and destruction in IL-1 receptor antagonist-deficient (IL-1Ra−/−) mice, a model of spontaneous arthritis. Taken together, these results suggest that the abnormal upregulation of PLD1 may contribute to the pathogenesis of IL-1β-induced chronic arthritis and that a selective PLD1 inhibitor might provide a potential therapeutic molecule for the treatment of chronic inflammatory autoimmune disorders.
There is no consensus on whether it is safe to re-administer tumor necrosis factor-alpha (TNFα) inhibitors in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) flared after withdrawal of TNFα inhibitors due to active tuberculosis (TB). We evaluated the safety of restarting anti-TNFα therapy in patients with TNFα-associated TB. We used data of 1,012 patients with RA or AS treated with TNFα inhibitors at Seoul St. Mary's Hospital between January 2003 and July 2013 to identify patients who developed active TB. Demographic and clinical data including the results of tuberculin skin tests (TST) and interferon-γ releasing assays (IGRA) were collected. Fifteen patients developed active TB. Five cases were occurred in RA and 10 cases in AS. Nine of 15 patients had a negative TST or IGRA and 6 TST-positive patients had received prophylaxis prior to initiating anti-TNFα therapy. All patients discontinued TNFα inhibitors with starting the treatment of TB. Eight patients were re-administered TNFα inhibitors due to disease flares and promptly improved without recurrence of TB. TNFα inhibitors could be safely resumed after starting anti-TB regimen in patients with RA or AS.
TNFα Inhibitor; Tuberculosis; Arthritis, Rheumatoid; Spondylitis, Ankylosing
Currently, infliximab is given for disease control for active rheumatoid arthritis (RA) patients despite methotrexate treatment. However, the efficacy and safety of infliximab in Korean patients has not been assessed appropriately. Therefore, we performed placebo-controlled, double-blind, randomized study and extension study. One-hundred forty-three patients with active RA were randomized to receive placebo or infliximab 3 mg/kg intravenously at week 0, 2, 6, 14, and 22 with methotrexate maintenance. Primary endpoint was American College of Rheumatology 20% improvement criteria (ACR20) at 30 week. After the clinical trial, patients on placebo (Group 1) and patients on infliximab who showed ACR20 response (Group 2) were treated with infliximab through another 84 week for evaluation of safety. During clinical trial, patients in infliximab group showed higher ACR20 at week 30 than patients in placebo group (50.1% vs 30.6%, P=0.014). A total of 92 patients participated in the extension study. The maintenance rate of infliximab was 62.0% at 84 weeks of extension study. The overall rate of adverse events was not different between Group 1 and Group 2. In Korean patients with active RA despite methotrexate treatment, infliximab in combination with methotrexate is effective and the long-term treatment with infliximab is well tolerated. (ClinicalTrials.gov No. NCT00202852, NCT00732875)
Arthritis, Rheumatoid; Infliximab; Placebo-Controlled Clinical Trial; Extension Study; Efficacy; Adverse Event
Interleukin (IL)-27 is a novel cytokine of the IL-6/IL-12 family that has been reported to be involved in the pathogenesis of autoimmune diseases and has a pivotal role as both a pro- and anti-inflammatory cytokine. We investigated the in vivo effects of IL-27 on arthritis severity in a murine collagen-induced arthritis (CIA) model and its mechanism of action regarding control of regulatory T (Tregs) and IL-17-producing T helper 17 (Th17) cells. IL-27-Fc-treated CIA mice showed a lower severity of arthritis. IL-17 expression in the spleens was significantly decreased in IL-27-Fc-treated CIA mice compared with that in the CIA model. The Th17 population was decreased in the spleens of IL-27-Fc-treated CIA mice, whereas the CD4+CD25+Foxp3+ Treg population increased. In vitro studies revealed that IL-27 inhibited IL-17 production in murine CD4+ T cells, and the effect was associated with retinoic acid-related orphan receptor γT and signal transducer and activator of transcription 3 inhibition. In contrast, fluorescein isothiocyanate-labeled forkhead box P3 (Foxp3) and IL-10 were profoundly augmented by IL-27 treatment. Regarding the suppressive capacity of Treg cells, the proportions of CTLA-4+ (cytotoxic T-lymphocyte antigen 4), PD-1+ (programmed cell death protein 1) and GITR+ (glucocorticoid-induced tumor necrosis factor receptor) Tregs increased in the spleens of IL-27-Fc-treated CIA mice. Furthermore, in vitro differentiated Treg cells with IL-27 exerted a more suppressive capacity on T-cell proliferation. We found that IL-27 acts as a reciprocal regulator of the Th17 and Treg populations in CD4+ cells isolated from healthy human peripheral blood mononuclear cells (PBMCs), as well as from humans with rheumatoid arthritis (RA) PBMCs. Our study suggests that IL-27 has the potential to ameliorate overwhelming inflammation in patients with RA through a reciprocal regulation of Th17 and Treg cells.
collagen-induced arthritis; interleukin-27; interleukin-17-producing T cells; regulatory T cells; rheumatoid arthritis
The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.
Antihypertensive Agents; Osteoporosis; Ovariectomized Mice; Thiazides; Telmisartan
Interleukin (IL)-33 is an important mediator of innate immunity. Behcet's disease (BD) is an autoinflammatory disorder characterized by hyperactivity of the innate immune response. We measured serum levels of IL-33 and its receptor soluble ST2 (sST2) in patients with BD to investigate their association with disease activity. Serum levels of both IL-33 and sST2 were higher in patients with BD compared with those in normal controls (IL-33: 594.48±175.04 pg/mL in BD and 224.23±56.64 pg/mL in normal controls [P=0.048], sST2: 99.01±15.92 pg/mL in BD and 23.56±3.25 pg/mL in normal controls [P<0.001]). IL-33 and sST2 expression in skin tissue, as shown by immunohistochemistry, was higher in patients with BD compared with that in the normal controls. Serum sST2 level correlated significantly with the BD currently active form (BDCAF), Iranian BD dynamic activity measure (IBDDAM), erythrocyte sedimentation rate and C-reactive protein. Multiple linear regression showed that serum sST2 was an independent factor associated with IBBDAM (regression coefficient, 0.374; P=0.004), and BDCAF (regression coefficient, 0.236; P=0.047). These results demonstrate that IL-33 and sST2 are highly expressed in patients with BD and that serum sST2 is an independent factor associated with IBDDAM and BDCAF, suggesting a potential role for sST2 as a surrogate marker of disease activity in patients with BD.
Interleukin-33; soluble ST2; Behcet Syndrome
A robust control scheme is proposed for the position control of the electrohydrostatic actuator (EHA) when considering hardware saturation, load disturbance, and lumped system uncertainties and nonlinearities. To reduce overshoot due to a saturation of electric motor and to realize robustness against load disturbance and lumped system uncertainties such as varying parameters and modeling error, this paper proposes an adaptive antiwindup PID sliding mode scheme as a robust position controller for the EHA system. An optimal PID controller and an optimal anti-windup PID controller are also designed to compare control performance. An EHA prototype is developed, carrying out system modeling and parameter identification in designing the position controller. The simply identified linear model serves as the basis for the design of the position controllers, while the robustness of the control systems is compared by experiments. The adaptive anti-windup PID sliding mode controller has been found to have the desired performance and become robust against hardware saturation, load disturbance, and lumped system uncertainties and nonlinearities.
Bone destruction and inflammation are closely linked. Cytokines play an important role in inflammatory bone destruction by upregulating the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). The direct role of cytokines that act in a non-RANKL-dependent manner has yet to be elucidated. The aim of this study was to investigate the direct osteoclastogenic properties of inflammatory cytokines at different time-points of osteoclastogenesis. Mouse bone marrow macrophages were stimulated with the macrophage colony-stimulating factor (M-CSF) and various concentrations of RANKL. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and IL-23, were added to the culture system of osteoclastogenesis. Two time-points of cytokine treatment were set. The ‘early’ effect of each cytokine was investigated at the time of first RANKL treatment, whereas the ‘late’ effect was investigated 48 h after the first RANKL challenge. Osteoclast differentiation and function were assessed using an osteoclast marker [tartrate-resistant acid phosphatase (TRAP)] and by visualization of pit formation. A permissive level of RANKL was required for cytokine-associated osteoclastogenesis in all experiments. In the M-CSF/RANKL monocellular culture system, IL-1β enhanced and IL-6 decreased osteoclast formation in a dose-dependent manner, regardless of temporal differences. Other cytokines showed various responses according to the phase of osteoclast maturation and the concentration of each cytokine and RANKL. Furthermore, luciferase assays showed that both IL-1β and RANKL activated the NF-κB signaling pathway. Collectively, our data revealed that targeting IL-1β may be a promising strategy to inhibit inflammation-associated bone destruction and osteoporosis.
inflammation; osteoclast; receptor activator nuclear factor-κB ligand; interleukin-1β; interleukin-6; nuclear factor-κB
We aimed to quantify periarticular osteoporosis and investigate its significance in 45 patients with rheumatoid arthritis (RA) and 106 controls. Dual-energy X-ray absorptiometry (DXA) was used to determine the ratio of shaft to periarticular bone mineral density (BMD) as an index of periarticular demineralization. Periarticular osteoporosis was measured by conventional radiography. The BMDs of shaft and periarticular regions in eight designated areas on proximal phalanges were quantified. Clinical variables were examined to identify risk factors for periarticular osteoporosis. The assessment of periarticular osteoporosis on X-ray images reached a moderate degree of interobserver agreement among four physicians (ĸ = 0.47). For BMD quantification, we designed three types of mathematical formulae: the ratio of shaft to periarticular BMD, the mean of the ratios, and the ratio of the sums. These ratios were significantly higher in the patients with early RA (disease duration ≤ 3 yr) than in controls (P < 0.01). The findings were not as distinctive in patients with established RA. Body mass index, cumulative dose of corticosteroid, and C-terminal telopeptide were correlated with BMD ratios. Conclusively, DXA-assisted localized quantification and BMD ratio calculations are feasible for assessing periarticular demineralization. Periarticular osteoporosis is a relatively distinctive feature of early RA.
Bone Density; Arthrits; Rheumatoid; Periarticular Osteopenia
X-rays are known to interact with metallic nanoparticles, producing photoelectric species as radiosensitizing effects, and have been exploited in vivo mainly with gold nanoparticles. The purpose of this study was to investigate the potential of sensitizing effect of iron oxide nanoparticles for photon activated therapy.
X-rays photon activated therapy (PAT) was studied by treating CT26 tumor cells and CT26 tumor-bearing mice loaded with 13-nm diameter FeO NP, and irradiating them at 7.1 keV near the Fe K-edge using synchrotron x-rays radiation. Survival of cells was determined by MTT assay, and tumor regression assay was performed for in vivo model experiment. The results of PAT treated groups were compared with x-rays alone control groups.
A more significant reduction in viability and damage was observed in the FeO NP-treated irradiated cells, compared to the radiation alone group (p < 0.04). Injection of FeO NP (100 mg/kg) 30 min prior to irradiation elevated the tumor concentration of magnetite to 40 μg of Fe/g tissue, with a tumor-to-muscle ratio of 17.4. The group receiving FeO NP and radiation of 10 Gy showed 80% complete tumor regression (CTR) after 15–35 days and relapse-free survival for up to 6 months, compared to the control group, which showed growth retardation, resulting in 80% fatality. The group receiving radiation of 40 Gy showed 100% CTR in all cases irrespective of the presence of FeO NP, but CTR was achieved earlier in the PAT-treated group compared with the radiation alone group.
An iron oxide nanoparticle enhanced therapeutic effect with relatively low tissue concentration of iron and 10 Gy of monochromatic X-rays. Since 7.1 keV X-rays is attenuated very sharply in the tissue, FeO NP-PAT may have promise as a potent treatment option for superficial malignancies in the skin, like chest wall recurrence of breast cancer.
Photon activated therapy; Iron oxide nanoparticles; Auger electron; Synchrotron monochromatic x-rays; Superficial malignancy
Disease progression of ankylosing spondylitis has been considered irreversible. However, we report a case of spontaneous regression of syndesmophyte development following allogeneic peripheral blood stem cell transplantation in a patient with acute myeloid leukemia, who was also diagnosed as having ankylosing spondylitis. To the best of our knowledge, this is the first case report presenting the partial radiologic regression of syndesmophytes.
A 39-year-old man with active ankylosing spondylitis achieved clinical remission and partial radiological regression of cervical spine syndesmophytes following a peripheral blood stem cell transplantation for acute myeloid leukemia. Our patient received an allogeneic peripheral blood stem cell transplantation following a pre-transplantation conditioning regimen of total body irradiation and cyclophosphamide. The donor was a human leukocyte antigen-matched 29-year-old man. Our patient has remained asymptomatic and has received no medication for ankylosing spondylitis for nearly three years.
Several explanations are proposed for the regression of syndesmophytes and clinical improvement in active ankylosing spondylitis observed in our patient, including changes in bone remodeling and immune reconstitution following stem cell transplantation, the effect of immunosuppressive agents, or fluctuation in the natural course of ankylosing spondylitis although further studies are required. The regression of syndesmophytes in ankylosing spondylitis in this case raises the possibility that stem cell transplantation might contribute to the development of a novel therapeutic strategy for treatment of the disease.
White fat cells secrete adipokines that induce inflammation and obesity has been reported to be characterized by high serum levels of inflammatory cytokines such as IL-6 and TNF-α. Rheumatoid arthritis (RA) is a prototype of inflammatory arthritis, but the relationship between RA and obesity is controversial. We made an obese inflammatory arthritis model: obese collagen-induced arthritis (CIA). C57BL/6 mice were fed a 60-kcal high fat diet (HFD) from the age of 4 weeks and they were immunized twice with type II collagen (CII). After immunization, the obese CIA mice showed higher arthritis index scores and histology scores and a more increased incidence of developing arthritis than did the lean CIA mice. After treatment with CII, mixed lymphocyte reaction also showed CII-specific response more intensely in the obese CIA mice than lean CIA. The anti-CII IgG and anti-CII IgG2a levels in the sera of the obese CIA mice were higher than those of the lean CIA mice. The number of Th17 cells was higher and the IL-17 mRNA expression of the splenocytes in the obese CIA mice was higher than that of the lean CIA mice. Obese CIA mice also showed high IL-17 expression on synovium in immunohistochemistry. Although obesity may not play a pathogenic role in initiating arthritis, it could play an important role in amplifying the inflammation of arthritis through the Th1/Th17 response. The obese CIA murine model will be an important tool when we investigate the effect of several therapeutic target molecules to treat RA.
arthritis, experimental; inflammation; mice; obesity; Th17 cells
Pericardial abscess is an extremely rare complication of Staphylococcus aureus bacteremia. We report a case of a 72-year-old woman with multiple acupuncture scars on both knees who presented with shortness of breath and general weakness. Transthoracic echocardiography and pericardiocentesis confirmed the presence of pericardial fluid collection. Staphylococcus aureus grew in both pericardial fluid and blood. Although an aggressive medical treatment including intravenous antibiotics and percutaneous drainage, the patient died 2 days after admission.
Staphylococcus aureus; Pericarditis; Acupuncture
Serum thyroid-stimulating hormone screening of asymptomatic individuals to diagnose subclinical hypothyroidism remains controversial. We evaluated the potential role of Sasang constitutional discrimination and ryodoraku testing as an alternative and complementary diagnostic tool for subclinical hypothyroidism. Among 1,105 potential subjects, 1,073 were included in this study. Of these, 134 subjects had subclinical hypothyroidism (SCH) and 939 were healthy (euthyroid; EU) control subjects. Blood parameters, including serum thyroid hormone levels, were measured. We classified the participants into the four Sasang constitutional types, Taeyang-type individuals, Taeeum-type individuals, Soyang-type individuals and Soeum-type individuals, and measured their ryodoraku scores (RS). The mean levels of free thyroxine (FT4), glucose, red blood cells and hematocrit in the SCH group were significantly lower compared to those in the EU group (p<0.0183, p=0.0006, p=0.0162 and p=0.0224, respectively). The mean FT4 level of the Soeum-type SCH patients was significantly lower compared to the Soeum-type EU patients (p=0.0423). The total RS was significantly higher in the Taeeum-type SCH patients (p=0.0253) and lower in the Soeum-type SCH patients (p=0.0094) compared to controls. Ryodoraku testing and Sasang constitutional discrimination have the potential to serve as alternative and complementary diagnostic tools for subclinical hypothyroidism.
subclinical hypothyroidism; Sasang constitution; ryodoraku
Axillary lymph node status is the strongest prognostic indicator of survival for women with breast cancer. The purpose of this study was to evaluate whether sentinel lymph node biopsy (SLNB) is required in patients with an initial diagnosis of ductal carcinoma in situ (DCIS).
A retrospective analysis was performed of 78 patients with an initial diagnosis of DCIS between December 2002 and April 2010 and who proceeded to have either SLNB or axillary node dissection performed as part of their primary surgical procedure. The study focused on the rates of axillary node metastasis and the underestimation of invasive carcinoma at an initial diagnosis.
Forty-eight patients underwent SLNB and 18 patients underwent axillary node dissection. Only 1 of 66 patients (1.5%) had a positive sentinel lymph node. After definite surgery, the final diagnosis was changed to invasive ductal carcinoma (IDC) in 12 patients and DCIS with microinvasion in 2 patients; 14 of 78 patients (17.9%) were therefore underestimated at preoperative histological examinations. In 35 patients who were diagnosed DCIS by core needle biopsy (CNB), 13 patients (37.1%) were upstaged into IDC or DCIS with microinvasion in the final diagnosis. The statistically significant factors predictive of invasive breast cancer were a large tumor size and HER2 overexpression.
The rates of SLNB positivity in pure DCIS are very low, and there is continuing uncertainty about its clinical importance. However in view of the high rate of underestimation of invasive carcinoma in patients with an initial diagnosis of DCIS, SLNB appears to be appropriate in these patients, especially in the case when DCIS is diagnosed by a core needle biopsy. In patients with an initial diagnosis of DCIS by CNB, SLNB should be considered as part of the primary surgical procedure, when preoperative variables show a tumor larger than 2.35 cm and with HER2 overexpression.
Breast; Ductal carcinoma in situ; Sentinel lymph node
Osteoarthritis (OA) is an age-related joint disease that is characterized by degeneration of articular cartilage and chronic pain. Oxidative stress is considered one of the pathophysiological factors in the progression of OA. We investigated the effects of grape seed proanthocyanidin extract (GSPE), which is an antioxidant, on monosodium iodoacetate (MIA)-induced arthritis of the knee joint of rat, which is an animal model of human OA. GSPE (100 mg/kg or 300 mg/kg) or saline was given orally three times per week for 4 weeks after the MIA injection. Pain was measured using the paw withdrawal latency (PWL), the paw withdrawal threshold (PWT) and the hind limb weight bearing ability. Joint damage was assessed using histological and microscopic analysis and microcomputerized tomography. Matrix metalloproteinase-13 (MMP13) and nitrotyrosine were detected using immunohistochemistry. Administration of GSPE to the MIA-treated rats significantly increased the PWL and PWT and this resulted in recovery of hind paw weight distribution (P < 0.05). GSPE reduced the loss of chondrocytes and proteoglycan, the production of MMP13, nitrotyrosine and IL-1β and the formation of osteophytes, and it reduced the number of subchondral bone fractures in the MIA-treated rats. These results indicate that GSPE is antinociceptive and it is protective against joint damage in the MIA-treated rat model of OA. GSPE could open up novel avenues for the treatment of OA.
antioxidants; grape seed proanthocyanidins; inflammation; interleukin-1β; osteoarthritis
The interleukin-33 (IL-33)/ST2 pathway has emerged as an intercellular signaling system that participates in antigen-allergen response, autoimmunity and fibrosis. It has been suggested that IL-33/ST2 signaling has been involved in the pathogenesis of rheumatoid arthritis (RA), because IL-33 and its receptor have been specifically mapped to RA synovium. The aim of this study was to determine the levels of IL-33 and sST2 in sera and synovial fluids in patients with RA. The serum level of IL-33 was significantly higher in patients with RA (294.9 ± 464.0 pg/mL) than in healthy controls (96.0 ± 236.9 pg/mL, P = 0.002). The synovial fluid level of IL-33 was significantly higher in RA patients than in osteoarthritis patients. The level of serum sST2 was higher in RA patients than in healthy controls (P = 0.042). A significant relationship was found between the levels of IL-33 and IL-1β (r = 0.311, P = 0.005), and IL-33 and IL-6 (r = 0.264, P = 0.017) in 81 RA patients. The levels of IL-33, sST2 and C-reactive protein decreased after conventional disease-modifying antirheumatic drugs treatment in 10 patients with treatment-naïve RA. Conclusively, IL-33 is involved in the pathogenesis of RA and may reflect the degree of inflammation in patients with RA.
Interleukin-33; sST2, ST2L; Arthritis, Rheumatoid
Indoleamine 2,3-dioxygenase (IDO) is a key negative regulator of immune responses and has been implicated in tumor tolerance, autoimmune disease and asthma. IDO was detected in the joint synovial tissue in the inflammatory microenvironment of rheumatoid arthritis (RA), but IDO expression in joint synovial tissue is not sufficient to overcome the inflamed synovial environment. This study aimed to unravel the mechanisms involving the failure to activate tolerogenic IDO in the inflamed joint. We demonstrate that both poly (I:C) and lipopolysaccharide (LPS) induce expression of IDO in synovial fibroblasts. However, inflammatory cytokines such as IL-17, TNF-α, IL-12, IL-23 and IL-16 did not induce IDO expression. Poly (I:C) appeared to induce higher IDO expression than did LPS. Surprisingly, toll-like receptor (TLR)4-mediated IDO expression was upregulated after depletion of myeloid differentiation primary response protein 88 (MyD88) in synovial fibroblasts using small interfering RNA (siRNA). IDO, TLR3 and TLR4 were highly expressed in synovial tissue of RA patients compared with that of osteoarthritis patients. In addition, RA patients with severe disease activity had higher levels of expression of IDO, TLR3 and TLR4 in the synovium than patients with mild disease activity. These data suggest that upregulation of IDO expression in synovial fibroblasts involves TLR3 and TLR4 activation by microbial constituents. We showed that the mechanisms responsible for IDO regulation primarily involve MyD88 signaling in synovial fibroblasts, as demonstrated by siRNA-mediated knockdown of MyD88.
indoleamine-pyrrole 2,3,-dioxygenase; myeloid differentiation factor 88; rheumatoid arthritis; TICAM1 protein, human; toll-like receptors
B cells play an important role in the pathogenesis of rheumatoid arthritis (RA). High levels of B cell activating factor (BAFF) are detected in autoimmune diseases. BAFF and BAFF receptor (BAFF-R) are expressed in B and T cells of RA synovium. The study was undertaken to identify the NF-κB signal pathway involved in the induction of BAFF-R in human B cells. Immunohistochemical staining of NF-κB p65, NF-κB p50, BAFF, and BAFF-R was performed on sections of synovium from severe and mild RA and osteoarthritis (OA) patients. Peripheral blood mononuclear cells (PBMCs) were isolated from control and RA patients and B cells were isolated from controls. BAFF-R was analyzed by flow cytometry, realtime PCR and confocal staining after treatment with NF-κB inhibitors. NF-κB p65, NF-κB p50, BAFF, and BAFF-R were highly expressed in severe RA synovium relative to mild RA synovium or OA synovium. BAFF-R expression was reduced by NF-κB inhibitors in PBMCs and B cells from normal controls. We also showed reduction in expression of BAFF-R via inhibition of the NF-κB pathway in PBMCs of RA patients. BAFF/BAFF-R signaling is an important mechanism of pathogenesis in RA and that BAFF-R reduction by NF-κB blocking therapy is another choice for controlling B cells in autoimmune diseases such as RA.
B-cell activation factor receptor; B-cell activating factor; B-lymphocytes; NF-κB; rheumatoid arthritis
Adipocytokines, such as leptin, resistin, and adiponectin, are associated with obesity and breast cancer. Several studies have indicated that adipocytokines may influence tumor growth or differentiation. The aims of this study were to determine the expression of leptin, leptin receptor (ObR), adiponectin and adiponectin receptor (AdipoR) in human breast cancer, to evaluate their prognostic significance in the breast cancer.
from 198 patients with primary breast cancer were enrolled, and representative paraffin tumor blocks were selected for constructing tissue microarrarys (TMA). Immunohistochemical staining for leptin, ObR, adiponectin, and AdipoR was performed using TMA, and the clinicopathologic characteristics were evaluated from the patient's medical records.
Stage 0 breast cancer accounted for 41 cases, and 157 cases were invasive cancer. Positive rates of leptin and ObR expression in the ductal carcinoma in situ (DCIS) group were significantly higher than those of the invasive cancer group (97.4% vs. 34.0%, p<0.001; 74.4% vs. 29.8%, p<0.001). However, positive rates of adiponectin and AdipoR expression in the invasive cancer group were significantly higher than those in the DCIS group (53.7% vs. 33.3%, p=0.024; 59.9% vs. 26.3%, p<0.001). High leptin expression was significantly associated with high Ki-67 expression (p=0.016). High adiponectin expression was significantly correlated with smaller tumor size (p=0.001).
We suggest that losses of leptin and ObR expression could be associated with invasive cancer, whereas high adiponectin and AdipoR expression may be associated with breast cancer invasiveness.
Adipocytokine; Adiponectin; Breast neoplasms; Leptin
This study was undertaken to investigate the pregnancy outcomes in patients with systemic lupus erythematosus (SLE) and the appropriate timing of pregnancy. We performed a retrospective evaluation of 183 pregnancies with SLE at Catholic University Medical Center during the 13-year period from 1998 to 2010. Pregnancy outcomes were compared according to SLE characteristics. The predictive value of the different cut-off points of the stable period before conception on adverse pregnancy outcomes was calculated by ROC (Receiver operating characteristics) curve analysis. In multivariate analysis, the presence of antiphospholipid antibodies (aPLs) increased the risk of pregnancy loss (p<0.0001) and premature birth (p=0.0040). Active disease at conception increased the risk of premature birth (p< 0.0001) and complications (IUGR, PIH, or both) (p= 0.0078). The other predictor of complications was found to be lupus flare (p=0.0252). At a cut-off level of stable period of 4 months before conception, sensitivity and specificity were 70.8% and 53.2%, 71.4% and 61.5%, and 63.6 % and 59.8 %, respectively on reducing pregnancy loss, premature birth, and complications. Pregnancies with aPLs, active disease at conception and SLE flares are at a higher risk of adverse outcomes. It is essential that disease activity remains stable at least 4 months before conception, for favorable pregnancy outcomes.
Systemic lupus erythematosus; Pregnancy outcomes; Disease activity
Angiogenesis, which is a critical step in the initiation and progression of rheumatoid arthritis (RA), involves pro-angiogenic factors, including interleukin (IL)-8 and vascular endothelial growth factor (VEGF). We investigated the role of Toll-like receptor 3 (TLR3) in the regulation of pro-angiogenic factors in RA fibroblast-like synoviocytes (FLS).
FLS were isolated from RA synovial tissues and stimulated with the TLR3 ligand, poly (I:C). The levels of VEGF and IL-8 in the culture supernatants were measured using enzyme-linked immunosorbent assays, and the mRNA levels were assessed by semiquantitative reverse transcription-polymerase chain reaction. The expression patterns of VEGF and IL-8 in the RA synovium and osteoarthritis (OA) synovium were compared using immunohistochemistry.
The expression levels of TLR3, VEGF, and IL-8 were significantly higher in the RA synovium than in the OA synovium. VEGF and IL-8 production were increased in the culture supernatants of RA FLS stimulated with poly (I:C), and the genes for these proteins were up-regulated at the transcriptional level after poly (I:C) treatment. Treatment with inhibitors of nuclear factor-kappaB (NF-κB), i.e., pyrrolidine dithiocarbamate and parthenolide, abrogated the stimulatory effect of poly (I:C) on the production of VEGF and IL-8 in RA FLS.
Our results suggest that the activation of TLR3 in RA FLS promotes the production of proangiogenic factors, in a process that is mediated by the NF-κB signaling pathway. Therefore, targeting the TLR3 pathway may be a promising approach to preventing pathologic angiogenesis in RA.
Toll-like receptor 3; Arthritis, rheumatoid; Vascular endothelial growth factor; Interleukin-8; Synovial fibroblast