Ankle Swelling Research Articles

Curcumin alleviates rheumatoid arthritis-induced inflammation and synovial hyperplasia by targeting mTOR pathway in rats.

PurposeRheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by aggressive and symmetric polyarthritis. Mammalian target of rapamycin (mTOR) was reported to be a new target for RA therapy and its inhibitor rapamycin can significantly reduce the invasive force of fibroblast-like synoviocytes. Here, we determined the effect of curcumin to alleviate inflammation and synovial hyperplasia for the therapy of RA.Materials and methodsCollagen-induced arthritis (CIA) was developed in Wistar rats and used as a model resembling RA in humans. Rats were treated with curcumin (200 mg/kg) and the mTOR inhibitor rapamycin (2.5 mg/kg) daily for 3 weeks. Effects of the treatment on local joint, peripheral blood, and synovial hyperplasia in the pathogenesis of CIA were analyzed.ResultsCurcumin and rapamycin significantly inhibited the redness and swelling of ankles and joints in RA rats. Curcumin inhibited the CIA-induced mTOR pathway and the RA-induced infiltration of inflammatory cells into the synovium. Curcumin and rapamycin treatment inhibited the increased levels of proinflammatory cytokines including IL-1β, TNF-α, MMP-1, and MMP-3 in CIA rats.ConclusionOur findings show that curcumin alleviates CIA-induced inflammation, synovial hyperplasia, and the other main features involved in the pathogenesis of CIA via the mTOR pathway. These results provide evidence for the anti-arthritic properties of curcumin and corroborate its potential use for the treatment of RA.

Toll-like Receptor 4/Nuclear Factor-κB Signaling in Synovial Tissue Is Involved in the Anti-inflammatory Effect of Moxibustion in Rats with Rheumatoid Arthritis

To observe the effect of moxibustion on Toll-like receptor 4/nuclear factor-κB (TLR 4/NF-κB) signaling in the synovial tissue of the ankle joint in rats with rheumatoid arthritis (RA), so as to analyze its biological mechanism underlying improvement of RA. Fifty male SD rats were randomly divided into normal control, model, moxibustion, moxibustion ＋ TLR 4 agonist, and moxibustion ＋ TLR 4 antagonist groups (n＝10 rats in each). The RA model was established by subcutaneous injection of Freund's complete adjuvant (FCA, 0.1 mL/rat) at the right hind-paw and by being raised in a wind (air fan blowing), cold (about 10 ℃) and wet (purling) environment for 20 days. After 3 days of modeling, mild moxibustion was applied to bilateral "Shenshu" (BL 23) and "Zusanli" (ST 36) for 20 minutes, once daily for successive 10 days. The TLR 4 agonist (lipopolysaccharide) or TLR 4 antagonist (TAK-242) (1 mg/mL) was separately administered via the tail vein 30 min before performing moxibustion every time in the agonist group and the antagonist group. The expression of NF-κB inhibitory factor ɑ (IκBɑ), IκB kinase complex β(IκKβ), myeloid differentiation factor 88 (MyD 88), TLR 4, and NF-κB p 65 proteins in the synovial tissue of the ankle joint was detected by using Western blot. Following modeling, the girth of the swollen ankle joint was obviously bigger (P<0.01), and the expression levels of IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 proteins in the synovial tissue were considerably increased in the model group relevant to the normal control group (P<0.01). After moxibustion intervention, the girth of the swollen ankle joint and the expression levels of IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 proteins were significantly down-regulated in the moxibustion, moxibustion ＋TLR 4 agonist, moxibustion＋TLR 4 antagonist groups compared with the model group (P<0.01, P<0.05). Comparison among the 3 moxibustion groups showed that the lowered levels of ankle-joint girth, and IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 expression were significantly smaller in the moxibustion＋TLR 4 agonist group than in the simple moxibustion and moxibustion＋TLR 4 antagonist groups (P<0.05，P<0.01). No significant differences were found between the moxibustion and moxibustion＋TLR 4 antagonist groups in the decreased ankle joint girth and IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 expression levels (P>0.05), suggesting that activation of TLR 4 reduced the anti-inflammatory effect of moxibustion intervention. Moxibustion can reduce the ankle joint swelling in RA rats, which may be closely associated with its effect in down-regulating the expression of IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 proteins and in inhibiting TLR 4/NF-κB signaling in the synovial tissue of the ankle joint.

Aronia melanocarpa ameliorates gout and hyperuricemia in animal models

ABSTRACT Aronia melanocarpa fruit (AM) strongly suppressed ankle swelling in rats with acute gout and reduced the levels of uric acid and xanthine oxidase (XO) in mice with hyperuricemia. AM reduced the inflammatory cell count and increased the ankle joint space, and suppressed the levels of interleukin (IL)-1β, IL-10, monocyte chemoattractant protein-1 and tumour necrosis factor-α in the serum of the rats with acute gout. In the mice with hyperuricemia, AM significantly reduced the serum levels of uric acid, blood urea nitrogen, and creatinine. 8-day administration of AM resulted in enhancements in the levels of glutathione peroxidase, superoxide dismutase and catalase and a reduction in the level of malondialdehyde in the serum of mice. All data suggested that the potential therapeutic effects of AM on gout are probably due to the regulation of pro- and anti-inflammatory cytokines and the suppression of XO activity via modulation of the oxidative stress status.

Inhibitory effects of Clematis orientalis aqueous ethanol extract and fractions on inflammatory markers in complete Freund's adjuvant-induced arthritis in Sprague-Dawley rats.

Clematis orientalis Linn has long been used as ethnopharmacy for the treatment of arthritis. This study is intended to evaluate the curative efficacy of Clematis orientalis in treating polyarthritis in rats. Aqueous ethanolic extract and fractions (hexane, butanol and aqueous) were administered orally at 200mg/kg for 28days after CFA immunization. Paw swelling, paw diameter, arthritic score, body weight, hematological parameters, radiographic and histological analysis of ankle joints were evaluated. Moreover, levels of various inflammatory markers through RT-PCR and ELISA were measured. DPPH and reducing power assays were used to appraise antioxidant capacity. Qualitative phytochemical analysis, determination of total phenolic and flavonoid contents were also carried out. Aqueous ethanolic extract and fractions significantly (p < 0.001) reduced paw volume, paw thickness and arthritic score and considerably prevented decrease in body weight along with anomalous alterations in hematological parameters in comparison with arthritic control. X-ray and histological examination revealed no significant structuralchanges in ankle joints of treated rats. Expression levels of IL-1β, TNF-α, IL-6, COX-2 and NF-Kβ were significantly (p < 0.05-0.001) suppressed as well as noteworthy increasein the levels of IL-4 and IL-10 among treated animalshas been detected. Overproduction of TNF-α and PGE2 was substantially prevented in animals given different treatments. Aqueous ethanol extract and its fractions demonstrated significant and concentration-dependent antioxidant potential. In general, among fractions aqueous fraction exhibited a greater anti-arthritic effect. Phytochemical analysis of aqueous fraction confirmed the presence of flavonoids and glycosides, 215.29mgGAE/ml phenolic content and 633.03μgQE/ml flavonoid content. Thus, we suggest Clematis orientalis as a potent strategy for the treatment of rheumatoid arthritis.

Multicentric Carpotarsal Osteolysis Mimicking Juvenile Idiopathic Arthritis

Background Multicentric carpotarsal osteolysis (MCTO), a skeletal dysplasia presents in early childhood mimicking juvenile idiopathic arthritis (JIA). Recognition of this syndrome is essential to avoid unnecessary treatment with immunosuppressive agents because of different course and treatment. Case Report A 3-year-old boy presented with swelling and restriction of right wrist joint and left ankle joint. Possibility of Oligoarticular (or pauciarticular) JIA was considered. On evaluation his inflammatory parameters were normal. There was poor response to oral steroids and methotrexate. He was lost to follow up and presented at 9 years of age with varus deformities of hand and feet. Radiographs revealed absent carpal and tarsal bones. Based on clinical and radiological examination- MCTO was diagnosed. Oral alendronate was started and clinical improvement was noted. Conclusion Mimickers of JIA like MCTO, Farber’s disease should be actively looked when inflammatory parameters are normal or response to therapy is not appropriate.

Cationic nanoparticle as an inhibitor of cell-free DNA-induced inflammation

Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here we show that ~40 nm cationic nanoparticles (cNP) can scavenge cfDNA derived from RA patients and inhibit the activation of primary synovial fluid monocytes and fibroblast-like synoviocytes. Using clinical scoring, micro-CT images, MRI, and histology, we show that intravenous injection of cNP into a CpG-induced mouse model or collagen-induced arthritis rat model can relieve RA symptoms including ankle and tissue swelling, and bone and cartilage damage. This culminates in the manifestation of partial mobility recovery of the treated rats in a rotational cage test. Mechanistic studies on intracellular trafficking and biodistribution of cNP, as well as measurement of cytokine expression in the joints and cfDNA levels in systemic circulation and inflamed joints also correlate with therapeutic outcomes. This work suggests a new direction of nanomedicine in treating inflammatory diseases.

CV2 - Identification of Low Risk Stable Cardiovascular Patients and Patient Acceptance for Fast-Track Medication Refill (FTMR) Service

This study aims to identify characteristics of patients who do not require medication change in a follow-up visit and thus are eligible to be offloaded for FTMR where patients could obtain their repeat medications from pharmacists. This study also aims to identify patient acceptance of this proposed service. Medical records of patients attended the Hypertension Clinic in Prince of Wales Hospital from April 2016 to March 2017 were collected and their relationships with medication change were analyzed by logistic regression. A questionnaire survey capturing patient satisfactions of the current waiting time and their acceptances of FTMR was conducted from January to March 2017. Multivariate logistic regressions performed using patient characteristics (N = 472) revealed that a higher HbA1C level (OR = 4.88), and presence of dizziness or syncope (OR = 3.04) and side-effects (OR = 3.19) increase the odds to changing HbA1C-lowering medications. A shorter time-within-therapeutic-range (TTR) for BP (OR = 0.22), a larger BP-therapeutic goal difference (OR = 0.91), male gender (OR = 2.76), and presence of ankle swelling (OR = 33.94), chest pain (OR = 2.16), palpitation (OR = 43.26), and side-effects (OR = 142.45) increase the odds to changing BP-lowering medications. A higher LDL level (OR = 3.51), a smaller LDL-TTR multiplication product (OR = 0.68), and presence of chest pain (OR = 31.82) and side-effects (OR = 8.45) increase the odds to changing LDL-lowering medications.The questionnaire survey (N = 92) revealed 59.78% of interviewees expressed preference for FTMR if their medication refills are to be authorized by a physician. Characteristics of patients not requiring medication change were identified. These patients are potential candidates for our proposed FTMR service, which is prefered by a majority of patients as a way to improve their satisfactions to the medical care.

Fire-needle Acupuncture Intervention Relieves Ankle-joint Inflammatory Reactions Possibly by Down-regulating Serum TNF-α and Anti-cyclic Citrullinated Peptide Antibody Levels in Collagen-induced Arthritis Rats

To observe the effect of fire-needle acupuncture of "Zusanli" (ST 36) and "Kunlun" (BL 60) on ankle-joint swelling and serum tumor necrosis factor-α (TNF-α) and anti-cyclic citrullinated peptide antibody (ACPA) contents in collagen-induced arthritis (CIA) rats, so as to study its mechanism underlying improvement of rheumatoid arthritis (RA)．. Thirty-two male Wistar rats were randomized into control, model, medication (Methotrexate) and fire-needling groups (n＝8 in each). The RA model was established by injecting type Ⅱ chicken collagen (0.1 mol/L) plus Freund's complete adjuvant (primary immunization) and Freund's incomplete adjuvant (immunization once more) into the subcutaneous tissues of the right foot bottom, back and tail root of rats. Fire-needling was applied to the left and right "Zusanli" (ST 36) and "Kunlun" (BL 60) alternatively for 3 times in each acupoint, once daily for 10 days. For rats of the medication group, Methotrexate sodium chloride solution (0.1 mg/100 g) was administrated by gavage, once every 5 days, twice together. The rats' right hind ankle diameter was measured before and after the treatment. The X-ray film of the right ankle was taken, and the contents of serum TNF-α and ACPA were assayed by ELISA. The ankle diameter and serum concentrations of TNF-α and ACPA were significantly increased in the model group compared to the control group (P<0.05), and X-ray film showed swollen and deformed tarsus joints, and narrowing of the joint space. After the intervention, the ankle diameter, serum TNF-α and ACPA levels were considerably decreased in both medication and fire-needle groups compared with the model group (P<0.05). Meanwhile, the joint swelling and bone deformity became relatively milder. There were no significant differences between the medication and fire-needling groups in the ankle diameter and the contents of serum TNF-α and ACPA (P>0.05). Fire-needling stimulation of ST 36 and BL 60, similar to Methotrexate, can relieve the inflammatory reactions of hind-ankle joint in CIA rats, which may be related to its effect in down-regulating ACPA and TNF-α levels.

Comparative study of anti-VEGF Ranibizumab and Interleukin-6 receptor antagonist Tocilizumab in Adjuvant-induced Arthritis

Although the precise etiology of Rheumatoid arthritis (RA) remains obscure, heightened immune response is thought to play a vital role in provoking joint inflammation and bone erosion. This study aims at comparatively evaluating the effects of two monoclonal antibodies Ranibizumab (RANI) as anti-VEGF antibody and Tocilizumab (TCZ) as interleukin-6 receptor (IL-6R) antagonist, against adjuvant induced arthritis in rats. CFA-induced arthritic rats were treated for three consecutive weeks with Methotrexate (MTX), TCZ and RANI monotherapy. Clinical assessment of RA, bone erosion, inflammatory, angiogenic and apoptotic markers were determined to assess the anti-arthritic effect. Liver enzymes and histopathological examination of liver and spleen were assessed to evaluate the toxicity profile of the tested therapeutic agents. MTX, TCZ and RANI monotherapy significantly enhanced the anti-arthritic parameters in comparison with the Complete Freund's Adjuvant (CFA)-induced arthritic rats through significant reduction of ankle and paw swelling. Also, they significantly reduced inflammatory, angiogenic and apoptotic markers. Importantly, Ranibizumab showed better effect than the standard anti-rheumatic drugs Methotrexate (MTX) or Tocilizumab (TCZ) in bone protection and cartilage health; hence proves to be a promising new therapeutic agent for RA.

Compressive Stockings After Hindfoot and Ankle Surgery

Category: Hindfoot Introduction/Purpose: Swelling and pain are common after foot and ankle procedures. We hypothesized that compressive stockings (CS) treatment after hindfoot surgery would positively influence patient outcomes. Methods: We undertook this randomized controlled trial in 87 consecutive patients to analyze the clinical effect of CS after hindfoot and ankle surgery and evaluate CS-wearing compliance using sensors that were implanted into CS. Ankle swelling, pain status, quality of life (SF-36 score), and the American Orthopaedic Foot &amp; Ankle Score (AOFAS) were set as the primary end points. The CS wearing time in hours and percentage were investigated as the secondary end points. All participants with CS (group I) were informed about the implanted sensor after the CS were taken off. A subgroup analysis of group I was performed to detect differences between patients with high vs low compliance. Results: At 12 weeks, the results of ankle swelling (mean 234 mm in group I and 232 mm in group II), pain in the visual analog scale (1.7 group I vs 1.9 in group II), the SF-36 score (38 points in group I vs 30 points in group II), and the AOFAS score (a mean of 76 points in both groups) showed no statistical differences between the 2 groups. The mean wearing time was 136 (range, 0-470) hours, which corresponds to a compliance rate of 65%. Sixteen participants had high compliance (&gt;80%, &gt;170 hours), and 21 patients had low or noncompliance. The clinical results of patients with high wearing compliance were not significantly better compared to the results of patients with low compliance. Conclusion: CS therapy after ankle and hindfoot surgery was associated with a low wearing compliance and did not influence ankle swelling, function, pain, and the quality of life compared to the control group. Furthermore, the clinical results of patients with high compliance were not better compared to the results of patients with low or noncompliance wearing behavior.

Preoperative Ankle Swelling and the Effect on Postoperative Wound Complications Following Ankle Fracture Surgery

Category: Trauma Introduction/Purpose: It is widely perceived that swelling in the first 24-48 hours following an ankle fracture precludes fixation, delaying operative treatment by 10-14 days to allow swelling to reduce. Such soft tissue management is assumed to be associated with better immediate soft tissue outcomes (wound closure) and mitigation of medium to long-term soft tissue problems. The aim of this study is to identify whether pre-operative ankle swelling has an independent effect on post-operative wound complications following ankle fracture surgery. The hypothesis of this study is that operative intervention at any point in time after the fracture of the ankle, irrespective of swelling, will show no better or worse soft tissue outcomes than those fixations delayed for swelling. The primary outcome measure will be wound complication. Methods: This is a prospective cohort study of patients presenting to a tertiary referral centre that were operatively managed for malleolar ankle fractures. Skeletally mature patients with closed, isolated ankle fractures were included in the study. Patients who were multiply-injured, had open fractures, and/or had known pre-existing limb oedema were excluded. Time to surgery was determined by the on-call attending orthopaedic surgeon. Ankle swelling of both the operative and non-operative limb was measured using the validated ‘Figure-of-eight’ measurement around the foot and ankle to quantify swelling of the affected ankle. A ratio of the patient’s 2 ankles was used as the measure of swelling to eliminate any bias between operators and standardise measurements between patients. Visual assessment of swelling was also recorded. Follow up was at 2, 6, and 12 weeks. Wound complications, patient co-morbidities, operative time, surgeon experience, and hospital stay duration were recorded Results: A total of 50 patients met inclusion criteria. Demographics were a 69% female predominance, a mean age of 45, and age range of 17- 69 years. A complication rate of 4% (n=2) was identified with both complications being superficial wound infections requiring oral antibiotics and wound episodes for treatment. Time to surgery had a mean of 6 days (range 0- 20). There was no significant difference in ankle swelling or time to surgery between patients with wound complications and those without. There were no significant differences identified between these groups when considering BMI, smoking status, diabetes, or peripheral vascular disease. Level of operating surgeon, operative time, tourniquet time, and closure material were also not significantly different between patients with and without wound complications. Conclusion: Our results show little post-operative soft tissue complications. If anything, our results are consistent with or show fewer soft tissue problems than the reported literature, despite a range of time to intervention. While we acknowledge that there may be a bias between surgeons in their preference in soft tissue management; we perceive that our study was sufficiently pragmatic to level this effect. Pre-operative swelling and time to operative intervention in ankle fracture surgery were not shown to correlate with change in soft tissue outcomes following ankle fracture surgery.

Treatment outcomes of buttress plating for posterior pilon fractures

Category: Ankle Introduction/Purpose: The purpose of current study was to retrospectively analyze the clinical outcomes of buttress plate treatment of posterior pilon fractures. Methods: Between January 2005 and December 2016, 58 patients with posterior pilon fractures underwent buttress plate fixation. There were 32 males and 26 females and the mean age was 40.2years (range, 23 to 73 years). Preoperative radiographs, CT scans and three dimensional reconstructions were used to evaluate the fracture patterns. On the basis of the extension of the fracture lines presented on the CT scans, a posterolateral approach or a combination of both posterolateral and posteromedial approaches were used to reduce and fixate the posterior malleolar fragments. Clinical and radiographic examinations were used for postoperative follow-up. The American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and the Visual Analogue Scale (VAS) were used to evaluate the functional outcomes. Results: According to the CT scan images, the posterior pilon fractures were classified into 3 types. 51 patients were available for follow-up. The mean time of follow-up was 44.8 months. The mean AOFAS score was 84.3 points, and the mean VAS score was 1.6 points. One patient was found with ankle joint swelling and long term walking discomfort at 2-year follow-up. Other patients received favorable functional outcomes. No hardware failure occurred. Conclusion: The clinical outcomes of buttress plate treatment of posterior pilon fractures were satisfactory. Buttress plating availed the patients to return to earlier weight-bearing and functional exercises.

Diabetes mellitus and heart failure: insights from a toxic relationship

Diabetes mellitus and heart failure: insights from a toxic relationship

Elevated levels of vitamin B12 in chronic stable heart failure: a marker for subclinical liver damage and impaired prognosis.

BackgroundElevated vitamin B12 is a sign for liver damage, but its significance in chronic stable heart failure (HF) is less known. The present study investigated the clinical correlates and prognostic significance of vitamin B12 levels in stable systolic HF.MethodsA total of 129 consecutive patients with HF and 50 control subjects were enrolled. Data regarding demographics, clinical signs, therapeutic and conventional echocardiographic measurements were recorded for all patients. Right-sided HF was defined as the presence of at least one of the typical symptoms (ankle swelling) or specific signs (jugular venous distention or abdominojugular reflux) of right HF. Cox proportional hazards regression analyses were performed to determine the independent prognostic determinants of mortality.ResultsBaseline B12 levels in HF patients (n=129) with and without right sided HF were significantly higher compared to healthy controls (n=50): Median 311 pg/mL and 235 pg/mL vs 198 pg/mL, respectively (P=0.005). Folic acid levels were similar between the study groups. Age, ejection fraction, left atrial size, estimated glomerular filtration rate, and direct and indirect bilirubin levels were significantly correlated to serum B12 level in univariate analysis. In multivariate analysis, independent correlates of B12 were direct bilirubin (R=0.51, P<0.001) and age (R=0.19, P=0.028). Patients with HF were followed-up for a median period of 32 months. Median B12 levels were significantly higher in patients who subsequently died (n=35) compared to survivors, but folic acid was not different between the two groups. ROC analysis showed that B12 values ≥270 pg/mL had 80% sensitivity and 58% specificity for predicting all-cause mortality (area under the curve=0.672, 95% CI=0.562−0.781; P=0.003). However, in Cox regression analysis, only left atrial diameter, level of direct bilirubin, and the presence of abdominojugular reflux were independent predictors of death.ConclusionIncreased B12 in stable HF patients is associated with increased direct bilirubin due to right HF, indicating a cardiohepatic syndrome, but neither B12 nor folic acid are independently associated with mortality.

Ankle Pain–Volleyball Player

HISTORY: An otherwise healthy 24 year old female volleyball player presented to the sports medicine clinic with a two week history of atraumatic severe left ankle pain and swelling. She localized the pain to her tibiotalar area. She described a sensation of “tightness” in the ankle. She denied any numbness or tingling or mechanical features to her pain, and she denied focal weakness. She did not endorse any other swollen or painful joints. She denied any history of autoimmune disease, inflammatory arthritis, or exposure to ticks. She had tried Ibuprofen and Tylenol with no significant relief. PHYSICAL EXAMINATION: Exam revealed a left ankle effusion and tenderness to touch over the anterior tibial-talar joint but not on the medial, lateral or posterior ankle. No laxity was noted with anterior drawer test. External rotation stress test was not painful. No pain was produced with resisted ankle motion in all planes. Neurologic exam did not reveal any focal strength or sensory changes in the lower extremities. Distal pulses and capillary refill were symmetric. DIFFERENTIAL DIAGNOSIS: 1. Septic Arthritis 2. Inflammatory Arthritis/Synovitis 3. Crystalline Monoarthritis 4. Lyme Arthritis 5. Internal Derangement 6. Occult Fracture 7. Pigmented Villonodular Synovitis 8. Synovial Chondromatosis TEST AND RESULTS: Laboratory testing showed normal white blood cell count. Sedimentation rate and C-reactive protein were slightly elevated. Lyme disease ELISA, rheumatoid factor, and CCP were all negative. X-ray showed left ankle effusion but no fractures. Attempted ultrasound guided aspiration showed extensive tibiotalar synovitis but did not produce any fluid for analysis. MRI of the left ankle showed extensive nodular synovial thickening of the anterior compartment consistent with Diffuse PVNS. FINAL WORKING DIAGNOSIS: Diffuse Pigmented Villonodular Synovitis(PVNS) TREATMENT AND OUTCOMES: 1. Modest improvement of pain with activity reduction 2. Orthopedic Foot and Ankle Surgery consult for planned arthroscopic nodule excision and synovectomy

Addition of apoptotic cells alters immune cell function and reduces ankle swelling in experimental Lyme arthritis

Abstract Experimental Lyme arthritis is induced by the infection of C3H mice with the spirochete, Borrelia burgdorferi, (Bb), and is a valuable model to study the regulation of inflammation during bacterial infection. We are interested in understanding the role that apoptotic cells (AC) play in inflammation resolution during murine Lyme arthritis. We show the number of AC within infected ankle joints significantly increases during arthritis resolution. Additionally, injection of AC into the tibio-tarsal joints of Bb infected mice reduces ankle swelling compared to control animals. In vitro studies using bone marrow derived macrophages (BMDM) co-cultured with Bb demonstrates the addition of AC decreases TNFα and KC production, while increasing IL-10 and PGE2 levels. The presence of AC in BMDM and also bone marrow neutrophils (BMN) cultures, decreases Bb phagocytosis, and also decreases BMN migration to LTB4. To further explore this mechanism, we measured expression of PPAR-γ (peroxisome proliferator-activated receptor gamma), which is known to regulate cytokine expression. Addition of AC to BMDM/Bb co-cultures increased PPAR-γ transcription in vitro, and also within infected ankle joints compared to mock treated mice in vivo. We also found AC themselves can produce PGE2, a bioactive lipid which activates PPAR-γ, setting up a positive feedback loop for the production PGE2. These results suggest AC can alter macrophage and neutrophil effector functions and may play a role in downregulating inflammatory responses, perhaps via activation of PPAR-γ. In addition, injection of AC into infected joints may limit inflammatory responses or induce their resolution.

RETRACTED: GZMB gene silencing confers protection against synovial tissue hyperplasia and articular cartilage tissue injury in rheumatoid arthritis through the MAPK signaling pathway

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. An Expression of Concern for this article was previously published while an investigation was conducted (see related editorial: https://doi.org/10.1016/j.biopha.2022.113812). This retraction notice supersedes the Expression of Concern published earlier. Concern was raised about the reliability of the Western blot data in Figure 7C, which appear to contain a similar phenotype to those found in other publications, as detailed here: https://pubpeer.com/publications/7DD2DDC979F8CE2B00555332B01F81; and here: https://docs.google.com/spreadsheets/d/1r0MyIYpagBc58BRF9c3luWNlCX8VUvUuPyYYXzxWvgY/edit#gid=262337249. The journal requested the corresponding author comment on these concerns and provide the associated raw data. The authors did not respond to this request and therefore the Editor-in-Chief decided to retract the article.

Akkermansia muciniphila is permissive to arthritis in the K/BxN mouse model of arthritis

Studies have identified abnormalities in the microbiota of patients with arthritis. To evaluate the pathogenicity of human microbiota, we performed fecal microbial transplantation from children with spondyloarthritis and controls to germ-free KRN/B6xNOD mice. Ankle swelling was equivalent in those that received patient vs control microbiota. Principal coordinates analysis revealed incomplete uptake of the human microbiota with over-representation of two genera (Bacteroides and Akkermansia) among the transplanted mice. The microbiota predicted the extent of ankle swelling (R2 = 0.185, p = 0.018). The abundances of Bacteroides (r = −0.510, p = 0.010) inversely and Akkermansia.(r = 0.367, p = 0.078) directly correlated with ankle swelling. Addition of A. muciniphila to Altered Schaedler’s Flora (ASF) resulted in small but statistically significant increased ankle swelling as compared to mice that received ASF alone (4.0 mm, 3.9 – 4.1 versus 3.9 mm, IQR 3.6 – 4.0, p = 0.041), as did addition of A. muciniphila cultures to transplanted human microbiota as compared to mice that received transplanted human microbiota alone (4.5 mm, IQR 4.3 – 5.5 versus 4.1 mm, IQR 3.9 – 4.3, p = 0.019). This study supports previous findings of an association between Akkermansia muciniphila and arthritis.

Mice with miR-146a deficiency develop severe gouty arthritis via dysregulation of TRAF 6, IRAK 1 and NALP3 inflammasome

BackgroundMicroRNAs (miRNAs) serve as important regulators of inflammatory and immune responses and are implicated in several immune disorders including gouty arthritis. The expression of miR-146a is upregulated in the peripheral blood mononuclear cells of patients with inter-critical gout when compared to normouricemic and hyperuricemic controls and those patients with acute gout flares. However, the role of miR-146a in the development of gout remains unknown. Here, we used miR-146a knockout (KO) mice to test miR-146a function in a monosodium urate (MSU)-induced gouty arthritis model.MethodsThe footpad or ankle joint of miR-146a KO and wild-type (WT) mice were injected with an MSU suspension to induce acute gouty arthritis. Bone marrow-derived macrophages (BMDMs) were stimulated with MSU and the gene expression of miR-146a; interleukin 1 beta (IL-1β); tumor necrosis factor-α (TNF-α); and the NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome was evaluated. TNF-α and IL-1β protein levels in BMDMs were assessed by fluorescence-activated cell sorting and western blot analyses. Gene and protein levels of TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase (IRAK1), the targets of miR-146a, were also measured.ResultsSignificantly increased paw swelling and index and ankle joint swelling were observed in miR-146a KO mice compared to WT controls after MSU treatment. MiR-146a expression in BMDMs from WT mice was dramatically upregulated at 4 h following MSU stimulation. Additionally, the expression of IL-1β, TNF-α, and NALP3 was higher in BMDMs from miR-146a KO mice after exposure to MSU crystals compared to those from WT mice. Consistent with the observed gene expression, the IL-1β and TNF-α proteins were upregulated in miR-146a KO mice. Additionally quantitative RT-PCR and western blot demonstrated that TRAF6 and IRAK1 were dramatically upregulated in BMDMs from miR-146 KO mice compared to those from WT mice.ConclusionsCollectively, these observations suggest that miR-146a provides negative feedback regulation of gouty arthritis development and lack of miR-146a enhances gouty arthritis via upregulation of TRAK6, IRAK-1, and the NALP3 inflammasome function.

1H NMR-based metabolomics approach to investigate the urine samples of collagen-induced arthritis rats and the intervention of tetrandrine

Tetrandrine is an effective ingredient isolated from the roots of a frequently used medicinal plant Stephania tetrandra S. Moore. It has been used for the management of arthritis in China, but the precise mechanism remains unclear. In the present study, a metabolomics method based on the 1H NMR was constituted to quantify the alterations of the endogenous metabolites in the urines of collagen-induced arthritis (CIA) rats treated with tetrandrine. Data showed that tetrandrine treatment could alleviate the ankle joint swelling and ameliorate histopathological changes in rats. The metabonomic analysis indicated that 23 potential biomarkers in urine were affiliated with CIA. They mainly participated in energy metabolism, amino acid metabolism, lipid metabolism and gut microbe metabolism. Moreover, our results implied that tetrandrine could reverse the pathological process of CIA through adjusting the unbalanced metabolic pathways. Thus, these metabolic pathways and potential biomarkers might be the potential therapeutic targets of tetrandrine, and these findings supplied new visions into the protective effect of tetrandrine against arthritis in rats.