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Tibiotalocalcaneal arthrodesis is frequently performed by foot and ankle surgeons in the management of complex ankle and hindfoot pathology. In this study, the authors describe the clinical and radiological outcomes of tibiotalocalcaneal arthrodesis using a solid posterior offset hindfoot arthrodesis nail. Forty-four consecutive patients underwent tibiotalocalcaneal arthrodesis by a single surgeon operating in two centers. Clinical and radiological outcomes were assessed preoperatively and at 6-month, 12-month and final follow-up (mean 47 months). Clinical outcomes were assessed with VAS, AOFAS and MOXFQ scores. Serial radiographs were used to assess union at each follow-up visit. Forty-four patients attended 12-month and final follow-up (mean 47 months). A total of 44 (100%) ankle joints and 44 (100%) subtalar joints were completely united at 12-month follow-up. The VAS score improved significantly from a mean of 6.5 preoperatively to a mean of 0.98 at final follow-up (P = <0.0001). AOFAS score improved significantly from a mean of 36.4 preoperatively to a mean of 73 at final follow-up (P = <0.0001). MOXFQ score improved significantly from a mean of 44.5 preoperatively to a mean of 12.7 at final follow-up (P = <0.0001). The mean change in frontal plane alignment was 5.7 degrees (P = 0.005). A total of 6 patients (13.6%) had an adverse event during the course of the study. Tibiotalocalcaneal arthrodesis with a solid posterior offset hindfoot arthrodesis nail is a safe and effective surgical option for patients with severe ankle and hindfoot pathology. It has a high union rate, low complication rate and significantly improves clinical outcomes. [ABSTRACT FROM AUTHOR]

Background Virtual fracture clinics are an alternative to the traditional model of fracture care. Since their introduction in 2011, they have become increasingly used in the United Kingdom and Ireland. The coronavirus disease 2019 (COVID-19) health crisis has driven institutions to examine such innovative solutions to manage patient care. The current controversies include quantifying safety outcomes, such as potential delayed or missed injuries, inadequate treatment, and medicolegal claims. Questions also exist regarding the potential for cost reductions and efficiencies that may be achieved. Physical distancing has limited the number of face-to-face consultations, so this review was conducted to determine if virtual fracture clinics can provide an acceptable alternative in these challenging times. Questions/purposes The aim of this systematic review was to describe (1) adverse outcomes, (2) cost reductions, and (3) efficiencies associated with the virtual fracture clinic model. Methods A systematic review of the PubMed, MEDLINE, and Embase databases was conducted from database inception to March 2020. The keywords “virtual” or “telemedicine” or “telehealth” or “remote” or “electronic” AND “fracture” or “trauma” or “triage” AND “clinic” or “consultation” were entered, using the preferred reporting items for systematic reviews and meta-analyses. Inclusion criteria included adults and children treated for injuries by a virtual clinic model at the initial review. Eligible injuries included injuries deemed to not need surgical intervention, and those able to be treated remotely using defined protocols. Exclusion criteria consisted of patients reviewed by telemedicine using video links or in person at the initial review. Initially, 1065 articles were identified, with 665 excluded as they did not relate to virtual fracture clinics. In all, 400 articles were screened for eligibility, and 27 full-text reviews were conducted on 18 studies (30,512 virtual fracture clinic encounters). Three subdomains focusing on adverse outcomes, cost reductions, and efficiencies were recorded. The term adverse outcomes was used to describe any complications, further surgeries, re-referrals back to the clinic, or deviations from the protocols. Efficiency described the number of patients reviewed and discharged using the model, savings in clinic slots, reduced waiting times, or a reduction in consumption of resources such as radiographs. All studies were observational and the quality was assessed using Newcastle-Ottawa tool, which demonstrated a median score of 6 ± 1.8, indicating moderate quality. Results Six studies reported adverse outcomes in detail, with events ranging from inappropriate splinting, deviations from protocols, and one patient underwent an osteotomy for a malunion. Efficiency varied from direct discharge proportions of 18% in early studies to 100% once the virtual fracture clinic model was more established. Cost reductions compared with estimates derived from conventional fracture clinics varied from USD 53 to USD 297 and USD 39,125 to USD 305876 compared with traditional fracture clinic visits. Conclusions Virtual fracture clinics may provide a means to treat patients remotely, using agreed-upon protocols. They have an important role in the current COVID-19 pandemic, due to the possibility to provide ongoing care in an otherwise challenging setting. More robust studies looking at this model of care will be needed to assess its long-term effects on patients, institutions, and health care systems. [ABSTRACT FROM AUTHOR]

Background: Virtual fracture clinics are an alternative to the traditional model of fracture care. Since their introduction in 2011, they have become increasingly used in the United Kingdom and Ireland. The coronavirus disease 2019 (COVID-19) health crisis has driven institutions to examine such innovative solutions to manage patient care. The current controversies include quantifying safety outcomes, such as potential delayed or missed injuries, inadequate treatment, and medicolegal claims. Questions also exist regarding the potential for cost reductions and efficiencies that may be achieved. Physical distancing has limited the number of face-to-face consultations, so this review was conducted to determine if virtual fracture clinics can provide an acceptable alternative in these challenging times.Questions/purposes: The aim of this systematic review was to describe (1) adverse outcomes, (2) cost reductions, and (3) efficiencies associated with the virtual fracture clinic model.Methods: A systematic review of the PubMed, MEDLINE, and Embase databases was conducted from database inception to March 2020. The keywords "virtual" or "telemedicine" or "telehealth" or "remote" or "electronic" AND "fracture" or "trauma" or "triage" AND "clinic" or "consultation" were entered, using the preferred reporting items for systematic reviews and meta-analyses. Inclusion criteria included adults and children treated for injuries by a virtual clinic model at the initial review. Eligible injuries included injuries deemed to not need surgical intervention, and those able to be treated remotely using defined protocols. Exclusion criteria consisted of patients reviewed by telemedicine using video links or in person at the initial review. Initially, 1065 articles were identified, with 665 excluded as they did not relate to virtual fracture clinics. In all, 400 articles were screened for eligibility, and 27 full-text reviews were conducted on 18 studies (30,512 virtual fracture clinic encounters). Three subdomains focusing on adverse outcomes, cost reductions, and efficiencies were recorded. The term adverse outcomes was used to describe any complications, further surgeries, re-referrals back to the clinic, or deviations from the protocols. Efficiency described the number of patients reviewed and discharged using the model, savings in clinic slots, reduced waiting times, or a reduction in consumption of resources such as radiographs. All studies were observational and the quality was assessed using Newcastle-Ottawa tool, which demonstrated a median score of 6 ± 1.8, indicating moderate quality.Results: Six studies reported adverse outcomes in detail, with events ranging from inappropriate splinting, deviations from protocols, and one patient underwent an osteotomy for a malunion. Efficiency varied from direct discharge proportions of 18% in early studies to 100% once the virtual fracture clinic model was more established. Cost reductions compared with estimates derived from conventional fracture clinics varied from USD 53 to USD 297 and USD 39,125 to USD 305876 compared with traditional fracture clinic visits.Conclusions: Virtual fracture clinics may provide a means to treat patients remotely, using agreed-upon protocols. They have an important role in the current COVID-19 pandemic, due to the possibility to provide ongoing care in an otherwise challenging setting. More robust studies looking at this model of care will be needed to assess its long-term effects on patients, institutions, and health care systems.Level Of Evidence: Level IV, therapeutic study. [ABSTRACT FROM AUTHOR]

First metatarsophalangeal joint (MTPJ) arthrodesis is a commonly utilised procedure. In this study, the authors aim to explore functional outcomes of patients undergoing nonsynchronous bilateral first MTPJ arthrodesis under the care of a single surgeon using a compression screw/locking plate construct. This is a prospectively collected, retrospectively analysed case series of fifty five patients who underwent bilateral nonsynchronous first MTPJ arthrodesis. Clinical and radiological outcomes were assessed preoperatively and at a minimum of two years postoperatively. Clinical outcomes were assessed using the Foot and Ankle Outcome Score (FAOS), the Self-Reported Foot and Ankle Score (SEFAS) and the Sports Questionnaire version 1 (SQ). Postoperative radiographs were used to assess evidence of union and compare both hallux valgus and intermetatarsal angles. Removal of hardware, revision surgery and correction of deformities were also recorded. Fifty five patients were included in the study. There was statistically significant improvements in all five facets of the FAOS (p value < 0.05). The mean postoperative SEFAS was 45.1. In total, patients participated in thirteen different sporting activities. This represented 92 patient specific activities preoperatively and 104 postoperatively. The most common activities were walking, cycling and swimming. Overall, 94.5% (N = 52) of the cohort were satisfied with their return to sport while 98.2% (N = 54) would recommend bilateral first MTPJ arthrodesis. Mean reductions in hallux valgus angles and intermetatarsal angles were noted at 18.87 and 4.69 degrees respectively. There was one non-union in the cohort which required revision surgery. One patient required removal of hardware. Bilateral first MTPJ arthrodesis is a safe and effective surgical option for patients with bilateral first MTPJ pathology. It has a high union rate, low complication rate and significantly improves clinical outcomes and allows patients reliably return to physical activities. [ABSTRACT FROM AUTHOR]

Background: Intra-articular phalangeal fractures involving the proximal interphalangeal joint (PIPJ) are notoriously difficult injuries to treat and often require regular follow-up to assess progress, guide treatment, and determine outcomes. Some patients often have to travel long distances for follow-up care. The aim of our study was to assess the clinical outcomes of intra-articular fractures of the PIPJ through use of clinical pictures sent through a mobile phone. Methods: A retrospective study was conducted of a consecutive group of patients treated with a static external fixator (Micro Hoffman-2 Stryker®) between 2006 and 2016 for an intra-articular fracture of the PIPJ. Range of motion (ROM) at the PIPJ was assessed through clinical pictures taken on a mobile phone. Results: Clinical images were received from 15 patients with a mean age of 31.9 years (range 15–51), of which 73.3% of patients were male. Mean length of follow-up was 39 months. Around 73.3% of injuries occurred while playing a sport. Mean PIPJ ROM assessed through the clinical images was 67°. Conclusion: Our study shows that it was possible to assess ROM at the PIPJ through the use of clinical pictures taken by mobile phone. The use of mobile phones to take images provided a simple, easy, and convenient means of assessing outcome in this cohort of patients. We describe a method of follow-up that may have a greater role in the future. [ABSTRACT FROM AUTHOR]

Purpose: Osteochondral lesions (OCLs) of the talus are a challenging and increasingly recognized problem in chronic ankle pain. Many novel techniques exist to try and treat this challenging entity. Difficulties associated with treating OCLs include lesion location, size, chronicity, and problems associated with potential graft harvest sites. Matrix-associated stem cell transplantation (MAST) is one such treatment described for larger lesions > 15 mm2 or failed alternative therapies. This cohort study describes a 3 year review of the outcomes of talar lesions treated with MAST.Methods: A review of all patients treated with MAST by a single surgeon was conducted. Pre-operative radiographs, MRIs, and FAOS outcome questionnaire scores were reviewed. Intraoperative classification was undertaken to correlate with imaging. Post-operative outcomes included FAOS scores, return to sport, revision surgery/failure of treatment, and progression to ankle fusion.Results: In this study, 38 OCLs in 32 patients were identified. Median patient age was 35 years of which (68.8%) were male. Median length of follow-up was 36.7 months (range 12-64 months). (83%) returned to playing sport. Twenty-three patients underwent MAST in the setting of a failed previous operative attempt, with just nine having MAST as a first option. Nine patients out of 32 had a further procedure. Improvements were seen in all domains of the FAOS (p < 0.05).Conclusion: MAST has demonstrated encouraging results in lesions which prove challenging to treat, even in a "failed microfracture" cohort.Level Of Evidence: IV. [ABSTRACT FROM AUTHOR]

Background: Ankle fractures account for 9% of all fractures and 40% require surgical management. The ankle is the most common site of hardware removal. The purpose of our study was to investigate the incidence, indication and economic cost associated with removal of hardware from the ankle.Methods: We conducted a ten-year retrospective review of 1482 patients treated by open reduction internal fixation for an unstable ankle fracture. Skeletally immature patients were excluded. Data collected was cross referenced from patient medical records, the radiological and electronic patient database. The casemix and hospital inpatient enquiry system (HIPE) were used to calculate costs.Results: The mean age was 39.9 years with 53.6% male. 185 patients (12.5%) underwent hardware removal with unplanned removal performed in 6% of cases. The average cost of removal was €1113.Conclusion: Removal of hardware continues to be a common operation with significant costs to all involved. More than one in 10 patients underwent future removal of hardware.Level Of Evidence: Level 3. [ABSTRACT FROM AUTHOR]

Background: The term osteochondral lesion (OCL) refers to a defect involving the chondral surface and or subchondral bone. These lesions are associated with ankle injuries with bony and soft tissue and cause pain, decreased range of motion, swelling and impact adversely on quality of life. To date the standard treatment has been isolated microfracture (BMS). The aim of this study was to compare the outcomes of BMS alone to BMS augmented with bone marrow aspirate concentrate (BMAC) in the treatment of ankle OCLs.Methods: This study was a prospective cohort study carried out from 2010-2015 in a single surgeon's practice. Patients from 2010-2012 were treated with microfracture alone while patients from 2013-2015 were treated with micro fracture augmented with bone marrow aspirate concentrate and fibrin glue. Self-reported patient outcome measures were measured. Complications, revision rates, and visual analogue pain scores were compared.Results: 101 patients were included in the study. 52 patients were in the microfracture group while 49 patients were in the microfracture/BMAC group. The minimum follow-up for both groups was 36 months. Both groups had a statistically significant improvement in pain scores, quality of life scores, participation in sport and activities of daily living. The revision rate was 28.8% in the microfracture group versus 12.2% in the microfracture/BMAC group, which was statistically significant, p=0.0145. The majority of the lesions were less than 1.5cm2 in diameter in both cohorts.Conclusions: Microfracture and bone marrow aspirate concentrate appears to be a safe and effective treatment option for osteochondral lesions of the talus. The addition of bone marrow aspirate concentrate does not result in any increase in ankle or donor site morbidity. It is a well-tolerated therapy which decreases revision rates for treatment of the osteochondral lesions when compared to microfracture alone.Level Of Evidence: Level III. [ABSTRACT FROM AUTHOR]

Appropriate innate and adaptive immune responses are essential for protection and resolution against chemical, physical or biological insults. Immune cell polarization is fundamental in orchestrating distinct phases of inflammation, specifically acute phase responses followed by resolution and tissue repair. Dysregulation of immune cell and inflammatory responses is a hallmark of multiple diseases encompassing atherosclerosis, rheumatoid arthritis, psoriasis and metabolic syndromes. A master transcriptional mediator of diverse inflammatory signaling and immune cell function is NF-kB, and altered control of this key regulator can lead to an effective switch from acute to chronic inflammatory responses. Members of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors crosstalk with NF-kB to regulate immune cell function(s). Within the NR superfamily the NR4A1-3 orphan receptors have emerged as important regulators of immune cell polarization and NF-kB signaling. NR4A receptors modulate NF-kB activity in a dynamic fashion, either repressing or enhancing target gene expression leading to altered inflammatory outcome. Here we will discuss the pivotal role NR4A's receptors play in orchestrating immune cell homeostasis through molecular crosstalk with NF-kB. Specifically, we will examine such NR4A/NF-kB interactions within the context of distinct cell phenotypes, including monocyte, macrophage, T cells, endothelial, and mesenchymal cells, which play a role in inflammation-associated disease. Finally, we review the therapeutic potential of altering NR4A/NF-kB interactions to limit hyper-inflammatory responses in vivo. [ABSTRACT FROM AUTHOR]

Inflammation is paradoxical; it is essential for protection following biological, chemical or physical stimuli, but inappropriate or misdirected inflammation is responsible for tissue injury in a variety of inflammatory diseases. The polarization of immune cells is critical in controlling the stages of inflammatory response. The acute phase of inflammation is characterized by a T-lymphocyte:Th2 cytokine profile and involves a co-ordinated migration of immune cells to the site of injury where production of cytokines and acute-phase proteins brings about healing. However, persistent inflammation can result in inappropriate and prolonged T-lymphocyte:Th1 cytokine-mediated action and reaction of self-molecules, leading to a chronic phase in diseases such as RA (rheumatoid arthritis), Ps (psoriasis) and atherosclerosis. The inflammatory response is also controlled by activated macrophage cells, with classically activated (M1) cells producing a wide variety of pro-inflammatory mediators, while alternatively activated (M2) macrophages participate in anti-inflammatory response. Members of the NR4A subfamily (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) of orphan NRs (nuclear receptors) have emerged as key transcriptional regulators of cytokine and growth factor action in diseases affecting our aging population. As ligand-independent and constitutively active receptors, the activity of these transcription factors is tightly controlled at the level of expression, post-translational modification and subcellular localization. NR4A subfamily members are aberrantly expressed in inflamed human synovial tissue, psoriatic skin, atherosclerotic lesions, lung and colorectal cancer cells. Significantly, prolonged or inappropriate inflammatory responses contribute to the pathogenesis of these diseases. In activated cells, NR4A receptors are rapidly and potently induced, suggesting that these receptors may act as important transcriptional mediators of inflammatory signals. NR4A receptors may contribute to the cellular processes that control inflammation, playing a critical part in the contribution of chronic inflammation or they may have a protective role, where they may mediate pro-resolution responses. Here, we will review the contribution of the NR4A orphan NRs to integration of cytokine signalling in inflammatory disorders. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing hormone (CRH) coordinates the systemic stress response via hypothalamic-pituitary-adrenal (HPA) axis activation with subsequent modulation of the inflammatory response. Stress is known to affect expression of immune-mediated inflammatory diseases, many of which are associated with HPA axis abnormalities. HPA axis components including CRH and its receptors (CRH-R) exist in the skin and exhibit differential expression according to cell type, physiological fluctuations and disease states. This confirms a local functioning cutaneous HPA-like system. Peripheral CRH may exhibit proinflammatory effects. Animal studies confirm that peripheral CRH is required for induction of the inflammatory response in vivo. CRH and CRH-R are upregulated in inflammatory arthritis synovium and psoriatic skin. CRH may influence mast cell activation, direct modulation of immune cells, angiogenesis and induction of the novel orphan nuclear receptor NURR1. This transcription factor is part of the steroid/thyroid superfamily of related nuclear receptors that includes receptors for steroids, retinoids and vitamin D; ligands of these receptors are effective in treating psoriasis. The roles of CRH and NURR1 in psoriasis and inflammatory skin diseases, especially those associated with stress, remain to be elucidated. This stress may be psychological or physical. CRH, produced locally or delivered by peripheral nerves, may mediate interactions between a cutaneous HPA axis-like system and the central HPA axis – the ‘brain-skin axis’. [ABSTRACT FROM AUTHOR]

Background: Collagenase clostridium histolyticum has become a widely used treatment in the management of Dupuytren disease. The aims of this study are to assess the immediate success of treatment of Dupuytren contracture with collagenase injection, to measure long-term patient-rated outcomes, to determine whether the risk factors for the disease impacted outcomes and to report complications of collagenase treatment. Methods: A prospective study was performed in a tertiary referral centre. Measurements were recorded pre-treatment, day 1 and day 90. Patient-rated outcome scores were measured using Disability of the Arm, Shoulder and Hand questionnaire (DASH) and the Michigan Hand Questionnaire (MHQ) at minimum 36 months post-injection. Results: The study included 45 patients with 53 hands with a mean age of 65.7 years. The treatment was successful in 62% of patients with the greatest improvement in the metacarpal-phalangeal joint of the little finger. Diabetes, epilepsy, gender, alcohol intake and positive family history had no statistically significant predictive value on successful outcomes. Patient satisfaction at 41 months was high with mean MHQ score of 97.3. Conclusions: Collagenase is effective in the treatment of Dupuytren contracture, with disease involving the little finger showing the greatest benefit. Risk factors for development of Dupuytren disease had no effect on successful outcome and long-term satisfaction rates are high. Level of Evidence: Level III (Therapeutic) [ABSTRACT FROM AUTHOR]

Adenosine is a purine nucleoside pivotal for homeostasis in cells and tissues. Stimulation of the adenosine receptors (AR) has been shown to regulate the nuclear orphan receptor 4A (NR4A1-3) family, resulting in attenuation of hyper-inflammatory responses in myeloid cells. The NR4A1-3 orphan receptors are early immediate response genes and transcriptional regulators of cell and tissue homeostasis. The signal transduction and transcriptional mechanism(s) of how AR-stimulation promotes NR4A expression in myeloid cells is unknown and is the focus of this study. We confirm that adenosine and the stable analogue, 5′-N-Ethylcarboxamidoadenosine (NECA), enhance NR4A1-3 expression in THP-1 cells. Pharmacological approaches identified that protein kinase D (PKD) mediates AR-stimulated NR4A expression in myeloid cells and reveals no involvement of PKA nor PKC. The role of NF-κB, a principal regulator of NR4A expression in myeloid cells, was examined as a possible transcriptional regulator downstream of PKD. Utilising BAY11-7082 and MG-132, inhibitors of the respective ubiquitin and proteasome pathways essential for NF-κB activation, suggested a prospective role for NF-κB, or more specifically signalling via IKKα/β. However, biological interventional studies using overexpression of IκBα in myeloid cells and MEF cells lacking IKKα and IKKβ (IKKα/β−/-) revealed the NF-κB pathway is not utilised in mediating AR-stimulated NR4A expression. Thus, this study contributes mechanistic insight into how AR signalling modulates the expression of NR4A receptors, pivotal regulators of inflammatory responses in myeloid cells. [Display omitted] • PKD is involved in adenosine receptor driven (AR) NR4A expression in myeloid cells. • Ubiquitin and proteasome pathways are involved in AR driven NR4A expression in myeloid cells. • NF-κB is not involved in AR driven NR4A expression in myeloid cells. [ABSTRACT FROM AUTHOR]

Orphan nuclear receptor subfamily 4A (NR4A) are key regulators of inflammatory responses, largely by their interactions with NF-κB. Over the last decade, several NR4A modulators have been developed, and they are showing potential as therapeutics, although their widespread use in laboratory settings is limited. Here, we have examined, using myeloid cell line THP-1, whether the NR4A modulator 3-[(4-Chlorophenyl)-(1H-indol-3-yl)methyl]-1H-indole (C-DIM12) can alter the inflammatory outcome of six inflammatory ligands: lipopolysaccharide (LPS), tumour necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), flagellin (FL), lipoteichoic acid (LTA), and zymosan (ZY). We demonstrate that C-DIM12 (10 µM) selectively alters the secretion of inflammatory chemokine MCP-1 following exposure to distinct inflammatory ligands in a concentration-dependent manner. Furthermore, data obtained from THP-1 Lucia cell experiments show that 10 µM C-DIM12, and not 1 µM C-DIM12, can significantly attenuate the increased NF-κB transcriptional activity observed following the exposure to several inflammatory ligands (LPS, FL, TNFα, LTA, and ZY). Lastly, experimental analysis confirms that the cellular action(s) of C-DIM12 is independent of changes in metabolic parameters. Thus, these data contribute to the understanding of how the NR4A modulator C-DIM12 alters inflammatory responses in a myeloid cell following exposure to multiple ligands. [ABSTRACT FROM AUTHOR]

Historically, a simple approach centered on palliation was applicable to the majority of patients with metastatic spinal disease. With advances in diagnosis and treatment, a more complicated algorithm has devolved requiring a multidisciplinary approach with institutional commitment and support. We performed a database review including pertinent articles exploring the multidisciplinary management of spinal metastatic disease. The wide variation in clinical presentation and tumor response to treatment necessitates a multidisciplinary approach that integrates the diagnosis and treatment of the cancer, symptom management, and rehabilitation for optimal care of patients with spinal metastases. Advances in the field of radiology have led to earlier and more focused diagnosis of spinal metastasis and acts to guide therapy. Advances in surgical techniques, neurophysiologic monitoring, and anesthetic expertise have allowed surgeons to perform more extensive procedures leading to improved outcomes and reduced morbidity. Radiation oncology input that is essential as external beam radiation therapy can provide significant pain relief. Non-operative measures may include bisphosphonate infusions, management of complications (e.g. hypercalcemia of malignancy), monoclonal antibody infusions, and chemotherapy if indicated in the treatment of the primary malignancy. Input from psychology services is necessary to address the biopsychosocial ramifications of spinal metastasis. Allied health professionals in the form of physiotherapists, social workers, and dieticians also contribute in maximizing patients' quality of life and well-being. [ABSTRACT FROM AUTHOR]

Abstract: Histamine promotes immune complex-induced vascular leakage in vivo, a critical and early event that leads to joint-specific autoimmune damage. Initial assessment, using explanted human synovial tissue (ST), indicates that histamine can modulate local expression of type 1 alpha CRH receptors (CRH-R1α). The objective of this study was to elucidate the signalling events and transcriptional mechanism(s) controlling histamine-dependent regulation of CRH-R1α expression in human inflammatory arthritis. Histamine significantly promotes CRH-R1α mRNA and protein expression in a time- and concentration-dependent manner in human endothelial and synoviocyte cells. Transactivation of the human CRH-R1 promoter is significantly enhanced by histamine which can be mimicked by treatment with a Ca2+ ionophore and completely diminished in the presence of a Ca2+ chelator. Histamine-mediated responses involve enhanced activation and nuclear localisation of transcription factors including CREB, NF-κB and NR4A2. Functional consequences of enhanced CREB, NF-κB and NR4A2 activity confirm that NF-κB/p65 selectively controls CRH-R1 promoter activity. Co-transfection of NF-κB/p65 potently transactivates the CRH-R1 promoter while co-expression of a dominant negative IκBα kinase inhibits endogenous and histamine-induced promoter activity. Bioinformatic analysis identifies three putative κB consensus binding sites at proximal and distal positions and 5′ deletional analysis identifies promoter region(s) required for activation by histamine and NF-κB/p65. We observe direct NF-κB/p65 interaction within the promoter region and site-directed mutagenesis reveals that all three κB sites are required to mediate histamine and NF-κB/p65 regulation of CRH-R1 promoter activity. These findings confirm that histamine, via enhanced Ca2+ signalling and NF-κB/p65 activity, contributes to changes in ST inflammation by promoting CRH-R1α-mediated responses. [Copyright &y& Elsevier]

Inflammation is a pivotal pathological factor in colorectal cancer (CRC) initiation and progression, and modulating this inflammatory state has the potential to ameliorate disease progression. NR4A receptors have emerged as key regulators of inflammatory pathways that are important in CRC. Here, we have examined the effect of NR4A agonist, Cytosporone B (CsnB), on colorectal tissue integrity and its effect on the inflammatory profile in CRC tissue ex vivo. Here, we demonstrate concentrations up 100 μM CsnB did not adversely affect tissue integrity as measured using transepithelial electrical resistance, histology and crypt height. Subsequently, we reveal through the use of a cytokine/chemokine array, ELISA and qRT-PCR analysis that multiple pro-inflammatory mediators were significantly increased in CRC tissue compared to control tissue, which were then attenuated with the addition of CsnB (such as IL-1β, IL-8 and TNFα). Lastly, stratification of the data revealed that CsnB especially alters the inflammatory profile of tumours derived from males who had not undergone chemoradiotherapy. Thus, this study demonstrates that NR4A agonist CsnB does not adversely affect colon tissue structure or functionality and can attenuate the pro-inflammatory state of human CRC tissue ex vivo. • NR4A agonist cytosporone B does not affect healthy human colon tissue structure or function ex vivo. • Cytosporone B attenuates pro-inflammatory mediators secreted by human colorectal cancer tissue ex vivo. • Cytosporone B has a more pronounced affect on colorectal cancer tissue derived from males who did not have chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Background During the current COVID-19 health crisis virtual geriatric clinics have become increasingly utilised to complete outpatient consultations, although concerns exist about feasibility of such virtual consultations for older people. The aim of this rapid review is to describe the satisfaction, clinic productivity, clinical benefit, and costs associated with the virtual geriatric clinic model of care. Methods A rapid review of PubMed, MEDLINE and CINAHL databases was conducted up to April 2020. Two independent reviewers extracted the information. Four subdomains were focused on: satisfaction with the virtual geriatric clinic, clinic productivity, clinical benefit to patients, costs and any challenges associated with the virtual clinic process. Results Nine studies with 975 patients met our inclusion criteria. All were observational studies. Seven studies reported patients were satisfied with the virtual geriatric clinic model of care. Productivity outcomes included reports of cost-effectiveness, savings on transport, and improved waiting list metrics. Clinical benefits included successful polypharmacy reviews, and reductions in acute hospitalisation rates. Varying challenges were reported for both clinicians and patients in eight of the nine studies. Hearing impairments and difficulty with technology added to anxieties experienced by patients. Physicians missed the added value of a thorough physical examination and had concerns about confidentiality. Conclusion Virtual geriatric clinics demonstrate evidence of productivity, benefit to patients, cost effectiveness and patient satisfaction with the treatment provided. In the current suboptimal pandemic climate, virtual geriatric clinics may allow Geriatricians to continue to provide an outpatient service, despite the encountered inherent challenges. [ABSTRACT FROM AUTHOR]

Adenosine receptor-mediated regulation of monocyte/macrophage inflammatory responses is critical in the maintenance of tissue homeostasis. In this study, we reveal that adenosine potently modulates the expression of NR4A1, 2, and 3 orphan nuclear receptors in myeloid cells, and this modulation is primarily through the adenosine A2a receptor subtype. We demonstrate that A2a receptor activation of NR4A1-3 receptor synthesis is further enhanced in TLR4-stimulated monocytes. After TLR4 stimulation, NR4A receptor-depleted monocyte/macrophage cells display significantly altered expression of cell-surface markers and produce increased inflammatory cytokine and chemokine secretion rendering the cells an enhanced proinflammatory phenotype. Exposure of TLR4 or TNF-α-stimulated monocytes to adenosine analogs directs changes in the expression of MIP-3α and IL-23p19, with NR4A2 depletion leading to significantly enhanced expression of these factors. Furthermore, we establish that nuclear levels of NF-κB/p65 are increased in TLR/adenosine-stimulated NR4A2-depleted cells. We show that, after TLR/adenosine receptor stimulation, NR4A2 depletion promotes significant binding of NF-κB/p65 to a ?B consensus binding motif within the MIP-3α proximal promoter leading to increased protein secretion, confirming a pivotal role for NF-κB activity in controlling cellular responses and gene expression outcomes in response to these mediators. Thus, these data demonstrate that during an inflammatory response, adenosine modulation of NR4A receptor activity acts to limit NF-κB-mediated effects and that loss of NR4A2 expression leads to enhanced NF-κB activity and hyperinflammatory responses in myeloid cells. [ABSTRACT FROM AUTHOR]

Abstract: Prolonged inappropriate inflammatory responses contribute to the pathogenesis of rheumatoid arthritis (RA) and to aspects of osteoarthritis (OA). The orphan nuclear receptor, NR4A2, is a key regulator and potential biomarker for inflammation and represents a potentially valuable therapeutic target. Both salmon calcitonin (sCT) and hyaluronic acid (HA) attenuated activated mRNA expression of NR4A1, NR4A2, NR4A3, and matrix metalloproteinases (MMPs) 1, 3 and 13 in three human cell lines: SW1353 chondrocytes, U937 and THP-1 monocytes. Ad-mixtures of sCT and HA further down-regulated expression of NR4A2 compared to either agent alone at specific concentrations, hence the rationale for their formulation in nanocomplexes (NPs) using chitosan. The sCT released from NP stimulated cAMP production in human T47D breast cancer cells expressing sCT receptors. When NP were injected by the intra-articular (I.A.) route to the mouse knee during on-going inflammatory arthritis of the K/BxN serum transfer model, joint inflammation was reduced together with NR4A2 expression, and local bone architecture was preserved. These data highlight remarkable anti-inflammatory effects of sCT and HA at the level of reducing NR4A2 mRNA expression in vitro. Combining them in NP elicits anti-arthritic effects in vivo following I.A. delivery. [Copyright &y& Elsevier]

Objective To elucidate histamine receptor-mediated signaling pathways, transcriptional events, and target gene expression in human cartilage. Methods Histamine modulation of cartilage destruction was assessed by Safranin O staining and proteoglycan release. H1, H2, H3, and H4 histamine receptor-dependent regulation of transcription factors (nuclear receptor 4A1 [NR4A1], NR4A2, and NR4A3), RANKL, and osteoprotegerin (OPG) messenger RNA (mRNA) levels were measured in primary and SW-1353 chondrocyte cells using quantitative polymerase chain reaction and selective histamine receptor antagonists. Soluble RANKL and OPG protein levels were determined using enzyme-linked immunosorbent assays. NR4A protein levels and transactivity were evaluated by Western blot analysis, immunocytochemistry, and luciferase reporter assays. Stable depletion of NR4A1-3 was achieved by lentiviral transduction of NR4A short hairpin RNA. Results Primary human chondrocyte cells expressed differential steady-state levels of H1-H4 histamine receptor mRNA. In combination with tumor necrosis factor α, histamine significantly promoted cartilage proteoglycan depletion and release. Histamine modulated the expression of NR4A1-3 orphan receptors in primary and immortalized human chondrocyte cells in a time- and concentration-dependent manner. Histamine selectively signaled through H1 and H2 histamine receptors in chondrocytes to modulate RANKL and NR4A2 expression. The temporal effects of histamine on NR4A2 gene transcription were reduced in cells pretreated with inhibitors directed against protein kinase A, MAPK, and NF-κB signaling pathways. Histamine modulated the expression of RANKL with modest effects on OPG levels, leading to increased RANKL:OPG mRNA and protein ratios. Stable knockdown of NR4A1-3 expression resulted in reduced endogenous OPG levels and the loss of histamine-dependent regulation of RANKL expression. Conclusion Our findings indicate that histamine, via H1 and H2 histamine receptors, contributes to joint disease by enhancing the ratio of RANKL to OPG expression through altered NR4A activity in human chondrocyte cells. [ABSTRACT FROM AUTHOR]

Objective To address the role of the nuclear receptor 4A (NR4A) family of orphan nuclear receptors in synoviocyte transformation, hyperplasia, and regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in models of inflammatory arthritis. Methods NR4A messenger RNA levels in synovial tissue and primary synoviocytes were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). NR4A2 was stably overexpressed in normal synoviocytes, and cell proliferation, survival, anchorage-independent growth, migration, and invasion were monitored in vitro. MMP and TIMP expression levels were analyzed by quantitative RT-PCR, and MMP-13 promoter activity was measured using reporter assays. Stable depletion of endogenous NR4A levels was achieved by lentiviral transduction of NR4A short hairpin RNA (shRNA), and the effects on proliferation, migration, and MMP-13 expression were analyzed. Results NR4A2 was expressed at elevated levels in normal, OA, and RA synovial tissue and in primary RA synoviocytes. Tumor necrosis factor α (TNFα) rapidly and selectively induced expression of NR4A2 in synoviocytes. Ectopic expression of NR4A2 in normal synoviocytes significantly increased proliferation and survival, promoted anchorage-independent growth, and induced migration and invasion. MMP-13 gene expression was synergistically induced by NR4A2 and TNFα, while expression of TIMP-2 was antagonized. NR4A2 directly transactivated the proximal MMP-13 promoter, and a point mutation in the DNA binding domain of NR4A2 abolished transcriptional activation. Depletion of endogenous NR4A receptors with shRNA reduced synoviocyte proliferation, migration, and MMP-13 expression. Conclusion The orphan nuclear receptor NR4A2 is a downstream mediator of TNFα signaling in synovial tissue. NR4A2 transcriptional activity contributes to the hyperplastic and invasive phenotype of synoviocytes that leads to cartilage destruction, suggesting that this receptor may show promise as a therapeutic target in inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Abstract: Expression of the orphan nuclear receptor NR4A2 is controlled by pro-inflammatory mediators, suggesting that NR4A2 may contribute to pathological processes in the inflammatory lesion. This study identifies the chemoattractant protein, interleukin 8 (IL-8/CXCL8), as a molecular target of NR4A2 in human inflammatory arthritis and examines the mechanism through which NR4A2 modulates IL-8 expression. In TNF-α-activated human synoviocyte cells, enhanced expression of IL-8 mRNA and protein correspond to temporal changes in NR4A2 transcription and nuclear distribution. Ectopic expression of NR4A2 leads to robust changes in endogenous IL-8 mRNA levels and co-treatment with TNF-α results in significant (p <0.001) secretion of IL-8 protein. Transcriptional effects of NR4A2 on the human IL-8 promoter are enhanced in the presence of TNF-α, suggesting molecular crosstalk between TNF-α signalling and NR4A2. A dominant negative IκB kinase antagonizes the combined effects of NR4A2 and TNF-α on IL-8 promoter activity. Co-expression of NR4A2 and the p65 subunit of NF-κB enhances IL-8 transcription and functional studies indicate that transactivation occurs independently of NR4A2 binding to DNA or heterodimerization with additional nuclear receptors. The IL-8 minimal promoter region is sufficient to support NR4A2 and NF-κB/p65 co-operative activity and NR4A2 can interact with NF-κB/p65 on a 39bp sequence within this region. In patients treated with methotrexate for active inflammatory arthritis, a reduction in NR4A2 synovial tissue levels correlate significantly (n =10, r =0.73, p =0.002) with changes in IL-8 expression. Collectively, these data delineate an important role for NR4A2 in modulating IL-8 expression and reveal novel transcriptional responses to TNF-α in human inflammatory joint disease. [Copyright &y& Elsevier]

Abstract: The mucoadhesive polymer, poly(dimethylamino)ethyl methacrylate, (pDMAEMA), was synthesised by living radical polymerisation and subsequently conjugated by quaternisation reaction to a functionalised anti-inflammatory corticosteroid dexamethasone, to separately yield two conjugates with either 9:1 or 18:1 molar ratios of dexamethasone:polymer respectively. The hypothesis was to test whether the active agent maintained in vitro bioactivity when exposed to the apical side of human intestinal epithelial monolayers, Caco-2 and mucos-covered HT29-MTX-E12 (E12). HPLC analysis indicated high conjugate purity. Similar to pDMAEMA, fluorescently-labelled dexamethasone–pDMAEMA conjugates were bioadhesive to Caco-2 and mucoadhesive to E12. Apical addition of conjugates suppressed mRNA expression of the inflammatory markers, NURR1 and ICAM-1 in E12 following stimulation by PGE2 and TNF-α, respectively. Conjugates also suppressed TNF-α stimulated cytokine secretion to the basolateral side of Caco-2 monolayers. Measurement of dexamethasone permeability from conjugates across monolayers suggested that conjugation reduced permeability compared to free dexamethasone. LDH assay indicated that conjugates were not cytotoxic to monolayers. Anti-inflammatory agents can therefore be successfully conjugated to polymers and they retain adhesion and bioactivity and have potential to be formulated for topical administration. [Copyright &y& Elsevier]

The orphan nuclear receptor NURR1 belongs to the NR4A subfamily of transcription factors which are emerging as important mediators of cytokine and growth factor signaling. The transcriptional function of these ligand-independent and constitutively active receptors is controlled at the level of expression and nuclear localization. This study examines the expression of NURR1 in psoriasis and biological effects on this receptor following inhibition of tumor necrosis factor-α (TNF-α) signaling. We report increased expression of NURR1 mRNA and protein in involved psoriasis skin compared with uninvolved and normal skin, which correlates significantly (P=0.0055) with clinical measures of the psoriasis area and severity index. Enhanced NURR1 expression localizes to both nucleus and cytoplasm of cells of involved epidermis, blood vessels, and inflammatory infiltrates, in contrast to predominant cytoplasmic distribution in uninvolved and normal skin. Endogenous NURR1 levels are rapidly and selectively increased in response to proinflammatory agonists and growth factors in normal dermal endothelial cells. Following TNF-α inhibition with infliximab or etanercept, NURR1 mRNA and protein levels in involved skin are significantly decreased and cytoplasmic distribution is restored. These findings establish the aberrant expression and distribution of NURR1 in psoriasis and suggest that clinical benefits of TNF-α inhibition may be mediated through altered NURR1 activity.Journal of Investigative Dermatology (2008) 128, 300–310; doi:10.1038/sj.jid.5701023; published online 2 August 2007 [ABSTRACT FROM AUTHOR]

The NR4A orphan receptors (Nur77, NURR1, and NOR-1) are emerging as key regulators of cytokine and growth factor action in chronic inflammatory diseases. In this study, we address the role of these receptors in cartilage homeostasis during inflammatory joint disease. We document for the first time expression of the NR4A receptors in osteoarthritic cartilage. Relative to Nut77 and NOR-1, NURR1 is expressed at the highest level and correlates with cyclooxygenase-2 levels in cartilage. Consistent with this observation, cyclooxygenase-2-derived prostaglandin E2 (PGE2) rapidly and potently induces NURR1 expression in chondrocytes, suggesting that this receptor may regulate PGE2-mediated processes in cartilage. We demonstrate that PGE2 represses interleukin-1β-induced matrix metalloproteinase (MMP)-1 and that transient over-expression of NURR1 is sufficient to antagonize expression of this gene. Furthermore, MMP-1 promoter activity is potently suppressed by NURR1, resulting in a significant reduction in endogenous MMP-1 mRNA and secreted pro-MMP-1 protein. In addition, NURR1 selectively antagonizes cytoldne-induced MMP-3 and -9 expression with minimal effects on MMP-2 and -13 and tissue inhibitor of matrix metalloproteinases-1 and -2. To explore the molecular mechanisms of NURR1 transrepression, we reveal that this receptor targets a critical region of the MMP-1 promoter (-1772 to -1546 bp) and that repression does not require consensus binding sites for NURR1. We confirm that NURR1 targets a 40-bp promoter sequence that is also positively regulated by ETS transcription factors. Finally, functional studies indicate that transcriptional antagonism exists between NURR1 and ETS1 on the MMP-1 promoter. We propose a protective function for NURR1 in cartilage homeostasis by selectively repressing MMP gene expression during inflammation. [ABSTRACT FROM AUTHOR]

Abstract: A range of N-glycosyl-thiophene-2-carboxamides, including a 6H-thieno[2,3-c]pyridin-7-one and a bivalent compound, have been synthesised and assayed for their effects on DNA synthesis in bovine aortic endothelial cells or on the growth of synoviocytes. Per-O-acetylated analogues of the glycoconjugates were significantly more effective inhibitors when compared to their corresponding non-acetylated analogues, indicating that the lower potency observed for hydroxylated derivatives is due to less efficient transport of these compounds across the cell membrane. Thiophene-2-carboxamide was inactive as an inhibitor of bFGF induced proliferation, confirming the requirement of the carbohydrate residue for the observed biological properties. Glucose, mannose, galactose and 2-amino-2-deoxy-glucose analogues were active as were a variety of substituted thiophene derivatives; the 6H-thieno[2,3-c]pyridin-7-one conjugate was inactive. Conformational analysis of the title compounds was investigated. X-ray crystal structural analysis of four N-glucosyl-thiophene-2-carboxamides showed that the pyranose rings adopted the expected 4 C 1 conformations and that Z-anti structures were predominant (H1–C1–N–H anomeric torsion angle varied from −168.2° to −175.0°) and that the carbonyl oxygen and sulfur of the thiophene adopted an s-cis conformation in three of the isomers. In a crystal structure of a 3-alkynyl derivative, the hydrogen atom of the NH group was directed toward the acetylene group. The distance between the hydrogen atom and acetylene carbons and angles between nitrogen, hydrogen and carbon atoms were consistent with hydrogen bonding and this was supported by IR and NMR spectroscopic studies. The geometries of thiophene-2-carboxamides were explored by density functional theory (DFT) and Møller-Plesset (MP2) calculations and the s-cis conformer of thiophene-2-carboxamide was found to be more stable than its s-trans isomer by 0.83kcalmol−1. The s-cis conformer of 3-ethynyl-thiophene-2-carboxamide was 5.32kcalmol−1 more stable than the s-trans isomer. The larger stabilisation for the s-cis conformer in the 3-alkynyl derivatives is explained to be due to a moderate hydrogen bonding interaction between the alkyne and NH group. [Copyright &y& Elsevier]

The cytokine tumor necrosis factor alpha (TNF-α) is a critical effector of the pathogenesis of rheumatoid arthritis (RA). We used oligonucleotide microarray (OM) analysis to assess TNF-α-modulated gene expression in cultured primary human synoviocytes in vitro. Genes identified include cytokines and inflammatory mediators, extracellular matrix and adhesion molecules, cell cycle and proliferation related proteins, transcription related proteins, and apoptotic mediators. OM identified 1185 differentially expressed genes in TNF-α-treated synoviocytes. The regulation of Nef-associated factor-1 (Naf1), an A20-binding, nuclear factor kappa B (NFκB) inhibitory protein was probed further given its putative role as an endogenous brake for the expression of some TNF-α-driven genes. Naf1 mRNA levels were higher in synovial biopsies from patients with active RA and seronegative arthropathy than in those from patients with osteoarthritis. These findings underscore the value of transcriptome analysis in cytokine-activated synoviocyte cultures in vitro as a means of identifying disease-associated genes in human arthritis, and implicate Naf1 as a potential modulator of TNF-α bioactivity in RA. [Copyright &y& Elsevier]