J K Chan

Alarmins: awaiting a clinical response.

Alarmins are endogenous molecules that are constitutively available and released upon tissue damage and activate the immune system. Current evidence indicates that uncontrolled and excessive release of alarmins contributes to the dysregulated processes seen in many inflammatory and autoimmune conditions, as well as tumorigenesis and cancer spread. Conversely, alarmins have also been found to play a major role in the orchestration of tissue homeostasis, including repair and remodeling in the heart, skin, and nervous system. Here, we provide an update and overview on alarmins, highlighting the areas that may benefit from this clinical translation.

TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells.

With an aging population, skeletal fractures are increasing in incidence, including the typical closed and the less common open fractures in normal bone, as well as fragility fractures in patients with osteoporosis. For the older age group, there is an urgent unmet need to induce predictable bone formation as well as improve implant fixation in situations such as hip joint replacement. Using a murine model of slow-healing fractures, we have previously shown that coverage of the fracture with muscle accelerated fracture healing and increased union strength. Here, we show that cells from muscle harvested after 3 d of exposure to an adjacent fracture differentiate into osteoblasts and form bone nodules in vitro. The osteogenic potential of these cells exceeds that of adipose and skin-derived stromal cells and is equivalent to bone marrow stromal cells. Supernatants from human fractured tibial bone fragments promote osteogenesis and migration of muscle-derived stromal cells (MDSC) in vitro. The main factor responsible for this is TNF-α, which promotes first MDSC migration, then osteogenic differentiation at low concentrations. However, TNF-α is inhibitory at high concentrations. In our murine model, addition of TNF-α at 1 ng/mL at the fracture site accelerated healing. These data indicate that manipulating the local inflammatory environment to recruit, then differentiate adjacent MDSC, may be a simple yet effective way to enhance bone formation and accelerate fracture repair. Our findings are based on a combination of human specimens and an in vivo murine model and may, therefore, translate to clinical care.

Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target

Significance Fibrosis, a hallmark of many clinical disorders, occurs because of uncontrolled myofibroblast activity. We studied Dupuytrens disease, a common hereditable fibrotic condition that causes the fingers to irreversibly curl toward the palm. We found that freshly isolated tissue from Dupuytrens patients contained macrophages and released proinflammatory protein mediators (cytokines). Of the cytokines, only TNF selectively converted normal fibroblasts from the palm of patients with Dupuytrens disease into myofibroblasts via activation of the Wnt signaling pathway. Conversely, blockade of TNF resulted in reversal of the myofibroblast phenotype. Therefore, TNF inhibition may prevent progression or recurrence of Dupuytrens disease. Dupuytrens disease is a very common progressive fibrosis of the palm leading to flexion deformities of the digits that impair hand function. The cell responsible for development of the disease is the myofibroblast. There is currently no treatment for early disease or for preventing recurrence following surgical excision of affected tissue in advanced disease. Therefore, we sought to unravel the signaling pathways leading to the development of myofibroblasts in Dupuytrens disease. We characterized the cells present in Dupuytrens tissue and found significant numbers of immune cells, including classically activated macrophages. High levels of proinflammatory cytokines were also detected in tissue from Dupuytrens patients. We compared the effects of these cytokines on contraction and profibrotic signaling pathways in fibroblasts from the palmar and nonpalmar dermis of Dupuytrens patients and palmar fibroblasts from non-Dupuytrens patients. Exogenous addition of TNF, but not other cytokines, including IL-6 and IL-1β, promoted differentiation into specifically of palmar dermal fibroblasts from Dupuytrens patients in to myofibroblasts. We also demonstrated that TNF acts via the Wnt signaling pathway to drive contraction and profibrotic signaling in these cells. Finally, we examined the effects of targeted cytokine inhibition. Neutralizing antibodies to TNF inhibited the contractile activity of myofibroblasts derived from Dupuytrens patients, reduced their expression of α-smooth muscle actin, and mediated disassembly of the contractile apparatus. Therefore, we showed that localized inflammation in Dupuytrens disease contributes to the development and progression of this fibroproliferative disorder and identified TNF as a therapeutic target to down-regulate myofibroblast differentiation and activity.

Soft-tissue reconstruction of open fractures of the lower limb: muscle versus fasciocutaneous flaps.

Early vascularized soft-tissue closure has long been recognized to be essential in achieving eventual infection-free union. The question of whether muscle or fasciocutaneous tissue is superior in terms of promoting fracture healing remains unresolved. In this article, the authors review the experimental and clinical evidence for the different tissue types and advocate that the biological role of flaps should be included as a key consideration during flap selection.

Low‐dose TNF augments fracture healing in normal and osteoporotic bone by up‐regulating the innate immune response

The mechanism by which trauma initiates healing remains unclear. Precise understanding of these events may define interventions for accelerating healing that could be translated to the clinical arena. We previously reported that addition of low‐dose recombinant human TNF (rhTNF) at the fracture site augmented fracture repair in a murine tibial fracture model. Here, we show that local rhTNF treatment is only effective when administered within 24 h of injury, when neutrophils are the major inflammatory cell infiltrate. Systemic administration of anti‐TNF impaired fracture healing. Addition of rhTNF enhanced neutrophil recruitment and promoted recruitment of monocytes through CCL2 production. Conversely, depletion of neutrophils or inhibition of the chemokine receptor CCR2 resulted in significantly impaired fracture healing. Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death. Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair. If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization.

Isometric Contraction of Dupuytren's Myofibroblasts Is Inhibited by Blocking Intercellular Junctions

Myofibroblasts (MFs) are responsible for both physiological wound and scar contraction. However, it is not known whether these cells act individually to contract the surrounding matrix or whether they behave in a coordinated manner. Therefore, we studied intercellular junctions of primary human MFs derived from patients with Dupuytrens disease, a fibrotic disorder of the dermis and subdermal tissues of the palm. The cells were maintained in anchored three-dimensional collagen lattices to closely mimic conditions in vivo. We found that selective blockade of adherens, mechanosensitive, or gap junctions effectively inhibited contraction of the collagen matrices and downregulated the MF phenotype. Our data indicate that MFs in part function as a coordinated cellular syncytium, and disruption of intercellular communication may provide a therapeutic target in diseases characterized by an overabundance of these contractile cells.

Body dysmorphia, self-mutilation and the reconstructive surgeon

Body dysmorphic disorder (BDD) is a disabling preoccupation with a slight or an imagined defect in appearance. It is recognised in some patients who present to the plastic surgeon requesting multiple cosmetic procedures. Very rarely, BDD patients may wish for amputation of a healthy limb and may even mutilate themselves deliberately in order to necessitate amputation. These patients pose a diagnostic challenge as BDD is uncommon and they are often uncooperative whilst appearing mentally sound. Furthermore, they raise difficult ethical and legal issues for the surgeon. Although there is some guidance for the management of BDD patients seeking elective amputation, there is currently none for the management of those who present in the emergency setting. Illustrated by the case of a man who, having failed to find a complicit surgeon, attempted self-amputation of the hand, we review the relevant ethical, legal and management issues with advice by the British Medical Association and General Medical Council.

Posterior interosseous nerve palsy in rheumatoid arthritis: case report and literature review

Posterior interosseous nerve (PIN) palsy, presenting with a loss of digital extension, is a rare neurological complication of rheumatoid arthritis (RA). It may be caused by nerve entrapment, vasculitis or drug toxicity. There is no consensus regarding the treatment of PIN palsy in RA. We present a case in which the diagnosis of PIN palsy was confounded by previous surgical intervention. It represents the first report of PIN palsy treated with anti-TNF-alpha therapy leading to full recovery without surgical intervention. We highlight the importance of electrophysiological studies in elucidating the underlying cause and hence the treatment. We suggest that the apparent success of surgical intervention in the literature may be misleading, but new pharmacological advances may obviate the need for surgery where electrophysiology demonstrates vasculitis as the cause. A literature review is presented and a treatment algorithm proposed.

Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to GAlert.

Significance While stem cell therapy has become the standard of care for hematological disorders, challenges remain for the treatment of solid organ injuries. Targeting endogenous cells would overcome many hurdles associated with exogenous stem cell therapy. Alarmins are released upon tissue damage, and here we describe how upregulation of a physiological pathway by exogenous administration of a single dose of HMGB1, either locally or systemically, promotes tissue repair by targeting endogenous stem cells. We show that HMGB1 complexed with CXCL12 transitions stem cells that express CXCR4 from G0 to GAlert. These primed cells rapidly respond to appropriate activating factors released upon injury. HMGB1 promotes healing even if administered 2 wk before injury, thereby expanding its translational benefit for diverse clinical scenarios. A major discovery of recent decades has been the existence of stem cells and their potential to repair many, if not most, tissues. With the aging population, many attempts have been made to use exogenous stem cells to promote tissue repair, so far with limited success. An alternative approach, which may be more effective and far less costly, is to promote tissue regeneration by targeting endogenous stem cells. However, ways of enhancing endogenous stem cell function remain poorly defined. Injury leads to the release of danger signals which are known to modulate the immune response, but their role in stem cell-mediated repair in vivo remains to be clarified. Here we show that high mobility group box 1 (HMGB1) is released following fracture in both humans and mice, forms a heterocomplex with CXCL12, and acts via CXCR4 to accelerate skeletal, hematopoietic, and muscle regeneration in vivo. Pretreatment with HMGB1 2 wk before injury also accelerated tissue regeneration, indicating an acquired proregenerative signature. HMGB1 led to sustained increase in cell cycling in vivo, and using Hmgb1−/− mice we identified the underlying mechanism as the transition of multiple quiescent stem cells from G0 to GAlert. HMGB1 also transitions human stem and progenitor cells to GAlert. Therefore, exogenous HMGB1 may benefit patients in many clinical scenarios, including trauma, chemotherapy, and elective surgery.

Preoperative blood tests in elective general surgery: cost and clinical implications.

A retrospective observational study was performed in our trust in October 2010 that examined compliance, and the financial and clinical implications of performing inappropriate preoperative blood tests on adult patients prior to elective surgery, against the 2003 NICE guidelines. An unacceptable proportion of inappropriate tests (31.3%) were being performed. None were associated with adverse outcome or changes in management. Based on our results, we estimate that an extrapolated cost of £11.2 million is being spent on inappropriate blood tests in NHS England and Wales.