Improving the care of patients with severe open fractures of the tibia: the effect of the introduction of Major Trauma Networks and national guidelines.

AIMS: The management of open lower limb fractures in the United Kingdom has evolved over the last ten years with the introduction of major trauma networks (MTNs), the publication of standards of care and the wide acceptance of a combined orthopaedic and plastic surgical approach to management. The aims of this study were to report recent changes in outcome of open tibial fractures following the implementation of these changes. PATIENTS AND METHODS: Data on all patients with an open tibial fracture presenting to a major trauma centre between 2011 and 2012 were collected prospectively. The treatment and outcomes of the 65 Gustilo Anderson Grade III B tibial fractures were compared with historical data from the same unit. RESULTS: The volume of cases, the proportion of patients directly admitted and undergoing first debridement in a major trauma centre all increased. The rate of limb salvage was maintained at 94% and a successful limb reconstruction rate of 98.5% was achieved. The rate of deep bone infection improved to 1.6% (one patient) in the follow-up period. CONCLUSION: The reasons for these improvements are multifactorial, but the major trauma network facilitating early presentation to the major trauma centre, senior orthopaedic and plastic surgical involvement at every stage and proactive microbiological management, may be important factors. TAKE HOME MESSAGE: This study demonstrates that a systemised trauma network combined with evidence based practice can lead to improvements in patient care.

Inhibitors of protein kinase C. 3. Potent and highly selective bisindolylmaleimides by conformational restriction.

The protein kinase inhibitor staurosporine has been used to design a series of selective bisindolylmaleimide inhibitors of protein kinase C (PKC). Guided by molecular graphics, conformational restriction of the cationic side chain has led to ATP competitive inhibitors of improved potency and selectivity. Two compounds have been further evaluated and were shown to inhibit PKC of human origin and prevent T-cell activation in a human allogeneic mixed lymphocyte reaction. One of these compounds was orally absorbed in mice and antagonized a phorbol ester induced paw edema in a dose-dependent manner. This compound also selectively inhibited the secondary T-cell mediated response in a developing adjuvant arthritis model in rats and provides evidence for the potential use of PKC inhibitors as therapeutic immunomodulators.

Novel, potent and selective inhibitors of protein kinase C show oral anti-inflammatory activity.

Clarification of the precise role of protein kinase C (PKC) in cellular functional responses has been hampered by a lack of potent, selective inhibitors. The structural lead provided by staurosporine, a potent but non-selective protein kinase (PK) inhibitor, was used to derive a series of bis(indolyl)maleimides of which the most potent, Ro 31-8425 (I50: PKC = 8 nM) showed 350-fold selectivity for PKC over cAMP-dependent protein kinase. Ro 31-8425 antagonised cellular processes triggered by phorbol esters (potent, specific PKC activators) and inhibited the allogeneic mixed lymphocyte reaction, suggesting a role for PKC in T-cell activation. Methylation of the primary amine in Ro 31-8425 produced an analogue. Ro 31-8830 which, when administered orally, produced a dose-dependent inhibition of a phorbol ester-induced paw oedema in mice (minimum effective dose = 15 mg/kg). Ro 31-8830 also selectively inhibited the secondary inflammation in a developing adjuvant arthritis model in the rat. The results presented here suggest that these selective inhibitors of PKC may have therapeutic value in the treatment of T-cell-mediated autoimmune diseases.