Peter Calder

A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome

BACKGROUND The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.).

The operative management of displaced intra-articular fractures of the calcaneum: a two-centre study using a defined protocol

The management of intra-articular calcaneal fractures remains controversial with strong arguments supporting both conservative and operative management. This study assesses the results of open reduction and internal fixation (ORIF) of displaced intra-articular fractures of the calcaneum in two independent centres where the indications for operative management had been strictly defined.Forty-seven patients (51 fractures) who had sustained such injuries underwent an ORIF performed by one of the senior surgeons using the technique described by Eastwood et al. [JBJS 75-B(1993)189] All of the fractures were assessed by plain X-ray and CT scan and graded according to the Sanders classification [Clin. Orthop. 290(1993)97]. Patients were assessed at a minimum of 2 years post-surgery both clinically and with a standardised questionnaire based on that described by Kerr et al. [Injury 27(1996)35]. The mean age at operation was 42 and 50 years for the two centres, and the mean follow-up was 44 months. Seventy-six per cent of the patients were male. Eighty-eight per cent of the injuries were due to a fall from a height. Fifteen patients had contralateral foot/ankle injuries. Thirty-four of 46 patients were in employment at the time of the injury, 24 of these were in physical jobs and 20 sustained their injury whilst at work.Overall, the satisfaction rate was 90%. Ninety-four per cent of patients in work returned to work at a median of 6 months. Bilateral injuries were associated with a significantly poorer outcome as were those with heel pad pain. Delay to operation greater than 14 days was associated with a higher infection rate. Smoking was not related to infection rate.

The use of tranexamic acid to reduce blood loss during total knee arthroplasty

HYPOTHESIS The fall in haemoglobin following unilateral total knee arthroplasty is reduced by tranexamic acid administration. METHODS 60 patients were studied in total, 30 received tranexamic acid 10 mg/kg on induction and a further dose shortly before the release of the tourniquet. Surgery was performed by the senior author in a standardised fashion using the Freeman Samuelson cemented total knee replacement. Haemoglobin levels were measured 2 weeks pre and 3 days post operatively. Any complications were noted. A control group was matched using the Bone and Joint Research Unit database for age, sex, disease and pre-operative haemoglobin level. This group had been monitored in the same way as the group treated with tranexamic acid. RESULTS In the group receiving no tranexamic acid the mean fall in haemoglobin was 2.8 g/dl (95% CI of mean 2.5-3.2) and in the group treated with tranexamic acid 1.7 g/dl (95% CI of mean 1.3-2) P<0.01. There were no complications in either group. CONCLUSIONS The administration of tranexamic acid is an effective method of reducing the haemoglobin fall following knee arthroplasty.

Diaphyseal forearm fractures in children treated with intramedullary fixation: outcome of K-wire versus elastic stable intramedullary nail

Intramedullary fixation of childrens diaphyseal forearm fractures is becoming the surgical technique of choice, in those cases that warrant surgical intervention. This method offers both technical advantages and patient benefits over alternative techniques and implants that have been used in the past. We present a two-centre study assessing the outcome of either Kirschner wires or elastic stable intramedullary nails (ESIN) as the method of fracture stabilisation in such diaphyseal forearm fractures.A total of 36 children underwent K-wire fixation and 24 children underwent ESIN fixation. All fractures united with no resultant subjective disability. The complication rate following K-wires was 16% and that following nail fixation 9%. Loss of forearm rotation was documented in four children in the K-wire group and three children stabilised with nails. These results confirm an excellent outcome following intramedullary fixation. We have demonstrated no difference in outcome between K-wires and ESIN, although the nails do offer some theoretical advantages.

The use of tranexamic acid to reduce blood loss during total hip arthroplasty: an observational study

INTRODUCTION To test the hypothesis that the fall in haemoglobin following total hip arthroplasty is reduced by tranexamic acid administration. PATIENTS AND METHODS A cohort of 64 patients were studied, 32 received tranexamic acid 20 mg/kg on induction. Surgery was performed by the senior author in a standardised fashion. Haemoglobin levels were measured 2 weeks pre- and 3 days postoperatively. Any complications were noted. The study group was matched using the bone and joint research database for age, sex, procedure, disease and pre-operative haemoglobin level. RESULTS In the group receiving no tranexamic acid, the mean fall in haemoglobin was 3.8 g/dl (CI of mean 3.4-4.3) and in the group treated with tranexamic acid 2.8 g/dl (CI of mean 2.5-3.2) P < 0.05. Complications included one non-fatal pulmonary embolus in the tranexamic acid group. CONCLUSIONS The administration of 20 mg/kg of tranexamic acid on induction of surgery is an effective method of reducing the haemoglobin fall following hip arthroplasty.

Assessment of the efficacy of Proguard RR-2 radio-protective gloves during forearm manipulation

The hazards of ionising radiation are well known and precautions, such as lead aprons and thyroid shields are routinely used. Orthopaedic surgeons hands are at particular risk from direct and scatter radiation, when manipulating forearm fractures, due to the proximity of the image intensifier. The use of lead gloves has been recommended in the literature but are seldom employed. Proguard RR-2 gloves provide similar tactile sensitivity to double gloves and are claimed by the manufacturer to provide up to 55% protection in vitro at a direct beam energy level of 60 kV. This claim was tested in a clinical setting. The gloves were worn during forearm manipulations and the radiation dose measured using thermoluminescent dosimeters (TLDs). The results demonstrated a radiation attenuation of 60-64%. These gloves appear to achieve a good compromise between protection and sensitivity and should be included in routine protection against ionising radiation during MUA.

The role of the intramedullary implant in limb lengthening

Limb lengthening is now an accepted practice in orthopaedic surgery. The principles of distraction osteogenesis have become well established with the use of external fixators, utilizing both monolateral and ring fixators. Corticotomy technique, frame stability, lengthening rate and rhythm all contribute to the formation of bone regenerate and tissues. Complications are however common including pin-site infection, soft tissue tethering from the pins and wires resulting in pain, regenerate deformity from soft tissue forces or fracture following frame removal and patient intolerance of the frames during treatment. Surgical techniques have changed to try and minimise these complications. The use of intramedullary nails have been used in conjunction with an external fixator or inserted after lengthening has been achieved, to reduce fixator time and prevent regenerate deformity. Implant innovation has led to the production of intramedullary lengthening nails. The initial devices used ratchet mechanisms with rotation of the bone fragments to achieve lengthening (Bliskunov, Albizzia and ISKD). More accurate control of lengthening and a reduction in pain, resulting from the manual rotation of the leg required to achieve the ratchet progression, was achieved by the use of a transcutaneous electrical conduit powered by external high frequency electrical energy (Fitbone). The most recent implant uses an external remote controller which contains two neodymium magnets. These are placed over the nail on the skin and rotate which in turn rotates a third magnet within the intramedullary nail (Precice). This magnet rotation is converted by a motor to extend or retract the extendible rod. There are multiple nail sizes and lengths available, and early results have shown accurate control with few complications. With such promising outcomes the use of this lengthening intramedullary nail is now recommended as the implant of choice in femoral lengthening. This article is an historical account of the intramedullary device and the impact on limb lengthening.

Short-term results of hemi-resurfacing for osteonecrosis of the femoral head

Published evidence has supported the use of femoral head resurfacing for patients with osteonecrosis of the femoral head. Between June 1999 and April 2001 we prospectively studied 15 femoral heads resurfaced in 12 patients with the Conserve Resurfacing Hemiarthroplasty. The male to female ratio was 8:4 and the mean age 38.7 years (range 26-60). The mean follow-up was 22.8 months (range 4-36). The senior author performed all procedures. There was one case of Ficat stage II, 9 cases of stage III and 5 cases of early stage IV. The mean time from onset of symptoms to surgery was 33.5 months (range 9-60). There were no intra or post-operative complications associated with any of the hemiarthroplasty procedures. RESULTS Nine of the fifteen patients had a poor result that warranted revision surgery within two years of prosthesis implantation. We conclude that in our hands the results of femoral resurfacing hemiarthroplasty are unpredictable and advise caution when recommending the procedure to patients with osteonecrosis of the femoral head. (Hip International 2004; 14: 174-81).

A protocol for the use of closed reduction in children with developmental dysplasia of the hip incorporating open psoas and adductor releases and a short-leg cast: Mid-term outcomes in 113 hips.

AIMS Our aim was to assess the effectiveness of a protocol involving a standardised closed reduction for the treatment of children with developmental dysplasia of the hip (DDH) in maintaining reduction and to report the mid-term results. METHODS A total of 133 hips in 120 children aged less than two years who underwent closed reduction, with a minimum follow-up of five years or until subsequent surgery, were included in the study. The protocol defines the criteria for an acceptable reduction and the indications for a concomitant soft-tissue release. All children were immobilised in a short- leg cast for three months. Arthrograms were undertaken at the time of closed reduction and six weeks later. Follow-up radiographs were taken at six months and one, two and five years later and at the latest follow-up. The Tönnis grade, acetabular index, Severin grade and signs of osteonecrosis were recorded. RESULTS A total of 67 hips (51%) were Tönnis grade 3/4 hips. By 12 months, 20 reductions (15%) had not been maintained, and these required open reduction. In all, 55% of these were Severin 1; the others were Severin 2, due to minor acetabular dysplasia. Of the 113 successful closed reductions, 98 hips (87%) were Severin 1. Surgery for residual DDH was offered for ten hips. Osteonecrosis was seen in 32 hips (29%) but was transient in 28. In total, two children (1.5%) had severe osteonecrosis. Bilateral dislocations were significantly more likely to fail and most Tönnis 4 hips failed. CONCLUSION Closed reduction, with concomitant adductor and psoas release when required and the use of a short leg plaster of Paris cast for three months, can produce good mid-term results in children with DDH aged less than two years. This protocol is not recommended for Tönnis 4 hips. Cite this article: Bone Joint J 2016;98-B:1548-53.

Posteromedial bowing of the tibia: a benign condition or a case for limb reconstruction?

Purpose To review the initial deformity and subsequent remodelling in posteromedial bowing of the tibia and the outcome of limb reconstruction in this condition. Patients and Methods In all, 38 patients with posteromedial bowing of the tibia presenting between 2000 and 2016 were identified. Mean follow-up from presentation was 78 months. A total of 17 patients underwent lengthening and deformity correction surgery, whilst three further patients are awaiting lengthening and deformity correction procedures. Results The greatest correction of deformity occurred in the first year of life, but after the age of four years, remodelling was limited. The absolute leg-length discrepancy (LLD) increased throughout growth with a mean 14.3% discrepancy in tibial length. In the lengthening group, mean length gained per episode was 45 mm (35 to 60). Mean duration in frame was 192 days, with a mean healing index of 42.4 days/cm. Significantly higher rates of recurrence in LLD were seen in those undergoing lengthening under the age of ten years (p = 0.046). Four contralateral epiphysiodeses were also performed. Conclusion Posteromedial bowing of the tibia improves spontaneously during the first years of life, but in 20/38 (53%) patients, limb reconstruction was indicated for significant residual deformity and/or worsening LLD. For larger discrepancies and persistent deformity, limb reconstruction with a hexapod external fixator should be considered as part of the treatment options. Level of evidence Level IV (Case series)