Adrian R. Kendal

Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance.

A new genetic mouse model demonstrates the necessity of Foxp3+ T reg cells for infectious tolerance.

Mortality rates at 10 years after metal-on-metal hip resurfacing compared with total hip replacement in England: retrospective cohort analysis of hospital episode statistics.

Objectives To compare 10 year mortality rates among patients undergoing metal-on-metal hip resurfacing and total hip replacement in England. Design Retrospective cohort study. Setting English hospital episode statistics database linked to mortality records from the Office for National Statistics. Population All adults who underwent primary elective hip replacement for osteoarthritis from April 1999 to March 2012. The exposure of interest was prosthesis type: cemented total hip replacement, uncemented total hip replacement, and metal-on-metal hip resurfacing. Confounding variables included age, sex, Charlson comorbidity index, rurality, area deprivation, surgical volume, and year of operation. Main outcome measures All cause mortality. Propensity score matching was used to minimise confounding by indication. Kaplan-Meier plots estimated the probability of survival up to 10 years after surgery. Multilevel Cox regression modelling, stratified on matched sets, described the association between prosthesis type and time to death, accounting for variation across hospital trusts. Results 7437 patients undergoing metal-on-metal hip resurfacing were matched to 22 311 undergoing cemented total hip replacement; 8101 patients undergoing metal-on-metal hip resurfacing were matched to 24 303 undergoing uncemented total hip replacement. 10 year rates of cumulative mortality were 271 (3.6%) for metal-on-metal hip resurfacing versus 1363 (6.1%) for cemented total hip replacement, and 239 (3.0%) for metal-on-metal hip resurfacing versus 999 (4.1%) for uncemented total hip replacement. Patients undergoing metal-on-metal hip resurfacing had an increased survival probability (hazard ratio 0.51 (95% confidence interval 0.45 to 0.59) for cemented hip replacement; 0.55 (0.47 to 0.65) for uncemented hip replacement). There was no evidence for an interaction with age or sex. Conclusions Patients with hip osteoarthritis undergoing metal-on-metal hip resurfacing have reduced mortality in the long term compared with those undergoing cemented or uncemented total hip replacement. This difference persisted after extensive adjustment for confounding factors available in our data. The study results can be applied to matched populations, which exclude patients who are very old and have had complex total hip replacements. Although residual confounding is possible, the observed effect size is large. These findings require validation in external cohorts and randomised clinical trials.

Infectious tolerance: therapeutic potential.

Infectious tolerance describes an in vivo process in which tolerance is passed on from one population of lymphocytes to another. In this way, short-term therapy aimed at generating infectious tolerance has the potential to achieve long term, self-perpetuating immune homeostasis in a clinical setting. In recent years, a number of differing strategies have successfully achieved tolerance in vivo. These include harnessing regulatory T cells and tolerogenic antigen presenting cells, promoting tolerogenic interactions or inhibiting activation of effector cells. Many of these are just beginning to face the harsh realities of the therapeutics industry.

Foxp3 Expression Is Required for the Induction of Therapeutic Tissue Tolerance

CD4+Foxp3+ regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGF-β–dependent manner. Foxp3+ Treg are also required to achieve tolerance to transplanted tissues when induced by coreceptor or costimulation blockade. Using TCR-transgenic mice to avoid issues of autoimmune pathology, we show that Foxp3 expression is both necessary and sufficient for tissue tolerance by coreceptor blockade. Moreover, the known need in tolerance induction for TGF-β signaling to T cells can wholly be explained by its role in induction of Foxp3, as such signaling proved dispensable for the suppressive process. We analyzed the relative contribution of TGF-β and Foxp3 to the transcriptome of TGF-β–induced Treg and showed that TGF-β elicited a large set of downregulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Retroviral-mediated conditional nuclear expression of Foxp3 proved sufficient to confer transplant-suppressive potency on CD4+ T cells and was lost once nuclear Foxp3 expression was extinguished. These data support a dual role for TGF-β and Foxp3 in induced tolerance, in which TGF-β stimulates Foxp3 expression, for which sustained expression is then associated with acquisition of tolerance.

Complications of Minimally Invasive Calcaneal Osteotomy Versus Open Osteotomy

Background: Calcaneal osteotomy is an established technique for correcting hindfoot deformity. Patients traditionally receive an osteotomy through the open lateral approach to the calcaneus. To reduce the rate of wound complications associated with a direct open lateral approach, a minimally invasive surgical (MIS) technique has been adopted. This uses a low-speed, high-torque burr to perform the same osteotomy under radiographic guidance. We hypothesized that the new MIS calcaneal osteotomy would be a safe alternative to open calcaneal osteotomy while obtaining the same displacement. Methods: The safety of the new MIS technique was investigated with a case controlled study on all patients who underwent displacement calcaneal osteotomy at the Nuffield Orthopaedic Centre from 2008 to 2014. The primary outcome measure was 30 day postoperative complication rate. Secondary outcome measures included operating time, duration of stay, fusion rates, and calcaneal displacement. Eighty-one patients underwent calcaneal osteotomy as part of their corrective surgery, 50 in the Open approach group and 31 in MIS group. The average age was 47.7 years (range 16-77) for the Open group and 50.1 (range 21-77) in the MIS group. Results: A mean calcaneal displacement of 9.4 mm (SD = 1.16, 8 to 11 mm) and 10.2 mm (SD = 1.06, 8 to 13 mm) was achieved through the MIS and Open approaches, respectively. There were significantly fewer wound complications in the MIS group (6.45%) compared to the Open group (28%, P = .022). The MIS group was associated with significantly lower rate of wound infection (3% versus 20%, P = .044). Three patients in the Open group experienced sural peripheral neuropathy. The average length of stay was 3.8 days following MIS and 4.3 days following open calcaneal osteotomy. Nonunion occurred in only 1 patient in the MIS group and none in the open group. Conclusions: MIS calcaneal osteotomy was found to be a safe technique. It was technically as effective as calcaneal osteotomy performed through an open lateral approach but was associated with significantly fewer wound complications and fewer nerve complications. Level of Evidence: Level III, comparative study.

Fracture healing in the elderly: A review

Older patients are commonly at a higher risk of experiencing a bone fracture. Complications during fracture healing, including delayed union and non-union, can arise as a result of a multitude of patient and treatment factors. This review describes those factors which contribute to a greater risk of delayed union and non-union with particular reference to the elderly population and discusses therapies that may enhance the fracture healing process in the hope of reducing the incidence of delayed union and non-union. Increasing age does seem to increase the risk of delayed union or non-union. In addition, smoking and the treatment of post-fracture pain with non-steroidal anti-inflammatory drugs (NSAIDs) put the patient at the greatest risk, while ultrasound therapy appears to be a non-invasive, effective treatment option to reduce the risk of delayed union or non-union. The use of growth factors and of stem cells and the role of surgery are also discussed.

Arthroscopic ankle fusion for avascular necrosis of the talus.

Background: Avascular necrosis (AVN) of the talus is a painful condition leading to destruction of the ankle-hindfoot complex. Moderate outcomes and high complication rates are reported in small numbers of advanced disease treated with tibiotalocalcaneal fusion, which has the additional disadvantage of sacrificing both the ankle and subtalar joints. The blood supply of the talus is tenuous, and open procedures risk further talar collapse by disrupting extraosseous vessels. This article reports the outcome of arthroscopic ankle fusion for late-stage AVN of the talus. Our hypothesis was that arthroscopic ankle fusion would relieve symptoms of advanced talar AVN, prevent collapse of the talus, and preserve the subtalar joint. Methods: A cohort study was performed on 16 patients with talar AVN treated with arthroscopic ankle fusion. Our primary outcome was fusion rate. Secondary outcomes included perioperative complications, ongoing pain, and further operative intervention. All radiologic investigations were reported independently by a senior radiologist. The average age of the patients was 53.5 years. The presumed causes of talar AVN were steroids, trauma, hematologic disorders, and alcoholism. The etiology was unknown in 7 patients. One patient was lost to follow-up. Results: Clinical and radiologic fusion at the ankle joint was confirmed in 15 of 15 available patients. Thirteen patients reported resolution of pain at follow-up. Three patients had ongoing pain and underwent a subsequent successful subtalar fusion. Conclusions: Arthroscopic ankle fusion was a safe and reliable treatment of symptomatic advanced talar AVN. It was a minimally invasive procedure with minimal complication rate, preserving the talus and sparing the subtalar joint. Level of Evidence: Level IV, retrospective case series.

Induced Foxp3+ T Cells Colonizing Tolerated Allografts Exhibit the Hypomethylation Pattern Typical of Mature Regulatory T Cells

Regulatory T cells expressing the transcription factor Foxp3 require acquisition of a specific hypomethylation pattern to ensure optimal functional commitment, limited lineage plasticity, and long-term maintenance of tolerance. A better understanding of the molecular mechanisms involved in the generation of these epigenetic changes in vivo will contribute to the clinical exploitation of Foxp3+ Treg. Here, we show that both in vitro and in vivo generated antigen-specific Foxp3+ Treg can acquire Treg-specific epigenetic characteristics and prevent skin graft rejection in an animal model.

Patient expectation and satisfaction after macular hole surgery.

Purpose. To assess patient expectation, visual improvement, and patient satisfaction after macular hole surgery. Methods. Fifty-three consecutive patients completed a self-administered questionnaire after macular hole surgery. Responses for expectation of visual improvement before surgery and subjective visual assessment after surgery were scored from 0 to 10 (0 = no improvement in vision, 10 = full improvement). Visual acuity was measured using Snellen charts and converted to logMAR equivalent for statistical analysis. Wilcoxon and Mann-Whitney U tests were performed using the Minitab statistical software program; p < 0.05 was considered significant. Results. Thirty-eight (71%) patients were satisfied with the outcome, 14 (26%) were not, and 1 was uncertain. Both satisfied and dissatisfied patients had no difference in baseline preoperative best-corrected visual acuity (BCVA; 6/60 and 6/60, respectively). There was also no significant difference in median postoperative BCVA between both groups (6/24 and 6/29, respectively, p = 0.6). In satisfied patients, median vision expectation score of 6 was equally similar to the median subjective postoperative vision improvement score of 6, p = 0.7. However, in dissatisfied patients, median vision expectation score (8) was significantly higher than median postoperative subjective vision improvement score (1), p = 0.0001. The commonest reason for dissatisfaction was perceived visual reduction (7/14 patients). Conclusions. In the dissatisfied patients, expectation was significantly higher, and subjective assessment of vision after surgery was lower than in satisfied patients, although they had similar improvement in BCVA. Visual acuity and patient satisfaction are not always directly correlated. An important factor in patient satisfaction is expectation.

Resorbable electrospun polydioxanone fibres modify the behaviour of cells from both healthy and diseased human tendons

Chronic tendinopathy in an active and ageing population represents an increasing burden to healthcare systems. Rotator cuff tendinopathy alone accounts for approximately 70 % of all shoulder pain. Tendinopathic tissue has a disorganised extracellular matrix, altered vasculature, and infiltration of fibroblasts and inflammatory cells. This altered biology may contribute to the limited success of surgical repair strategies. Electrospun resorbable scaffolds can potentially enhance endogenous repair mechanisms by influencing the tissue microenvironment. Polydioxanone (PDO) has an established safety profile in patients. We compared the response of healthy and diseased human tendon cells to electrospun PDO fibres using live cell imaging, proliferation, flow cytometry, and gene expression studies. Within 4 h of initial contact with electrospun PDO, healthy tendon cells underwent a marked transformation; elongating along the fibres in a fibre density dependent manner. Diseased tendon cells initially responded at a slower rate, but ultimately underwent a similar morphological change. Electrospun fibres increased the proliferation rate of diseased tendon cells and increased the ratio of type I:IIIcollagenmRNA expression. Flow cytometry revealed decreased expression of CD106, a marker of mesenchymal stem cells, and increased expression of CD10 on healthy versus diseased tendon cells. PDO electrospun scaffolds further promoted CD106negCD10pos expression of healthy tendon cells. Despite their behavioural differences, both healthy and diseased human tendon cells responded to electrospun PDO fibres. This encourages further work establishing their efficacy in augmenting surgical repair of diseased tendons.