HLA-E: exploiting pathogen-host interactions for vaccine development.

Viruses, when used as vectors for vaccine antigen delivery, can induce strong cellular and humoral responses against target epitopes. Recent work by Hansen et al. describes the use of a cytomegalovirus-vectored vaccine, which is able to generate a stable effector-memory T cell population at the sites of vaccination in rhesus macaques. This vaccine, targeted towards multiple epitopes in simian immunodeficiency virus (SIV), did not induce classical CD8+ T cells. However, non-canonical CD8+ T cell induction occurred via major histocompatibility complex (MHC) class II and MHC-E. The MHC-E-restricted T cells could recognize broad epitopes across the SIV peptides, and conferred protection against viral challenge to 55% of vaccinated macaques. The human homologue, human leucocyte antigen (HLA)-E, is now being targeted as a new avenue for vaccine development. In humans, HLA-E is an unusually oligomorphic class Ib MHC molecule, in comparison to highly polymorphic MHC class Ia. Whereas MHC class Ia presents peptides derived from pathogens to T cells, HLA-E classically binds defined leader peptides from class Ia MHC peptides and down-regulates NK cell cytolytic activity when presented on the cell surface. HLA-E can also restrict non-canonical CD8+ T cells during natural infection with various pathogens, although the extent to which they are involved in pathogen control is mostly unknown. In this review, an overview is provided of HLA-E and its ability to interact with NK cells and non-canonical T cells. Also discussed are the unforeseen beneficial effects of vaccination, including trained immunity of NK cells from bacille Calmette-Guérin (BCG) vaccination, and the broad restriction of non-canonical CD8+ T cells by cytomegalovirus (CMV)-vectored vaccines in pre-clinical trials.

The synovial fold of the distal tibiofibular joint: A morphometric study.

Impingement of the synovial fold of the distal tibiofibular joint (DTFJ) may contribute to the development of chronic ankle pain and disability after ankle inversion sprain. The morphology of the synovial fold of the DTFJ and recess is poorly understood. The purpose of this study was to describe and quantify the synovial fold and recess of the DTFJ. Thirty-three pairs of adult embalmed ankle joints were dissected and the presence, disposition, morphology, and dimensions of the synovial fold were determined in relation to the DTFJ and its recess. A synovial fold was present in all specimens examined and extended from the deep posterior tibiofibular ligament along the DTFJ line an average of 15.31 mm [standard deviation (SD), 4.42 mm]. The majority of synovial folds were elongated in shape with smooth borders and occupied more than two thirds of the DTFJ line. In 70% of ankles examined, the synovial folds were found to extend a mean of 20.05 mm (SD, 7.01 mm) from the DTFJ line into the recess where they were loosely attached to the fibular wall. In the remaining ankles, the synovial fold was limited to the DTFJ line leaving the recess devoid of a synovial fold. Intra-observer and inter-observer reliability of measurements was good to excellent (intra-class correlation coefficient, 0.61-0.99). An understanding of the morphology of the DTFJ synovial fold might help to explain ongoing ankle pain after injury, and why arthroscopic removal of the tissue might be therapeutic.

Injuries sustained at a temporary ice-skating rink: prospective study of the Winchester experience 2007-2008.

Anecdotal reports when a temporary ice-rink opened in Winchester, suggested a burden on the Emergency Department (ED) and Trauma & Orthopaedic (T&O) services. This study was undertaken to assess, prospectively, the workload created as a consequence of ice-rink injuries, when the facility was reopened over Christmas 2007. All patients attending from the ice-rink were included and their injuries reviewed. Costs of care were calculated based on ED attendance, out-patient appointments (OPA's), radiography, plaster immobilisation and government tariffs for surgical procedures. The ice-rink was open for 39 days welcoming 43,000 skaters. Sixty-two accidents were recorded in the accident book, 43 attended the ED. Radiographic investigation was necessary for 31 patients. Nineteen had diagnoses of soft tissue injury, 3 of head/facial injuries. T&O received 23 referrals; all fractures were in the upper limb, 6 requiring admission and surgery. Fifty-eight ED, fracture clinic and physiotherapy OPA's were required. Additional costs to The Royal Hampshire County Hospital (RHCH) were calculated as 33,718.50 pounds. This temporary facility created a smaller than predicted burden for the ED and T&O service, however, sufficient consideration of OPA requirements should be made when planning service provision whilst temporary recreational facilities, such as this, are open.

Pressure characteristics of pelvic binders.

We present a study of the pressures developed at the bony prominences (greater trochanter, iliac crest and sacrum) when a pelvic binder was applied to 10 healthy individuals. The pressures developed between the pelvic binder and the skin over the prominences were all greater than the pressure recommended at interfaces to avoid the development of pressure sores. This suggests that patients with pelvic fractures who are treated with temporary pelvic binders are at risk of developing pressure sores. This should be recognised and the skin inspected if the binder is to be in place for a prolonged period.

Clinical significance of variations in the interconnections between flexor digitorum longus and flexor hallucis longus in the region of the knot of Henry.

Tendon transfer of the flexor digitorum longus tendon (FDLT) or the flexor hallucis longus tendon (FHLT) into the tibialis posterior tendon is carried out in patients with tibialis posterior dysfunction. FDLT and FHLT are connected in the region of the knot of Henry. The present study has investigated the anatomical variations of this tendinous interconnection. The results could be used to determine which of the two tendons should be transected proximal to the region of the knot of Henry in the surgical treatment of tibialis posterior dysfunction. In over two-thirds of cadaver specimens investigated, tension applied solely to FHLT resulted in flexion of all digits and the hallux. On the basis of these results, we propose that identification of the tendon to be transected should be decided at the time of surgery depending on the anatomical pattern. Based on the evidence provided by 16 cadaveric dissections, transection of FDLT proximal to the region of the knot of Henry for the repair of tibialis posterior dysfunction would result in retention of function of the hallux and lesser digits in the majority of cases.

Small fragment wounds: biophysics, pathophysiology and principles of management.

Military surgical doctrine has traditionally taught that all ballistic wounds should be formally managed by surgical intervention. There is now, however, both experimental and clinical evidence supporting the nonoperative treatment of selected small fragment wounds. Low energy-transfer wounds affecting the soft tissues, without neuro-vascular compromise and with stable fracture patterns, may be suitable for early antibiotic treatment. The management of ballistic wounds to the gastrointestinal tract requires surgical intervention but, advances in the treatment of these wounds, especially those involving the colon, may allow more effective treatment with a reduced morbidity.

Efficacy of delayed administration of benzylpenicillin in the control of infection in penetrating soft tissue injuries in war.

In war, uncomplicated penetrating injuries to limbs require evacuation to a surgical facility. A delay is inevitable between injury and definitive surgical treatment. This paper describes an experimental model that has been developed to assess the efficacy of antibiotics in such war wounds; the aim is to develop a treatment protocol to prevent the development of infection before casualties reach a surgical facility. The model is described in detail. Its use to determine efficacy of an antibiotic regimen, and the consequences of delay in the initial administration of antibiotic, are summarized. Streptococcus Lancefield Group L (Strep L) is a pig pathogen analogous to the Streptococcus pyogenes Lancefield Group A in man. The latter is perceived as a major threat to the casualty with a neglected penetrating wound. Strep L caused reproducible infection in a low-energy-transfer fragment wound to a pig thigh. When the wound was observed over a period of 7 days, the only other organisms that appeared consistently were pig pathogenic and nonpathogenic staphylococcal species. Despite the site of the wound, fecal organisms were not observed to colonize the wound significantly, neither were they a cause of early wound infection. The treatment regimen studied as benzylpenicillin, 1 megaunit (6 hourly), given intramuscularly. When commenced 1 hour after wounding, this prevented wound infection for 3 days, when Strep L was deliberately inoculated at the time of wounding. If the start of antibiotics was delayed until 6 hours after wounding, antibiotic regimen was less effective; the wound track remained infected at 3 days. In a further series of experiments, Staphylococcus hyicus, a potential pig pathogen (which is penicillin resistant through beta-lactamase production), was introduced in addition to Strep L. The antibiotic regimen remained effective when the Strep L plus 10(3) S. hyicus were inoculated. When 10(4) S. hyicus were introduced, treatment was less effective, but still of some benefit. Inoculation of > 10(5) S. hyicus rendered treatment commencing at 1 hour ineffective. If the start of treatment was delayed to 6 hours after injury, this treatment regimen was adversely affected by the introduction of only 10(3) S. hyicus. In conclusion, an intramuscular benzylpenicillin regimen, commenced 1 hour after wounding, can prevent infection in penetrating soft tissue missile wounds for up to 3 days. A delay of 6 hours renders treatment ineffective.

Small fragment wounds: biophysics and pathophysiology.

This paper considers the wounding effects of small fragments in modern warfare. Small fragment wounds may be expected to predominate on a future conventional battlefield; however, studies and models of "military" wounds have tended to focus on bullets as the wounding projectile. This paper discusses briefly the types of fragment projectile expected from modern munitions. It goes on to define a model for such projectiles, and describes the interaction with soft tissue simulants. The extent of penetration, temporary cavitation, and contamination by foreign material are all considered. This work with simulants is validated by experimental shots against animal tissue. A wound model in an experimental animal is described. This model was used to investigate the hematologic, biochemical, and histologic effects of a small fragment wound. The effects on skin and skeletal muscle are described. By sampling at various times (up to 1 week) after wounding, the natural progress of these wounds has been ascertained. The results from 28 experimental animals, with untreated fragment wounds, are reported. The most important findings are that the skin damage is very localized and that the muscle damage is limited, with little necrotic tissue in the track. Furthermore, the extent of the muscle damage, peripheral to the wound track, improves with time, healing within a few days, provided the wound remains free from infection. There was no clinical or microbiologic evidence of infection in those animals followed for up to 3 days. However, of eight animals followed to 1 week, three developed infected wounds. This work has implications for the management of soft tissue wounds caused by fragmentation munitions. The conventional military approach has been to treat penetrating war wounds by exploration, debridement, excision of dead tissue, and delayed primary closure; conservative treatment has largely been regarded as inappropriate. The work presented here shows that the potential culture medium within the wound is small and can be removed by the normal bodily responses. There is no need for surgery, provided that infection can be prevented. It may be inferred that if bacterial colonization can be prevented in the early stages by the timely use of antibiotics, surgery may be unnecessary. Further studies are planned to investigate this possibility.

Management of small fragment wounds: experience from the Afghan border.

Fragmenting munitions have caused the majority of casualties in recent conflicts. These wounds are often multiple, many affecting only the soft tissues of the extremities. The management of these wounds is controversial; some surgeons advocate aggressive surgical treatment; others believe that a nonoperative policy is appropriate in selected cases. The International Committee of the Red Cross has a great deal of experience in treating the wounds of war. It maintains a war surgery hospital in Pakistan, close to the Afghan border, receiving wounded from the ongoing conflict in Afghanistan. This paper describes the number, distribution, and severity of more than 1200 fragment wounds. These injuries were sustained by 83 casualties who presented to the hospital during a recent flare-up in the fighting. The majority of these fragment wounds affected the limbs. Small-fragment wounds affecting only the skin and muscle were managed nonoperatively, with antibiotics and dressings. More than 850 wounds were managed in this way. There were complications in only two of the 63 casualties who had wounds that were treated nonoperatively. The complications were localized abscesses, one of which required surgical drainage. The policy of carefully assessing the wounds and treating selected wounds conservatively appears to have been both successful, in terms of saved surgical resources, and safe, with no life- or limb-threatening complications. This paper makes recommendations as to which wounds might be suitable for nonoperative management, but acknowledges that further work is needed to define the optimal treatment of these common wounds.

Management of small fragment wounds in war: current research.

The majority of war wounds are caused by antipersonnel fragments from munitions such as mortars and bomblets. Modern munitions aim to incapacitate soldiers with multiple wounds from very small fragments of low available kinetic energy. Many of these fragments may be stopped by helmets and body armour and this has led to a predominance of multiple wounds to limbs in those casualties requiring surgery. The development of an appropriate management strategy for these multiple wounds requires knowledge of the contamination and extent of soft tissue injury; conservative management may be appropriate. The extent of skin and muscle damage associated with a small fragment wound, the way in which these wounds may progress without intervention and their colonisation by bacteria has been determined in an experimental animal model. Results from 12 animals are presented. There was a very small (approximately 1 mm) margin of nonviable skin around the entrance wound. The amount of devitalised muscle in the wound tract was a few hundred milligrams. Some muscles peripheral to the wound track also showed signs of damage 1 h after wounding, but this improved over 24 h; the proportion of fragmented muscle fibres in the tissue around the track decreased as time went on. There was no clinical sign or bacteriological evidence of the track becoming infected up to 24 h after wounding. This preliminary work suggests that, in the absence of infection, the amount of muscle damage caused by small fragment wounds begins to resolve in the first 24 h after injury, even without surgical intervention.

Afghan war wounded: application of the Red Cross wound classification.

OBJECTIVE: This study was designed to illustrate the application of the Red Cross classification system as a guide to treatment and to demonstrate its ease of use, especially in situations where the treating surgeons may have little experience with or knowledge of ballistic details. DESIGN: The wounds of 123 victims of fighting in Afghanistan are described and categorized according to the Red Cross classification system. MATERIALS AND METHODS: Recent factional fighting in Afghanistan resulted in 123 casualties being admitted to an International Committee of the Red Cross (ICRC) hospital in Quetta, Pakistan, close to the Afghan border. These casualties suffered more than 1300 wounds in total; the two most severe wounds in each casualty were categorized according to the Red Cross classification, described here. This wound classification is quick and easy to apply; it focuses the surgeon's attention on the wound, without requiring any familiarity with terminal ballistics. MEASUREMENTS AND MAIN RESULTS: The majority of wounds, caused by antipersonnel fragments (68.3% of casualties), affected only the soft tissues. Bullet wounds were fewer (22.8% of casualties), but tended to be more severe, often involving a fracture, vascular damage, or injury to a vital structure. CONCLUSIONS: The Red Cross classification permits identification of wound patterns and provides a data base for review of clinical practice and outcome. It is hoped that further data gathered in this manner from ICRC hospitals and others receiving war wounded will add to the understanding of the clinical practice and problems in war surgery.

Pattern of injury in those dying from traumatic amputation caused by bomb blast.

Traumatic amputation of limbs caused by bomb blast carries a high risk of mortality. This paper describes 73 amputations in 34 deaths from bomb blast in Northern Ireland. The principal aim was to determine the sites of traumatic amputation to provide a biophysical basis for the development of protective measures. Few amputations were through joints; nearly all were through the bone shafts. The most common site in the tibia was the upper third. The distribution of femoral sites resulting from car bombs differed from that characterizing other types of explosion. For car bombs the principal site of amputation was the upper third; for other types of device it was the lower third. It is concluded that flailing is not a notable contributor to limb avulsion. The pattern of amputation is consistent with direct local pressure loads leading to bone fracture; the amputation itself is a secondary event arising from the flow of combustion products.

Antibiotic release from impregnated pellets and beads.

Antibiotic impregnated beads are being used increasingly in the initial treatment of open fracture wounds, producing high antibiotic levels locally, over the first few days. Pellets were prepared to assess the release of the following antibiotics: benzylpenicillin, flucloxacillin, amoxycillin, amoxycillin-clavulanate (Co-Amoxiclav), ciprofloxacin, imipenem, or gentamicin; the carrier material was either polymethylmethacrylate (PMMA) or plaster of Paris (PoP). Elution of antibiotic over 72 hours from the pellets in vitro was determined using an agar-diffusion microbiologic assay. The initial rapid release of antibiotic lasted 12-24 hours, with release from PoP pellets at least four-fold greater than that from corresponding PMMA pellets. A second phase consisted of a sustained but gradually diminishing elution. The release of antibiotics from PoP pellets compared favorably with that from the PMMA beads currently used. We conclude that PoP pellets may be particularly suitable for short-term applications such as infection prophylaxis in open fractures.