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At the surrender of Singapore on 15 February 1942, over 100,000 men became prisoners of the Japanese. This included many medical officers who, over the ensuing years, treated men (and some women) suffering the ravaging effects of disease, worsened by the inhumane conditions of captivity. Many medical officers stand out for their work. One in particular, Jacob Markowitz, developed a blood transfusion service, under the most extreme conditions, for the sick working as slave labour on the Burma Railway. Although he qualified 20 years before the outbreak of war, little has been written of Markowitz's early life, or of the impact of this on his war-time contributions. [ABSTRACT FROM AUTHOR]

The anti-globulin test was described in 1945, and ever since has been synonymous with the lead author, Robin Coombs, a young veterinary surgeon, at that time embarking on a career in immunological research. This was marked by a number of important contributions in the field, including the description and categorisation of hypersensitivity reactions, co-authored with Philip Gell. Together they wrote the classical text, Clinical Aspects of Immunology, which has been updated and republished over the ensuing 50 years. Although Robin Coombs is best remembered for his contributions to medical immunology, he made a number of significant early advances in the field of veterinary immunology.

This article details the remarkable life of Dr Thomas Somerville, who qualified both as a veterinary surgeon and medical practitioner, served in two world wars and was recommended for the nation's highest award for gallantry. In doing so, it records the life of a man whose repeated gallantry on the battlefield has been overlooked.

Primary thoracic blast injury causes a triad of bradycardia, hypotension and apnoea mediated in part via a vagal reflex. Blast casualties may also suffer blood loss, and the response to progressive simple haemorrhage is biphasic: an initial tachycardia followed by a vagally mediated reflex bradycardia which can be attenuated by micro opioid agonists. The aims of this study were to determine the effects of thoracic blast injury on the response to subsequent haemorrhage, and the effects of morphine, administered after blast, on the response to blood loss. Male Wistar rats, terminally anaesthetised with alphadolone-alphaxolone (19-21 mg x kg(-1) h(-1) I.V.), were allocated randomly to one of three groups: Group I, sham blast; Group II, thoracic blast; Group III, thoracic blast plus morphine (0.5 mg x kg(-1) I.V. given 5 min after blast). Blast (Groups II and III) resulted in significant (P < 0.05, ANOVA) bradycardia, hypotension and apnoea. Sham blast (Group I) had no effect. Ten minutes later, haemorrhage (40 % of the estimated total blood volume (BV)) in Group I produced a biphasic response comprising a tachycardia followed by a peak bradycardia after the loss of 33 % BV. Arterial blood pressure did not fall significantly until the loss of 13.3 % BV. In Group II the haemorrhage-induced tachycardia was absent and the bradycardia was augmented: peak bradycardia was seen after the loss of 23 % BV. Mean arterial blood pressure (MBP) began to fall as soon as haemorrhage commenced and was significant after the loss of 10 % BV. Morphine (Group III) prevented the haemorrhage-induced bradycardia and delayed the significant fall in MBP until the loss of 30 % BV. It is concluded that the response to thoracic blast injury augments the depressor response to haemorrhage while morphine attenuates this response.

An ovine model was developed to study the outcome following intramedullary nailing of a heavily contaminated fracture. Animals in the control group received no treatment directed at controlling infection, whereas those in the treatment group received wound debridement, lavage and the use of appropriate systemic antibiotics. Despite this, infection developed at the osteotomy site and along the entire length of the implant in all animals in both groups. It was felt that standard methods of wound management might be inadequate when applied at the time of intramedullary nailing since the spread of contamination following the use of reamers was demonstrated in all animals. Results from this study support the clinical impression that heavily contaminated fractures should not be treated by primary intramedullary nailing.

This study aimed to develop a reproducible model of phosgene-induced lung injury in the pig to facilitate the future development of therapeutic strategies. Ten female young adult large white pigs were used. Following induction of anaesthesia using a halothane/oxygen/nitrous oxide mixture, arterial and venous catheters were inserted together with a pulmonary artery thermodilution catheter, and a suprapubic urinary catheter by laparotomy. Anaesthesia was maintained throughout the experiment by intravenous infusion of ketamine, midazolam and alfentanil. On completion of surgery the animals were allowed to equilibrate for 1 h and then were divided into two groups. Group 1 (n = 5) was exposed to phosgene for 10 min (mean Ct = 2443 +/- 35 mg min m(-3)) while spontaneously breathing, whereas control animals (Group 2 n = 5) were exposed to air. At 30 min post-exposure, anaesthesia was deepened in order to allow the initiation of intermittent positive pressure ventilation and the animals were monitored for up to 24 h. Cardiovascular and respiratory parameters were monitored every 30 min and blood samples were taken for arterial and mixed venous blood gas analysis and clinical chemistry. A detailed post-mortem and histopathology was carried out on all animals following death or euthanasia at the end of the 24-h monitoring period. Control animals (Group 2) all survived until the end of the 24-h monitoring period with normal pathophysiological parameters. Histopathology showed only minimal passive congestion of the lung. Following exposure to phosgene (Group 1) there was one survivor to 24 h, with the remainder dying between 16.5 and 23 h (mean = 20 h). Histopathology from these animals showed areas of widespread pulmonary oedema, petechial haemorrhage and bronchial epithelial necrosis. There was also a significant increase in lung wet weight/body weight ratio (P < 0.001). During and immediately following exposure, a transient decrease in oxygen saturation and stroke volume index was observed. From 6 h there were significant decreases in arterial pH (P < 0.01), P(a)O(2) (P < 0.01) and lung compliance (P < 0.01), whereas oxygen delivery and consumption was reduced from 15 h onwards in phosgene-exposed animals. Mean pulmonary artery pressure of phosgene-exposed animals was increased from 15 h post-exposure, with periods of increased pulmonary vascular resistance index being recorded from 9 h onwards. We have developed a reproducible model of phosgene-induced lung injury in the anaesthetized pig. We have followed changes in cardiovascular and pulmonary dynamics for up to 24 h after exposure in order to demonstrate evidence of primary acute lung injury from 16 h post-exposure. Histopathology showed evidence of widespread damage to the lung and there was also a significant increase in lung wet weight/body weight ratio (P < 0.001)., (Copyright Crown copyright 2002. Reproduced with the permission of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.)

The management of open fractures requires excision of all devitalised tissues, both bony and soft tissue, and failure to do so is likely to increase the risk of infection. This study evaluated the applicability of laser Doppler flowmetry for the objective evaluation of fracture fragment viability in an experimental open ballistic fracture over a period of 12 h. The results indicate that this technique could not be used to distinguish between vascularised and non-vascularised fragments at any time, and did not aid the surgeon in their decision making at the time of wound excision. Subjective evaluation, based upon the degree of soft tissue attachment of fragments, was a far better indicator of fragment vascularity, although it had a relatively low specificity. There remains the need for education and training for trauma surgeons in the evaluation of fragment viability to ensure adequate wound excision as part of fracture management.

This study allowed the development of an in vitro model of a high-energy ballistic fracture. Direct fractures are more heavily contaminated than indirect fractures, and the spread of contamination is more extensive than examination of the wounds, particularly the entry wounds, would suggest. The major spread of contamination is along tissue planes, and we would recommend that these are thoroughly lavaged in the management of the fracture. The fracture site is heavily contaminated, with endosteal spread in direct fractures. However, there appears to be relatively little bony contamination beyond the fracture site.

The use of hypertonic saline Dextran (HSD) for resuscitation following trauma has many potential benefits, especially for the treatment of military casualties, but there is very limited data on the responses following multiple dosing with this fluid. The effects of a second dose of hypertonic saline dextran for resuscitation of uncontrolled intra-abdominal haemorrhage were studied in an experimental model. Under general anaesthesia, 17 large white pigs (weight range, 48-67 kg) were subjected to uncontrolled hemorrhage produced by a tear in the common iliac artery. This resulted in a significant (P < 0.01) reduction of both mean arterial pressure (MAP) and cardiac index. One hour after injury, animals were assigned to one of three groups, receiving either no resuscitation (Group A), or two doses of HSD (at a dose rate of 4 mL/kg), administered either 1 and 4 h after injury (Group B) or 1 and 7 h after injury (Group C). Animals were monitored for 12 h post-injury. A second infusion of HSD caused a significant hypernatremia and diuresis (P< 0.01) in both Groups B and C. There was a non-significant rise in MAP in both treatment groups, and in Group B only, there was a significant increase in cardiac index (P= 0.014). It is concluded that repeat administration of HSD for the resuscitation of uncontrolled hemorrhage results in limited cardiovascular improvements, but that the metabolic sequelae are potentially detrimental to survival.

An animal model was used to study the pathogenesis of pin track infection. The roles of fluid accumulation around the pin/bone interface and mechanical loosening of the pin were specifically studied. In addition, the spread of bacteria in relation to the clinical appearance of the pin track was assessed. This study demonstrated that fluid accumulation around the interface is an important factor in the spread of infection from the superficial wound track to the medulla of the bone. Spread occurs despite the absence of mechanical pin loosening, and can occur before any clinical features of infection are apparent.

Blast injuries represent a problem for civilian and military populations. Primary thoracic blast injury causes a triad of bradycardia, hypotension and apnoea. The objective of this study was to investigate the reflex nature of this response and its modulation by vagotomy or administration of atropine. The study was conducted on terminally anaesthetised (alphadolone/alphaxalone, 18-24 mg x kg x h(-1), I.V.) male Wistar rats randomly allocated to the groups indicated below. Blast injuries were produced with compressed air while sham blast involved the sound of a blast only. Primary blast injury to the thorax resulted in a bradycardia (measured as an increase in the interval between beats, or heart period (HP) to 489 +/- 37 ms from 133 +/- 3 ms with a latency of onset of 4.3 +/- 0.3 s, mean +/- S.E.M.), hypotension (fall in mean arterial blood pressure (MBP) from 128.1 +/- 3.7 mmHg to 34.8 +/- 4.1 mmHg, latency of onset 2.0 +/- 0.1 s) and apnoea lasting 28.3 +/- 2.3 s. Sham blast had no effect. The bradycardia and apnoea following thoracic blast were abolished by cervical vagotomy while the hypotension was attenuated. Atropine (0.3 mg x kg(-1), I.V.) caused a significant reduction in the bradycardia (HP increasing from 124 +/- 3 ms to 142 +/- 4 ms) but did not modulate either the hypotension or apnoea. It is concluded that a reflex involving the vagus nerve mediates the bradycardia, apnoea and a component of the hypotension associated with thoracic blast. The pattern of this response is similar to effects that follow stimulation of the pulmonary afferent C-fibres.

Implant sepsis. due to previous external fixator pin track infection, is the most common complication of secondary intramedullary (IM) nailing of the tibia. We have developed an animal model, which allows different treatment methods to be studied. Using an established ovine model of a pin track infection, Staphylococcus aureus was used to infect the external fixator pins, two weeks prior to reamed IM nailing. In the control group, the animals were killed at a mean of 10.5 days following nailing, when widespread infection was evident, with septic arthritis, abscess formation, and infection of the entire length of the tibia in all six animals. In the treatment group, before IM nailing, the pin sites were debrided, and both local and systemic antibiotics were administered. All surgical wounds healed without evidence of infection, 4 of the 6 animals survived for 28 days, and bacteria were only isolated from 1 of the 6 implants. Treatment was successful at reducing, but not eliminating, infection after secondary nailing.

Background: The mortality rate from sepsis has improved little over the past two decades. One reason for this has been the use of flawed or inappropriate experimental models in preclinical sepsis studies., Methods: A literature review of animal models of sepsis was performed following a Medline search based on the following medical subject headings: disease models, endotoxin, inflammation, peritonitis and sepsis. Additional references were identified from the papers identified in the search., Results and Conclusion: Many animal models of sepsis have been described but none has proved to be superior. Extrapolation of results from endotoxicosis or bacterial infusion models should be regarded with caution. Peritonitis models should be accepted as the 'gold standard' but the use of appropriate virulent bacterial species needs to be ensured. A standardized panel of animal models for the preclinical assessment of immunomodulatory agents should be established, including at least one immuno- suppressed model to simulate the immunocompromised patient with sepsis. A uniform and valid definition of sepsis applicable to both small and large animal species is required.

We used laser Doppler flowmetry (LDF) to measure flux in cortical bone fragments as a method of determining their vascular status and viability. In an experimental tibial osteotomy measurements of flux were made from specific cortical sites both before and after osteotomy. Flux levels fell rapidly in non-vascularised fragments and remained significantly reduced throughout the experiment. By contrast, those in vascularised fragments were significantly reduced one and two hours after the osteotomy but then increased. From three hours after the osteotomy there was no significant difference in flux levels between the vascularised fragments and proximal bone stock. We conclude that measurement of bone flux by LDF may have a role in the objective evaluation of the viability of bone fragments, but that further studies are required to validate the technique before its adoption in the management of the injured patient.

Pentoxifylline is a phosphodiesterase inhibitor, known to suppress tumour necrosis factor-alpha production and improve cardiopulmonary parameters and survival in animal models of sepsis. Using a porcine model of abdominal trauma resulting from the combined insults of haemorrhage and infection, a randomised placebo-controlled trial was conducted of pentoxifylline (20 mg/kg bolus followed by 20 mg/kg infusion over 1 h) administered in addition to a colloid resuscitation regimen. Female Large White pigs (45-60 kg) were bled 40% of their blood volume and peritonitis was induced using E. coli (O18: K1: H7) in an autoclaved faecal suspension. Animals were resuscitated with either colloid alone (n=5) or colloid plus pentoxifylline (n=5). Pentoxifylline attenuated increases in mean arterial and pulmonary artery pressures and reduced both systemic and pulmonary vascular resistance. It worsened the lactic acidosis associated with 'septic shock' and failed to reduce serum TNF-alpha levels. Pentoxifylline, in the high doses used in this study, does not have a role as an adjunct to resuscitation in this clinically relevant model of trauma.

Profound physiological changes occur following primary blast exposure but the contribution of cardiac arrhythmias is unknown. Thirteen rats, under intravenous anaesthesia, were exposed to a blast wave directed at the thorax (Group II); 10 other animals underwent abdominal blast (Group III) and nine animals acted as controls (Group I). Animals were monitored before, during and after blast exposure. Group II animals demonstrated apnoea, bradycardia and hypotension. No significant physiological changes were seen in Groups I or III. Group II displayed a variety of ECG disturbances, from ventricular extrasystoles to ventricular fibrillation. All abnormalities reverted to sinus rhythm within minutes except in fatally injured animals. These ECG changes probably result from stress wave injury. Significant disturbances might account for some fatalities following primary blast exposure and may exacerbate the triad of apnoea, bradycardia and hypotension. Such observations may have important consequences for the management of blast casualties.

The physiological responses to either hemorrhage or sepsis have been well documented, however, their simultaneous delivery, as often seen in penetrating trauma, has not been extensively studied. A terminally-anesthetized porcine model of fixed-volume hemorrhage combined with intraperitoneal sepsis was developed. Large White pigs (45-60 kg) were bled 40% of blood volume and peritonitis was induced using an E. coil (O18:K1:H7) culture. Three groups of animals were sequentially studied. Group A (n = 8) received 10(8) bacteria, and Groups B (n = 4) and C (n = 5) received 10(10) organisms. All animals were maintained on a 2.5 mL/kg/h infusion of 0.9% saline. Group C was autotransfused at 1 h. Animals were monitored for up to 24 h. Cardiovascular features of hypovolemia were recorded in all animals. Animals in Group A improved clinically with little microbiological evidence of systemic sepsis. Group B showed rapid cardiovascular collapse, early E. coil-positive blood cultures, and an early rise in serum TNF-alpha levels. Autotransfusion of Group C significantly improved cardiopulmonary parameters, acid-base status, and survival. A reproducible model of hemorrhage and peritonitis, appropriate for abdominal trauma, which allows investigation of resuscitative and pharmacological interventions has been characterized.

We developed an ovine model of an external-fixator pin-tract infection. With use of a novel method of tissue sampling, infection of the medullary canal was confirmed in all (10 of 10) external-fixator pins that were contaminated with Staphylococcus aureus after they were inserted. In addition, all (five of five) adjacent, uncontaminated pins became infected. We demonstrated that pin-tract infection can be difficult to diagnose clinically, despite gross infection of the tract, and that bacteria can spread within the medulla. Three of the infected pins (20%) did not appear clinically infected, were not loose, and were normal on radiographs after 1 week. Staphylococcus aureus was isolated from the medulla around all 15 pin tracts, and nine other organisms were isolated from the tracts. Despite the presence of infection, the majority of the pins remained well fixed in the bone after 2 weeks.

Objective: To assess the effect of rifampicin on the haemostatic function of a fibrinogen-impregnated collagen fleece., Design: Laboratory experiment., Setting: Government research establishment, UK., Material: Six Large White pigs., Interventions: Four 5 cm incisions were made in the spleen of each animal. Three of the wounds were each covered with a sheet of either dry, saline-soaked or rifampicin-soaked fibrinogen-impregnated collagen., Main Outcome Measures: The bleeding time and blood loss from each wound was recorded. Systemic serum rifampicin concentrations were measured using a Staphylococcus aureus inhibition assay., Results: Dry fibrinogen-impregnated collagen resulted in significantly less blood loss (112 (21) compared with 39 (13)ml, p < 0.05) and shorter bleeding time (16 (2) compared with 9 (1) min, p < 0.01) than in untreated control wounds. Pre-soaking in saline or rifampicin solution had no significant effect on its haemostatic function. Rifampicin concentrations above the minimum inhibitory concentration were recorded in the systemic circulation 45 minutes after injury and persisted for the duration of the experiment., Conclusions: Fibrinogen-impregnated collagen is an effective haemostatic agent in splenic trauma that may be of use for both the local and systemic delivery of antibiotics.

Background: Primary repair of penetrating wounds of the colon is gaining increasing acceptance in surgical practice. This study compared two techniques for the repair of experimental colonic perforations in the presence of peritonitis., Methods: Multiple colonic perforations were created in the colon of 24 pigs. Following a 6-h delay the perforations were closed either by local excision and suture or by skin staples applied to the seromuscular layers of the colon. The repairs were assessed biomechanically and histologically for up to 14 days after surgery., Results: All animals had diffuse peritonitis at the time of colonic repair. Stapled repairs were completed significantly faster than sutured repairs (mean(s.d.) 4.8(1.6) versus 30.7(4.0) min, P < 0.001). Bio- mechanical evaluation of repairs revealed no significant differences between the two techniques. Histological examination of repairs closed by staples demonstrated more advanced healing compared with suture closure, on the basis of tissue apposition and inflammatory changes., Conclusion: Experimental colonic injuries may be treated successfully by primary repair in the presence of peritonitis. The use of skin staples for repair does not appear to prejudice colonic wound healing.

Small-fragment injury to the colon may occur in approximately 5% of battlefield casualties. The surgical management aims to reduce the risk of retrocolic infection and provide optimal conditions for colonic wound healing. This study aimed to quantify the risk of retrocolic infection. Steel fragments were fired through exteriorized porcine colon and caught in 20% gelatin. The fragments, and resultant tracks, were extracted and subjected to quantitative bacteriological examination to determine the extent of contamination. The median bacterial count for complete tracks was 1.2 x 10(4) CFU/g (interquartile range 1.8 x 10(3) to 2.7 x 10(4)). Counts were highest in the initial 1 cm of the track and reduced along its length. This study does not support wound track excision or missile fragment removal in cases of retrocolic trauma following penetrating colonic injury. Either or both procedures will increase local trauma and are likely to prejudice colonic wound repair.

Background: The aetiology and pathophysiology of ulcerative colitis remains unclear; however, there is increasing recognition of the critical role of inflammatory cytokines in the pathogenesis of this disease. Among these, tumour necrosis factor alpha (TNF alpha) seems to play an important role., Aim: To study the effects of an engineered human monoclonal antibody to TNF alpha (CDP571) in the treatment of idiopathic ulcerative colitis in the cottontop tamarin., Methods: Six cottontop tamarins with confirmed ulcerative colitis received repeated doses of CDP571. Progression of disease was assessed by measuring both body weight and rectal biopsy pathology., Results: All animals showed a rapid improvement in clinical condition and rectal biopsy pathology that was maintained following completion of the therapy., Conclusion: These studies indicate the efficacy of selective antibody therapy to TNF alpha for the treatment of ulcerative colitis in a primate and suggest that similar therapy in human could be of value.

Two trials, each involving 56 calves less than one month old, demonstrated that the responses of calves to food and water deprivation during 24 hours of transport were similar to those observed in older cattle and lambs. There was increasing utilisation of body reserves and a measurable increase in dehydration, coupled with an increased loss of liveweight. Feeding 1 litre of glucose/electrolyte solution at eight-hour intervals did reduce the effects of food and water deprivation, but it is suggested that the minor benefits of mid-transport feeding during a 24-hour journey would not justify the disruption that would be caused by unloading and feeding. It would be better to complete the journey in as short a time as possible, providing the calves were carried under suitable conditions. Liveweight and the levels of plasma beta-hydroxybutyrate, non-esterified fatty acids, total protein and albumin had all returned to approximately pre-transport values after 24 hours of recovery. However, the calves had not started to gain in liveweight until some time after 24 but before 72 hours of recovery. The calves did not show the same marked responses in heart rate, plasma cortisol and plasma glucose that are observed in older cattle and in other species. They also appeared to be unable to regulate their body temperature closely, when they were transported during the winter. It is suggested that their lack of response to transport was not because they were unaffected but because they were physiologically unadapted to coping with transport.

Three lorry loads, each of approximately 530 lambs, were monitored during August 1994 while they were transported from the Midlands to France. Each lorry underwent a similar journey, designed to study the effects of a) 22 hours on a lorry broken by two hours of feed, water and rest after 15 hours, b) 34 hours on a lorry broken by eight hours of feed, water and rest after 24 hours and c) 24 hours on a lorry and lairage for the following 48 hours. Measurements were made on 180 lambs in each load, of liveweight, plasma betahydroxybutyrate (BHB), non-esterified fatty acids (NEFA), urea, total protein, albumin, osmolality, creatine kinase (CK), cortisol and glucose, before, during and after transport. Twenty-four hours of transport resulted in changes in some of the variables measured that were little different from those observed after 24 hours of feed and water deprivation; however, the high ambient temperatures during the transport resulted in a greater degree of dehydration. For journeys longer than 15 hours a two-hour rest in lairage with access to water and a palatable food source was beneficial in allowing some slight recovery. Although all the differences were in the direction that would be expected with recovery, they were often small and, within the sensitivity of the study, were only significant for NEFA and C.K. For journeys longer than 24 hours, an eight-hour rest in lairage with access to water and a palatable food source was beneficial and allowed material realimentation and rehydration before further transport for up to 10 hours. After 24 hours of transport, however, liveweight, plasma urea, total protein and albumin had only returned to basal levels after 24 hours in lairage and plasma BHB, CK and osmolality after 48 hours of lairage.

Colitis occurs spontaneously in the cottontop tamarin; it shares similar clinical, endoscopic and histological features with, and has a similar response to treatment as, human ulcerative colitis. An association between human ulcerative colitis and the presence of DNA from multiple herpesviruses (human herpesvirus 6 (HHV-6), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in the colon has been described. Intestinal herpesvirus infection may be involved in the pathogenesis of this condition. In a pilot study, coded full thickness colonic specimens from 27 cottontop tamarins were examined for the presence of HHV-6, CMV and EBV DNA using the nested polymerase chain reaction. The sections represented a spectrum of disease activity ranging from histologically normal bowel to severe colitis. A low prevalence of DNA from these viruses was found, which bore no relation to the presence of inflammation. Although these herpesviruses may have a pathogenetic role in human ulcerative colitis, they are not associated with colitis in this animal model.

Five groups of 20 slaughter sheep of approximately 37.9 kg liveweight were transported by road for either three, nine, 15, 18 or 24 hours and three groups were not transported, one of them being deprived of food and water for 24 hours. Before and after transport the liveweight and various blood variables were measured and heart rate and behavioural observations were recorded from subsets of the animals. With increased journey time there was a decrease in liveweight and an increase in the plasma levels of free fatty acids, beta-hydroxybutyrate and urea; however, the changes over 24 hours were similar to those in the group deprived of food and water. In the transported sheep, the heart rate and levels of plasma cortisol and glucose were increased by the stresses of loading and the initial stages of the journey, but after nine hours the sheep appeared, to some extent, to have adapted. They were able to lie down and did not appear to be physically stressed. Measurements of plasma osmolality, total plasma protein and albumin did not indicate that the sheep had become severely dehydrated after 24 hours of transport but upon their return, feeding and drinking activity was greater than that observed before the journey.

The Epstein-Barr virus (EBV) is associated with a range of life-threatening diseases in humans. Development of an effective vaccine has therefore been an important objective. One problem in the development of a subunit vaccine for human administration is the selection of a satisfactory adjuvant since the only one currently licensed for human use is alum, although this is not considered to be very effective. The present study demonstrated that a subunit vaccine composed of the EBV envelope glycoprotein gp340 with alum as the adjuvant did elicit protective immunity against EBV-induced lymphoma in three out of five cottontop tamarins. Furthermore, rabbits immunized with gp340/alum developed the same range of antibody responses as rabbits immunized with gp340/SAF-1, an experimental adjuvant claimed to be more effective than alum. Therefore, these results indicate that alum should be evaluated as an adjuvant as part of a human trial of a gp340-based subunit vaccine.

External skeletal fixation is used widely in the management of fractures. Frame configuration is known to affect frame stiffness and, thereby, the local mechanical environment at the fracture site. In previous investigations of the influence of mechanical conditions upon fracture healing, the frames have always been applied so that they influence the biological environment in different ways. As a result, the influence of stiffness, per se, could not be studied as a single variable, and its effect on the repair process remains unclear. In this study, using a standard osteotomy of the ovine tibia, stabilised by an external skeletal fixator, the local mechanical environment was altered solely by increasing the 'offset' distance between the bone and the fixator frame. The biological conditions at the fracture remained identical in both groups. Increasing the frame stiffness by 40%, brought about by reducing the offset distance of the fixator bar by 10 mm, caused a significant reduction in the rate of healing. In addition, the frame stiffness influenced the ground reaction force with greater weight-bearing in the initial stages in the more rigid group, but despite this, the resultant interfragmentary displacement in this group appeared to be insufficient to stimulate fracture healing. This work emphasises the importance of the local mechanical environment on the process of fracture healing. It also demonstrates the value of in vivo assessment of fracture stiffness as a means of monitoring mechanical events during fracture healing.

A replication-defective recombinant adenovirus (Ad) expressing the full length Epstein-Barr virus (EBV) major envelope glycoprotein gp340/220 was tested for its ability to protect against EBV-induced lymphoma in the cottontop tamarin. Antibody responses against Ad capsid proteins and EBV gp340/220 were observed but these antibodies did not neutralize EBV in vitro. However, all immunized animals were protected against challenge following three intramuscular doses of the recombinant Ad. These data indicate that the recombinant Ad is potentially a useful vector for vaccination.

Inoculation with Epstein-Barr virus (EBV) induces malignant lymphomas in the cottontop tamarin (Saguinus oedipus oedipus). This provides an experimental animal model for assessing the efficacy of candidate EBV vaccines which are intended to reduce the incidence of human tumours associated with EBV infection. Previous work has shown that experimental vaccines based on the major virus envelope glycoprotein gp340 prepared from the membranes of EBV-infected cells are effective in protecting cottontop tamarins against EBV-induced disease. However, not all purified gp340 preparations induce protective immunity against EBV lymphoma in the tamarin. In this work, cottontop tamarins were immunized with recombinant gp340, produced using a bovine papillomavirus (BPV) expression vector, and a threonyl muramyl dipeptide adjuvant formulation. Although the recombinant-derived gp340 lacked the membrane anchor sequence of authentic gp340 and was expressed in mouse cells, it was immunogenic and induced virus-neutralizing antibodies. Healthy vaccinated tamarins were protected against EBV-induced disease. The demonstration that a recombinant gp340 product is able to elicit protective immunity in the cottontop tamarin is a significant step in the development of an EBV vaccine because previously it had not been clear whether a recombinant product would have the exact tertiary structure, including the necessary carbohydrate components, to induce protective immunity. A recombinant gp340 vaccine offers various advantages over production of the authentic molecule by laborious biochemical separation, including lower cost and the absence of potentially oncogenic EBV DNA. Therefore, recombinant gp340 produced using the BPV expression vector is suitable for development as a candidate EBV vaccine for a human Phase I trial and beyond.