Purpose Epstein-Barr virus (EBV) is associated with several cancers in which the tumour cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumour antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses. Experimental Design Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC), received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5×107 and 5×108 plaque forming units (pfu). Blood samples were taken at screening, after each vaccine cycle and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations. Results Vaccination was generally well-tolerated. Immunity increased after vaccination to at least one antigen in 8/14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments respectively. Conclusions MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South East Asia where NPC is most common. The highest dose (5×108 pfu) is recommended for investigation in current phase IB and II trials.

Summary The likelihood of finding evidence of inflammation in 551 tracheal washes collected endoscopically from 278 Thoroughbred racehorses increased with the number of bacterial colony forming units (cfu) per ml of wash (P<0.00l). The aerobic bacteria Streptococcus zooepidemicus, Pasteurella/Actinobacillus‐like species and Streptococcus pneumoniae were significantly associated with lower airway inflammation whereas coagulase‐negative Staphylococcus spp., α‐haemolytic Streptococcus spp., Acinetobacter spp., Bacillus spp., Escherichia coli, Pseudomonas aeruginosa, non‐haemolytic Streptococcus spp. and Enterobacteriaceae were not; Bordetella bronchiseptica was not isolated. Lower airway inflammation was particularly associated with bacteria in horses ≤3 years of age. S. zooepidemicus, S. pneumoniae and Pasteurella/Actinobacillus‐like species were isolated from 167 of 551 washes, either alone or in combination.

Structured risk assessment should guide clinical risk management, but it is uncertain which instrument has the highest predictive accuracy among men and women. In the present study, the authors compared the Psychopathy Checklist-Revised (PCL-R; R. D. Hare, 1991, 2003); the Historical, Clinical, Risk Management-20 (HCR-20; C. D. Webster, K. S. Douglas, D. Eaves, & S. D. Hart, 1997); the Risk Matrix 2000-Violence (RM2000[V]; D. Thornton et al., 2003); the Violence Risk Appraisal Guide (VRAG; V. L. Quinsey, G. T. Harris, M. E. Rice, & C. A. Cormier, 1998); the Offenders Group Reconviction Scale (OGRS; J. B. Copas & P. Marshall, 1998; R. Taylor, 1999); and the total previous convictions among prisoners, prospectively assessed prerelease. The authors compared predischarge measures with subsequent offending and instruments ranked using multivariate regression. Most instruments demonstrated significant but moderate predictive ability. The OGRS ranked highest for violence among men, and the PCL-R and HCR-20 H subscale ranked highest for violence among women. The OGRS and total previous acquisitive convictions demonstrated greatest accuracy in predicting acquisitive offending among men and women. Actuarial instruments requiring no training to administer performed as well as personality assessment and structured risk assessment and were superior among men for violence.

Summary To investigate whether horses were able to acclimate to conditions of high temperature and humidity, 5 horses of different breeds were trained for 80 min on 15 consecutive days on a treadmill at 30°C and 80% RH. Training consisted of a combination of long duration low‐intensity exercise, medium duration medium intensity exercise and short duration high intensity exercise. Between training sessions the horses were maintained at 11 ± 3°C and 74 ± 2% RH. Before (PRE‐ACC) and after acclimation (POST‐ACC) the horses undertook a simulated Competition Exercise Test (CET), designed to represent the Speed and Endurance Test of a 3‐day event, at 30°C/80% RH. Maximal oxygen uptake (VO2PEAK) was not changed following acclimation (PRE‐ACC 141 ± 8 ml/min/kg bwt vs. POST‐ACC 145 ± 9 ml/min/kg bwt [STPD], P>0.05). Following acclimation, 4 of the 5 horses were able to complete a significantly greater amount of Phase D in the CET (PRE‐ACC 6.3 ± 0.3 min vs. POST‐ACC 7.3 ± 0.3 min, P<0.05; target time = 8 min). Resting body temperatures (pulmonary artery [TPA], rectal [TREC] and tail‐skin [TTSK] temperatures) were all significantly lower following acclimation. During exercise, metabolic heat production (M) and heat dissipation (HD), for the same exercise duration, were both significantly lower following acclimation (P<0.05), although heat storage (HS) was significantly higher (P<0.05). The higher heat storage following acclimation was associated with a lower TTSK for a given TPA and a decreased total fluid loss (% bodyweight, P<0.05). Plasma volume was not changed following acclimation. The relationship of sweating rate (SR) to TPA or TTSK on either the neck or the gluteal region was not significantly altered by acclimation, although the onset of sweating occurred at a lower TPA or TTSK following acclimation (P<0.05). The horses in the present study showed a number of physiological adaptations to a period of 15 days of exposure to high heat and humidity consistent with a humid heat acclimation response. These changes were mostly similar to those reported to occur in man and other species and were consistent with thermal acclimation and an increased thermotolerance, leading to an improved exercise tolerance. It is concluded that a 15 day period of acclimation is beneficial for horses from cooler and or drier climates, that have to compete in hot humid conditions and that this may redress, to some extent, the decrement in exercise tolerance seen in nonacclimated horses and reduce the risk of heat related disorders, such as heat exhaustion.

A glycoprotein H (gH)-deleted herpes simplex virus type 2 (HSV-2) was evaluated as a vaccine for the prevention of HSV-induced disease. This virus, which we term a DISC (disabled infectious single cycle) virus, can only complete one replication cycle in normal cells and should thus be safe yet still able to stimulate broad humoral and cell-mediated antiviral immune responses. A gH-deleted HSV-2 virus that has been tested as a vaccine in the guinea pig model of recurrent HSV-2 infection was constructed. Animals vaccinated with DISC HSV-2 showed complete protection against primary HSV-2-induced disease, even when challenged 6 months after vaccination. In addition, the animals were almost completely protected against recurrent disease. Even at low vaccination doses, there was a high degree of protection against primary disease. A reduction in recurrent disease symptoms was also observed following therapeutic vaccination of animals already infected with wild type HSV-2.

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Prolonged low-medium intensity exercise is associated with increased oxidative stress in humans. We hypothesized that competitive equine endurance racing would induce changes in circulatory antioxidants and produce systemic oxidative stress. Forty horses competing in a 140-km endurance race in warm conditions [shade temperature 15-19 degrees C; 62-88% relative humidity (%RH)] were sampled before (Pre), immediately after exercise (End) and at approximately 16 h into recovery (+16 h). Plasma ascorbic acid concentration was not different between Pre [11.1 (median); 4.6-20.3 micromol/L (range)] and End [9.7; 3.0-38.9 (range) micromol/L] but was significantly decreased at +16 h (5.5; 2.8-15.5 micromol/L; P < 0.05). Total red cell hemolysate glutathione (TGSH) concentration was significantly reduced by exercise (Pre 1261; 883-1532 micromol/L; End 1065; 757-1334 micromol/L; P < 0.05) and at +16 h recovery (1032; 752-1362 micromol/L; P < 0.05). Glutathione redox ratio was unchanged by exercise but was significantly decreased at +16 h compared with that at both Pre and End (P < 0.05). The concentration of total barbituric acid reactive substances (TBARS) in plasma was increased compared with that at Pre (309; 66-1048 nmol/L), both at End (408; 170-1196 nmol/L; P < 0.05) and +16 h (380; 99-1161 nmol/L; P < 0.05). alpha-Tocopherol was unchanged by exercise or recovery. Mean race speed was 16.5 +/- 1.6 km/h and ranged from 13.9 to 19.7 km/h. Mean speed during competition in horses that completed the full 140 km (n = 28) was significantly correlated with end of exercise ascorbic acid (r = 0.622; P = 0.0004). Although there were increases in creatine phosphokinase (CK), aspartate aminotransferase (AST) and TBARS and a loss of TGSH, this study failed to demonstrate evidence of classical oxidative stress.

Summary Whereas the efficacy of cold water cooling of horses has been demonstrated by several studies, the dynamics of temperature changes within and between compartments (primarily muscle, blood [core], skin and deep core [rectal]) have not been investigated. Changes in body temperature associated with cold water cooling were investigated in the hyperthermic horse. Muscle (TMU), pulmonary artery (TPA), rectal (TREC), tail‐skin (TTSK) and coat surface (TCOAT) temperatures, were monitored continuously in 5 Thoroughbred horses during and after exercise in hot humid (30°C and 80% RH) conditions on a treadmill. Horses were cooled in the hot humid environment with cold water (∼6°C) for 6 30 s periods. Between each 30 s cooling period the horses stood for 30 s. A total of 180 1 of cold water was applied. Horses were monitored for a further 4 min following the final cooling period. From the end of exercise to the end of the final cooling (6.5 min), mean (± s.e.) rates of decrease for TTSK and TPA were similar (0.8 ± 0.1 and 0.8 ± 0.1°C/min, respectively). The effects on TMU and TREC were less marked, with average rates of 0.2 ± 0.1 and 0.0 ± 0.1°C/min, respectively. During the first 4 min of cooling, TPA fell during the 30 s period of water application and rose during each 30 s period of standing. When TPA fell below ∼36.5°C, these variations were suppressed and TPA rose steadily, despite continued applications; TREC and TMU continued to fall, although less rapidly than before. These observations are consistent with the onset of skin vasoconstriction at low TPA. The mechanism is mediated through a cooling of circulating blood volume providing a greater capacity for heat transfer between muscle and circulation. Intermittent application of cold water (∼6°C) improves heat removal without apparent deleterious effects and is well tolerated. Even when hypothermia develops (based on TPA), muscle and rectal temperatures continue to fall.