Abstract: Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators.

Abstract: The spontaneous behaviour and the apparent digestibility of dry matter and fibre and transit times of digesta were compared in four normal horses and four crib-biters. A technique was developed for measuring total gut transit times (TGTT) by using single-stool analysis of the passage of radio-opaque polyethylene markers. Longer TGTT were recorded in the crib-biters than in the normal horses but the orocaecal transit times did not differ. The crib-biters rested less than the normal horses.

Abstract: There is confusion in the veterinary literature concerning the definition of oral based stereotypies in the horse. This study reports the use of fluoroscopy and endoscopy during cribbiting/wind-sucking in afflicted horses. This permitted observations of movements of the pharyngeal and oesophageal tissues and of the air column within during the stereotypic behaviour. The findings reported show that the sequence of events during crib-biting/wind-sucking is not related to deglutition and that air is not swallowed to the stomach. Transient dilation of the upper oesophagus was recorded and the characteristic noise of wind-sucking coincided with the in-rush of air through the cricopharynx. The oesophageal distension was relieved when the air returned to the pharynx although small quantities passed caudally. It is proposed that the role of contraction of the strap muscles of the neck is to create a pressure gradient in the soft tissues surrounding the oesophagus which provokes movement of air from the pharynx into the oesophagus. The findings suggest that the definitions currently used in the sale of horses are in need of revision.

Abstract: Abstract The aim of our study was to explore the association between dominance rank and body condition in outdoor group-living domestic horses, Equus caballus. Social interactions were recorded using a video camera during a feeding test, applied to 203 horses in 42 herds. Dominance rank was assigned to 194 individuals. The outcome variable body condition score (BCS) was recorded using a 9-point scale. The variables age and height were recorded and considered as potential confounders or effect modifiers. Results were analysed using multivariable linear and logistic regression techniques, controlling for herd group as a random effect. More dominant (p = 0.001) individuals generally had a higher body condition score (p = 0.001) and this association was entirely independent of age and height. In addition, a greater proportion of dominant individuals fell into the obese category (BCS >= 7/9, p = 0.005). There were more displacement encounters and a greater level of interactivity in herds that had less variation in age and height, lending strength to the hypothesis that phenotypic variation may aid cohesion in group-living species. In addition there was a strong quadratic relationship between age and dominance rank (p < 0.001), where middle-aged individuals were most likely to be dominant. These results are the first to link behavioural predictors to body condition and obesity status in horses and should prompt the future consideration of behavioural and social factors when evaluating clinical disease risk in group-living animals.

Abstract: Although horses are social animals they are often housed individually with limited social contact to other horses and this may compromise their welfare. The present study included eight young female horses and investigated the strength of motivation for access to full social contact, head contact and muzzle contact, respectively, to a familiar companion horse. Horses were housed individually next to their companion horse and separations between pens prevented physical contact. During daily test sessions horses were brought to a test area where they could access an arena allowing social contact. Arena access during 3 min was given after completion of a predetermined number of responses on a panel. Fixed ratios (FR) of 8, 16, 24, 32 and 40 responses per arena access were applied in a random order, one per daily test session, within each test week (Monday to Friday), and the number of rewards per daily test session was recorded. All horses could access all three types of social contact in a cross-over design, and an empty arena was used as control. Motivational strength was assessed using elasticity of demand functions, which were estimated based on the number of rewards earned and FR. Elasticities of demand for the three types of social contact were low (-0.20), and not significantly different, although increasing FR still resulted in a decrease in rewards obtained for all three types of social contact (P < 0.001). Across FR-levels horses earned more rewards for social contact than for an empty arena, as shown by much higher intercept values (2.51 vs. 0.99; P < 0.001). However, the elasticity of demand for infrequent access to an empty arena (-0.08) was lower than for social contact (P < 0.01) and not significantly different from zero (P = 0.07). Horses performed more social behaviour the lesser the restriction on social contact (full > head > muzzle). However, the finding that horses showed a similar and high motivation for all three types of social contact suggests that they are valued equally highly in a situation where the alternative is no social contact.