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: International statistics indicate that there is a close correlation between the consumption of saturated fats (dairy fats and meat fats) and the mortality from coronary heart disease (CHD), and this conception has been confirmed by many epidemiological studies. Such studies alone, however, cannot prove the existence of a cause-and-effect relationship between these two variables; dietary intervention trials are needed. The Finnish Mental Hospital Study was such a trial, conducted in two hospitals near Helsinki in 1959--1971. Practically total replacement of dairy fats by vegetable oils in the diets of these hospitals was followed by a substantial reduction in the mortality of men from CHD. Total mortality also appeared to be reduced. As to the causes of death other than CHD, none was significantly influenced by dietary change. This was also true for malignant neoplasms. To alleviate the burden of CHD on public health, many investigators have recommended important changes in the quantity and quality of dietary fats.

Abstract: Whereas the way animals perceive human contact has been particularly examined in pet animals, a small amount of investigations has been done in domestic ungulates. It was nevertheless assumed that, as pet animals, non-aggressive forms of tactile contact were as well rewarding or positive for these species, even though the features of intraspecific relationships in pet animals and domestic ungulates may be to some extent different.We test here the hypothesis that horses may not consider physical handling by humans as a positive event. When comparing different early human-foal interactions, we found that early exposure to a motionless human enhanced slightly foals reactions to humans whereas forced stroking or handling in early life did not improve later human-foal relation. Foals that were assisted during their first suckling (e.g., brought to the dam's teat) even tended to avoid human approach at 2 weeks, and physical contact at 1 month of age.We argue that interspecies differences may exist in how tactile stimulation is perceived. It may be important for the establishment of a bond that a young animal is active in the process and able, through its behavioral responses, to help define what is positive for it. This way of investigation may have important general implications in how we consider the development of social relations, both within and between species.

Abstract: We examined how the brain organizes interrelated facts during learning and how the facts are subsequently manipulated in a transitive inference (TI) paradigm (e.g., if A<B and B<C, then A<C). This task determined features such as learned facts and behavioral goals, but the learned facts could be organized in any of several ways. For example, if one learns a list by operating on paired items, the pairs may be stored individually as separate facts and reaction time (RT) should decrease with learning. Alternatively, the pairs may be stored as a single, unified list, which may yield a different RT pattern. We characterized RT patterns that occurred as participants learned, by trial and error, the predetermined order of 11 shapes. The task goal was to choose the shape occurring closer to the end of the list, and feedback about correctness was provided during this phase. RT increased even as its variance decreased during learning, suggesting that the learnt knowledge became progressively unified into a single representation, requiring more time to manipulate as participants acquired relational knowledge. After learning, non-adjacent (NA) list items were presented to examine how participants reasoned in a TI task. The task goal also required choosing from each presented pair the item occurring closer to the list end, but without feedback. Participants could solve the TI problems by applying formal logic to the previously learnt pairs of adjacent items; alternatively, they could manipulate a single, unified representation of the list. Shorter RT occurred for NA pairs having more intervening items, supporting the hypothesis that humans employ unified mental representations during TI. The response pattern does not support mental logic solutions of applying inference rules sequentially, which would predict longer RT with more intervening items. We conclude that the brain organizes information in such a way that reflects the relations among the items, even if the facts were learned in an arbitrary order, and that this representation is subsequently used to make inferences.