The rationale and design of the perindopril genetic association study (PERGENE): A pharmacogenetic analysis of angiotensin-converting enzyme inhibitor therapy in patients with stable coronary artery disease

Background: Angiotensin-converting enzyme (ACE) inhibitors reduce clinical symptoms and improve outcome in patients with hypertension, heart failure, and stable coronary artery disease (CAD) and are among the most frequently used drugs in these patient groups. For hypertension, treatment is guided by the level of blood pressure. In the secondary prevention setting, there are no means of guiding therapy. Prior attempts to target ACE-inhibitors to those patients that are most likely to benefit have not been successful, mainly due to the consistency in the treatment effect in clinical subgroups. Still, for prolonged prophylactic treatment with ACE-inhibitors it would be best to target treatment to only those patients most likely to benefit, which would considerably lower the number needed to treat and increase cost-effectiveness. A new approach for such "tailored-therapy" may be to integrate information on the genetic variation between patients. Until now, pharmacogenetic research of the efficacy of ACE-inhibitor therapy in CAD patients is still in a preliminary stage. Methods: The PERindopril GENEtic association study (PERGENE) is a substudy of the EUROPA trial, a randomized double-blind placebo-controlled multicentre clinical trial which demonstrated a beneficial effect of the ACE-inhibitor perindopril in reducing cardiovascular morbidity and mortality in 12.218 patients with stable coronary artery disease (mean follow-up 4.2 years). Blood tubes were received from patients at the beginning of the EUROPA trial and buffy coats were stored at -40°C at the central core laboratory. Candidate genes were selected in the renin-angiotensin-system and bradykinin pathways. Polymorphisms were selected based on haplotype tagging principles using the HapMap genome project, Seattle and other up-to-date genetic database platforms to comprehensively cover all common genetic variation within the genes. Selection also took into consideration the functionality of SNP's, location within the gene (promoter) and existing relevant literature. The main outcome measure of PERGENE is the effect of genetic factors on the treatment benefit with ACE-inhibitors. The size of this pharmacogenetic substudy allows detection with a statistical power of 98% to detect a difference in hazard ratios (treatment effect) of 20% between genotypes with minor allele frequency of 0.20 (two-sided alpha 0.05). Conclusion: The PERGENE study is a large cardiovascular pharmacogenetic study aimed to assess the feasibility of pharmacogenetic profiling of the treatment effect of ACE-inhibitor use with the perspective to individualize treatment in patients with stable coronary artery disease

Transport Properties of the Quark-Gluon Plasma -- A Lattice QCD Perspective

Transport properties of a thermal medium determine how its conserved charge densities (for instance the electric charge, energy or momentum) evolve as a function of time and eventually relax back to their equilibrium values. Here the transport properties of the quark-gluon plasma are reviewed from a theoretical perspective. The latter play a key role in the description of heavy-ion collisions, and are an important ingredient in constraining particle production processes in the early universe. We place particular emphasis on lattice QCD calculations of conserved current correlators. These Euclidean correlators are related by an integral transform to spectral functions, whose small-frequency form determines the transport properties via Kubo formulae. The universal hydrodynamic predictions for the small-frequency pole structure of spectral functions are summarized. The viability of a quasiparticle description implies the presence of additional characteristic features in the spectral functions. These features are in stark contrast with the functional form that is found in strongly coupled plasmas via the gauge/gravity duality. A central goal is therefore to determine which of these dynamical regimes the quark-gluon plasma is qualitatively closer to as a function of temperature. We review the analysis of lattice correlators in relation to transport properties, and tentatively estimate what computational effort is required to make decisive progress in this field.Comment: 54 pages, 37 figures, review written for EPJA and APPN; one parag. added end of section 3.4, and one at the end of section 3.2.2; some Refs. added, and some other minor change

Could Work Be a Source of Behavioural Disorders? A Study in Horses

Stress at work, as shown by a number of human studies, may lead to a variety of negative and durable effects, such as impaired psychological functioning (anxiety, depression…). Horses share with humans this characteristic of working on a daily basis and are submitted then to work stressors related to physical constraints and/or more “psychological” conflicts, such as potential controversial orders from the riders or the requirement to suppress emotions. On another hand, horses may perform abnormal repetitive behaviour (“stereotypies”) in response to adverse life conditions. In the present study, we investigated whether the type of work the horses are used for may have an impact on their tendency to show stereotypic behaviour (and its type) outside work. Observations in their box of 76 horses all living in the same conditions, belonging to one breed and one sex, revealed that the prevalence and types of stereotypies performed strongly depended upon the type of work they were used for. The stereotypies observed involved mostly mouth movements and head tossing/nodding. Work constraints probably added to unfavourable living conditions, favouring the emergence of chronic abnormal behaviours. This is especially remarkable as the 23 hours spent in the box were influenced by the one hour work performed every day. To our knowledge, this is the first evidence of potential effects of work stressors on the emergence of abnormal behaviours in an animal species. It raises an important line of thought on the chronic impact of the work situation on the daily life of individuals

Contribution to a Concept of Behavioral Abnormality in Farm Animals Under Confinement

Farm animals housed in close confinement often engage in activities that do not occur with animals maintained in traditional and more complex environments. Many of these activities consist of species-typical motor patterns directed towards unsuited or inappropriate objects, or performed as vacuum activities. For example, piglets fed from a trough from day 2 to day 21 after parturition display much nosing. of penmates and ear sucking (DeBoer and Hurnik 1984). Similarly, confined veal calves in crates may lick their pelage excessively, or, when housed in groups, may suck the naval area of penmates; laying hens and broilers often engage in feather pecking and cannibalism. A list of reports in the literature concerning such behavior is given in Fox (1984). These behaviors are not adaptive, that is, they do not contribute to species-typical development, maintenance, or reproduction and they may even result in physical damage to the performer or its pen- or cagemates (Tschanz 1982). It is widely agreed that the occurrence of these abnormal behaviors is indicative of environmental inadequacy and animal suffering (Sambraus 1981; Fox 1984). Because abnormal behavior is believed to be an important criterion in evaluating animal housing systems and management practices, there is a need for a general concept of behavioral abnormality in farm animals that would facilitate making judgments about the acceptability of given production systems, and to predict effects of environmental changes on animal welfare (Duncan 1983). This paper contributes to the development of a concept of behavioral abnormality by comparing the situation of animals in an artificial environment to an experimental learning situation. The concept is based on behavioristic theory developed by Seligman (1970) and Staddon and Simmelhag (1971 ). The concept provides a novel perspective of behavioral normality and abnormality

Applied Animal Behaviour Science 74 1 15 28 Amsterdam, Netherlands: Elsevier Science B.V..

A retrospective cross-sectional survey of dog-owning veterinary clients was undertaken in 1996 in three Canadian provinces (New Brunswick, Nova Scotia, and Prince Edward Island) to generate a population of dogs for future use in a more detailed survey on canine behaviour. The questionnaire was designed to detect which dogs had or had not bitten a person living in the same household, and included both demographic and behaviour questions. Twenty veterinary clinics were enlisted to administer the questionnaire to their clientele. Data was collected on 3226 dogs and a response rate of 81.4% was observed. The dogs were predominantly purebred (60.1%) and neutered (71.6%). Of the 110 breeds, the Labrador Retriever was the most commonly reported. There were slightly more female than male dogs, and significantly more female dogs were neutered (P < 0.001). Questions elicited information about three forms of aggression: growling, possessive aggression, and biting. The reported frequencies of aggression problems were significantly associated with age, gender, neuter status, and breed. Biting behaviour was reported for 15.6% of all dogs. The highest frequency of biting was reported for dogs less than one year of age. Relative to intact female dogs of at least 1 year of age, the odds ratio for having bitten a member of the household was highest for neutered male dogs (OR: 3.23; 95% CI: 1.83-5.71), followed by neutered female dogs (OR: 2.13; 95% CI: 1.21-3.75). Similar trends were seen for growling and possessive aggression. Our results indicate that excellent response rates can be achieved in behavioural research by utilizing general veterinary practices and their clientele, that canine aggression in a household setting is a frequent problem, and that the relationship between neutering and behaviour warrants further investigation.

Applied Animal Behaviour Science 74 1 29 42 Amsterdam, Netherlands: Elsevier Science B.V..

A detailed telephone survey of dog owners was undertaken in 1996 to determine the risk factors for biting behaviour of dogs in a household setting. Individuals were selected from a cross-sectional population of veterinary clientele in the Canadian provinces of New Brunswick, Nova Scotia, and Prince Edward Island. Interviews were successfully completed with 515 of 640 individuals selected from a study population of 3226 dogs by a formal random process. For the risk factor analysis, 227 biting and 126 non-biting dogs were selected according to a strict criteria to evaluate the association of potential risk factors to biting behaviour. Biting behaviour was carefully defined in the telephone interview to avoid including activity associated with playful mouthing by the dog. All dogs were at least 6 months of age. Both the mean weight and age of biting dogs were significantly lower (P<0.05) than that of non-biting dogs. Significant risk factors for an outcome of biting were as follows: the dog being female (particularly if small), the presence of one or more teenage children in the home, a history of a pruritic or malodorous skin disorder which had received veterinary treatment, aggression over food in the first 2 months of ownership, the dog having slept on someone's bed in the first 2 months of ownership, and the dog having been given a significantly higher ranking for excitability based on its behaviour in the first 2 months of ownership. Small dogs were also determined to have a higher risk of biting than large dogs when exposed to certain lifestyle and health factors, suggesting a relationship between body size and reactivity, or possibly greater owner tolerance of aggression in smaller dogs. Biting dogs were more likely to have exhibited fear of children, men, and strangers. The risk factors identified provide a useful focus for the veterinarian in general practice when counselling owners in the prevention of canine aggression.