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Data from the official milk recording scheme of the Austrian Simmental population were analysed to estimate variance components due to genomic imprinting. Traits regarded were milk yield, fat and protein content, persistency, days open (first, second and third lactation) and herd life. All dairy traits were preadjusted for BLUP herd-year effects. After applying some data restrictions, the number of records ranged from 3391 (persistency, third lactation) to 33 993 (days open, first lactation). Two different estimation approaches were used: (i) estimation of the maternal and paternal gametic component by a dam and sire model, respectively, and (ii) estimation of the animal and an additional gametic component (maternal or paternal) by treating gametes as homozygous diploid individuals. All models also accounted for year of first calving and the cytoplasmic effect of maternal lineages. In tendency, the results of both approaches were fairly well in line with each other. For the majority of the investigated traits, no substantial imprinting effects were detected. Significant evidence of genomic imprinting on a multiple type I error ≤ 0.10 was only found for protein content and days open. For protein content in the second and third lactation, the proportions of variance due to the paternal gametic effect exceeded those of the maternal by 0.096 and 0.152, respectively. For days open in the second lactation, however, the proportion of variance of the maternal gamete effect exceeded that of the paternal by 0.036. In tendency, indication of paternal imprinting was found for all fitness-related traits. For true and functional herd life, significant differences (pairwise type I error ≤ 0.05) of 0.040 and 0.032 were found between the proportions of variance due to the maternal and paternal gamete effect. Significant variance components of cytoplasmic effects (multiple type I error ≤ 0.01) were found for first lactation of milk yield (0.020), for first, second and third lataction of persistency (0.026, 0.035 and 0.033) and of days open (0.029, 0.016 and 0.022) and for true and functional herd life (0.019 and 0.029).

Treating gametes as homozygous diploid individuals, TIER and SOLKNER (Theor. Appl. Genet. 85: 868–872, 1993) proposed a method which manages the use of available computer programs with a common animal model to estimate variance components caused by imprinting effects. Despite some relevant model restrictions, this approach has already been used in some field data analyses by an adapted version of the widely used DFREML computer program, subsequently indicated by DFREMLa. The main objective of this study was to ascertain the properties of DFREMLa by computer simulation and to examine other alternative estimation approaches. The most important results may be summarized as follows: (1) Treating gametes as homozygous diploid individuals has the consequence that one-half of the actually realized gametic effect is totally abstracted in variance component estimation. Thus, an additional adjustment of the phenotypic variance calculated by DFREMLa is necessary to get correct values of estimated variance component ratios. (2) Adjusted DFREMLa estimates yielded correct results when animals were unselected and only maternal or paternal imprinting (not both simultaneously) occurred. (3) When the model did not adequately account for the additive genetic component within a maternal lineage, significant upward biases for the cytoplasmic component were observed. (4) The use of a simple dam and sire model with appropriate relationship matrices can be recommended when only the difference of maternal and paternal imprinting effects is of primary interest and the covariance between maternal halfsibs is not substantially increased by common environmental effects. (5) An adequate estimation of variance components for all possible imprinting situations requires the use of an animal model augmented by both maternal and paternal gametic effects. Unfortunately, a computer program on the basis of such a model does not yet exist. Schatzung von Varianzkomponenten fur Imprintingeffekte mittels DFREML und VCE: Ergebnisse einer Simulationsstudie TIER and SOLKNER (Theor. Appl. Genet. 85: 868–872, 1993) schlugen eine Methode zur Schatzung von imprintingbedingten Varianzkomponenten vor, die mit einem einfach zu adaptierenden Computerprogramm auf der Basis eines ublichen Tiermodells vorgenommen werden kann, indem sie Gameten wie homozygot diploide Individuen behandelten. Obwohl dieser Ansatz einige praxisrelevante Einschrankungen hat, wurde er bereits bei einigen Felddatenanalysen verwendet. Fur diesen Zweck wurde eine entsprechend adaptierte Version des haufig verwendeten Computerprogrammes DFREML eingesetzt, die im folgenden mit DFREMLa bezeichnet wird. Das Ziel der vorliegen Untersuchung lag darin, die Eigenschaften von DFREMLa bei verschiedenen Imprintingsituationen zu uberprufen und weiters die Brauchbarkeit anderer moglicher Schatzansatze zu uberprufen. (1) Werden Gameten wie diploide homozygote Individuen aufgefast, dann geht bei der Schatzung von Varianzkomponenten mit DFREMLa eine Halfte des tatsachlich wirksamen Gameteneffektes vollig verloren. Das heist, die von DFREMLa ausgewiesenen Ergebnisse mussen nachtraglich entsprechend adjustiert werden, um korrekte Schatzergebnisse fur alle jene Quotienten von Varianzkomponenten zu erhalten, bei denen die gesamte phanotypische Varianz im Nenner steht. (2) Die adjustierten DFREMLa Schatzwerte lieferten in all jenen Fallen korrekte Ergebnisse, wo keine Selektion der Tiere erfolgte und entweder nur maternales oder paternales Imprinting (nicht beide gleichzeitig) auftrat. (3) Alle Modelle, bei denen die additiv genetische Komponente innerhalb einer Kuhfamilie keine adaquate Berucksichtigung fand, fuhrten zu einer systematischen Uberschatzung der zytoplasmatischen Varianzkomponente. (4) Ist nur jene Varianzkomponente von Interesse, die durch unterschiedlich starkes maternales bzw. paternales Imprinting erklart werden kann, dann kann auch die Verwendung einfacher Vater-bzw. Muttermodelle empfohlen werden. Voraussetzung hierfur ist allerdings, das die Kovarianz zwischen mutterlichen Halbgeschwistern durch keine gemeinsame Umwelt erhoht ist. (5) Eine fur alle Imprintingsituationen problemadaquate Schatzung von Varianzkomponenten verlangt die Anwendung eines Tiermodelles, erweitert um beide imprintingbedingten Gameteneffekte. Leider fehlt gegenwartig hierfur noch ein entsprechendes Computerprogramm.

This paper describes the current state of toxicokinetics in Canada from a regulator’s viewpoint. The Canadian Health Protection Branch supports the use of toxicokinetics and believes that an integrated approach which combines toxicokinetic evaluations with selective well-conducted toxicological studies to establish the relationship between drug concentration and biological response is needed.

The synthesis of analogues of the antipsychotic drug butaclamol bearing chloro substituents on the benzene rings is described. On the basis of a perceived topographical similarity of a putative chlorophenylethylamine pharmacophore present in these analogues and in VUFB-10032 and doclothepin, agents related to octoclothepin which do not induce catalepsy, they have been tested for "noncataleptic" neuroleptic activity. None of the butaclamol analogues exhibit this type of activity. Depending on the position of the chlorine, the analogues either retained butaclamol-like activity or were inactive.

Rats were trained in a three-chambered discrimination box to avoid an electric shock which was preceded by the presentation of light. Tetrabenazine, at a subcutaneous dose of 6 mg/kg suppressed this conditioned avoidance response (CAR) without abolishing the unconditioned escape response (UER). The three classes of antidepressant drugs affected differently the tetrabenazine-induced suppression of CAR. The tricyclic antidepressants, imipramine and desmethylimipramine (DMI), did not prevent the suppression of the CAR while the monoamine oxidase (MAO) inhibitors, iproniazid and pargyline did. The stimulant drugs d-amphetamine and methylphenidate, in addition to preventing also reversed the effect of tetrabenazine. The action of two experimental compounds, butriptyline and Lu3-010 was also investigated.

Partially purified pregnant mare urine extracts when injected intraperitoneally into rats in a dose of 1.1–1.2 g/kg induced hypnosis both at room temperature and at an elevated ambient temperature. Furthermore, doses of extract which induced hypnosis caused a profound fall of rectal temperature (6–8°C). The extract potentiated the hypnotic effect of hexobarbital both at room and elevated ambient temperatures. Pretreatment with graded doses of picrotoxin, metrazol and nikethamide antagonized the hypnotic but not the hypothermic effect of the extract. On the other hand amphetamine pretreatment significantly decreased or reversed extract induced hypothermia. Pretreatment with iproniazid potentiated while iproniazid + alpha-methyl-meta-tyrosine pretreatment antagonized extract-induced hypothermia.

The role of the regenerated adrenal gland in adrenal-regeneration hypertension has been explored in a series of experiments in the rat. Sensitization of the animals by unilateral nephrectomy and replacement of the drinking water by 1% saline were instituted at various intervals after unilateral adrenalectomy and contralateral adrenal enucleation. Comparisons were made of blood pressure, heart and kidney weight, and cardiovascular lesion in groups of rats sensitized at 0, [Formula: see text], 5 and [Formula: see text] weeks after adrenal enucleation. The results suggest an inverse relationship between the degree of adrenal regeneration present and the severity of the hypertension which developed following sensitization.

The synthesis of analogues of the antipsychotic drug butaclamol bearing chloro substituents on the benzene rings is described. On the basis of a perceived topographical similarity of a putative chlorophenylethylamine pharmacophore present in these analogues and in VUFB-10032 and doclothepin, agents related to octoclothepin which do not induce catalepsy, they have been tested for "noncataleptic" neuroleptic activity. None of the butaclamol analogues exhibit this type of activity. Depending on the position of the chlorine, the analogues either retained butaclamol-like activity or were inactive.

The design and synthesis of a series of 3H-benz[e]indol-8-amines are described. Two of the compounds are potent, orally active dopaminergic agents as established by their ability to induce contralateral turning in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway, to induce ambulation in rats rendered akinetic by bilateral injections of 6-hydroxydopamine into the anterolateral hypothalamus, and to antagonize reserpine-induced catalepsy in mice. The dopamine agonist activity of the 3H-benz[e]indol-8-amines establishes that a pyrrolo ring and a phenolic hydroxyl group can interact similarly with the dopamine receptor and provides evidence for the existence of a hydrogen-bond acceptor nucleus on the dopamine receptor macromolecule that is involved in the behavioral manifestations of dopamine agonists.

The synthesis and some pharmacological effects of 16 3-aryl analogues of butaclamol, a new antipsychotic drug, are described. The animal models were predictive of neuroleptic activity as well as side effects commonly associated with neuroleptic therapy. The results indicate that the 3-substituent plays a critical role with regard to the potency of the compounds as well as to their tendencies to induce extrapyramidal side effects and/or hypotension.

A comparison is described between the activity of the melanocyte-stimulating hormone release inhibiting factor (MIF) and those of five synthetic tripeptide analogues of MIF. The comparison was based upon the ability of the compounds to potentiate the behavioral effects of L-dopa in mide and to antagonize fluphenazine-induced catalepsy in rats. Three of the tripeptides potentiated L-dopa in a manner similar to that of MIF. All of the synthetic analogues antagonized fluphenazine after a single dose although their potency and their duration of action differed. MIF was active in the latter test only following chronic administration. The possible mechanism of action and the potential clinical applicability of the tripeptides are briefly discussed.

The design and synthesis of a series of 3H-benz[e]indol-8-amines are described. Two of the compounds are potent, orally active dopaminergic agents as established by their ability to induce contralateral turning in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway, to induce ambulation in rats rendered akinetic by bilateral injections of 6-hydroxydopamine into the anterolateral hypothalamus, and to antagonize reserpine-induced catalepsy in mice. The dopamine agonist activity of the 3H-benz[e]indol-8-amines establishes that a pyrrolo ring and a phenolic hydroxyl group can interact similarly with the dopamine receptor and provides evidence for the existence of a hydrogen-bond acceptor nucleus on the dopamine receptor macromolecule that is involved in the behavioral manifestations of dopamine agonists.

A series of novel 1,3,4,9-tetrahydro-1-methyl-thiopyrano-[3,4-b]indole-1-ethanamines has been synthesized and examined for effects on reserpine-induced ptosis and reserpine-induced hypothermia in mice. One member of the series, the 9-ethyl-N,N-dimethyl derivative V (tandamine), was selected for further studies in regard to its possible use as an antidepressant agent. Tandamine has been resolved, and the levorotatory enantiomer was found to be more active than the racemic compound. The N-desmethyl derivative XIII, a metabolite of tandamine, has been prepared. The 5-ethyl-1,3,4,5-tetrahydro-N,N,1-trimethylthiopyrano[4,3-b]indole-1-ethanamine XXI, an analog of tandamine with the isomeric ring system, has also been synthesized and evaluated. In the primary pharmacological screening and in the drug-interaction studies with reserpine, tetrabenazine, and tremorine, tandamine was compared to the clinically effective tricyclic antidepressants--desipramine, imipramine, and amitriptyline. Tandamine was more effective than these agents in several screening procedures indicative of potential antidepressant activity.

A novel hypocholesterolemic agent, trans- 1,4-bis- (2-chlorobenzylaminomethyl) cyclohexane dihydrochloride (AY- 9944), was administered orally to rats, pigs, dogs, monkeys, pigeons and guinea pigs. While AY-9944 decreased the sterol concentration in plasma of all the species tested, adrenal weights were increased only in rats, pigs and dogs. In rats, a decrease in sterol concentration of the adrenal gland was found. The order of adrenal enlargement was: pig >rat > dog. Considerable sex differences existed in response to AY-9944 with respect to the enlargement of the gland. The increase in weight of the adrenals was attributed to the following adrenocortical changes: hypertrophy and sinusoidal congestion. When the treatment with the hypocholesterolemic agent was discontinued, the weight and histological appearance of the adrenals rapidly returned to normal. It is suggested that AY-9944 not only lowered the level of serum sterols, but also reduced the amount of precursor (s) available for corticoid synthesi...

Gastric acid secretion in response to graded doses of histamine was determined in 32 male and 50 female guinea pigs. The findings were as follows, (a) The subcutaneous injection of 0.1 mg histamine per kg brought about an identical response in both sexes, (b) Following the administration of 0.2 mg of histamine per kg, both the volume and the acidity were found to be higher in the male than in the female guinea pigs, (c) The subcutaneous injection of 0.4 mg histamine per kg induced a maximal secretory response in both sexes. Under these circumstances, the secretory response (volume, free and total acidity) was found to be significantly higher in the male guinea pigs, (d) Similar results could be obtained after the subcutaneous injection of 0.8 or 1.2 mg histamine per kg. It is concluded that the 'maximum' response to histamine of gastric acid secretion is significantly greater in the male than in the female guinea pig.

THE belief that hypercholesterolaemia plays a contributory part in the aetiology of atherosclerosis has stimulated the search in many laboratories for compounds which would lower serum cholesterol by inhibition of endogenous cholesterol synthesis. Recent work in our laboratories has led to the synthesis of trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride (mol. wt. 464.3)—‘AY–9944’, and the subsequent demonstration that this compound represents a new class of inhibitors of the biosynthesis of cholesterol1.