Antiestrogenic and antitumor properties of the new triphenylethylene derivative toremifene in the rat

The effects of toremifene, a new triphenylethylene derivative, on the uterus and DMBA-induced mammary tumors in rats were compared to tamoxifen. The ability of toremifene to compete with [3H]estradiol for cytoplasmic estrogen receptor from rat uterus was similar to tamoxifen, the IC50 being 26 and 23 microM respectively. In immature intact rats the two compounds, administered orally for three consecutive days, had similar intrinsic partial estrogenic efficacy, at 50 mg/kg, about 40% of that of estradiol benzoate (EB). However, at doses less than or equal to 10 mg/kg, the estrogenic effect of toremifene was seen at doses about 40 times higher than that of tamoxifen. The two compounds, administered together with a standard dose of EB, expressed the same maximal antiestrogenic efficacy (about 65% inhibition) at 50 mg/kg. However, the minimal effective antiestrogenic dose of toremifene was about 10 times that of tamoxifen and the ratio between antiestrogenic/estrogenic properties was favourable to toremifene. The duration of the antiestrogenic (antiuterotrophic) effect of a single oral dose (10 mg/kg) of the two compounds proved similar: at least 4 days in intact rats and 3 days in ovariectomized rats. In DMBA-induced tumor bearing rats toremifene was administered p.o., 6 times/week for 4 weeks at 0.08, 0.4, 2, 10 and 50 mg/kg. It was effective at the doses of 2, 10 and 50 mg/kg, inducing 39, 35 and 46% tumor regressions. The activity of toremifene at the minimal effective dose of 2 mg/kg was then compared with that of tamoxifen given at the same dose level. The compounds had comparable activity (47 vs 44% tumor regressions).     

Reproductive performance of Coopworth ewes following oral doses of zearalenone before and after mating

The reproductive performance of Coopworth ewes after administration of zearalenone was determined in two trials. In Trial I, zearalenone was administered to groups of 33 ewes at rates of 0, 1.5, 3.0, 6.0, 12.0 and 24.0 mg/ewe/day for 10 days, starting on Day 7 of the oestrous cycle before mating. There was a linear decline (P less than 0.001) in ovulation rate with dose of zearalenone; also cycle length decreased and duration of oestrous increased with increasing dose levels. Reductions in the incidence of ovulation and in fertilization were seen only at doses of 12 and 24 mg. In Trial 2, groups of 50 ewes were given the same range of doses of zearalenone for 10 days, starting 5 days after mating to entire rams. There was no effect of zearalenone treatment after mating on pregnancy rate or embryonic loss. These results indicate that the effects of zearalenone, administered orally, on ewe reproduction, at the dose levels examined, were restricted to ewes exposed before mating. Intakes of zearalenone of 3 mg/ewe/day or more during this period would be reflected as depressed ovulation rates and lower lambing percentages.     

A case of hereditary persistence of fetal hemoglobin caused by a gene not linked to the β-globin cluster

Summary The pattern of inheritance of several polymorphic restriction sites associated with the -gene cluster, and spanning a region of 52 kb, demonstrates that a determinant for hereditary persistence of fetal hemoglobin (HPFH) segregates independently from the non- globin gene cluster, as we postulated several years ago on purely genetical grounds. This finding provides additional evidence for the existence of diffusible factors affecting -chain expression. Moreover, we have identified a private HinccII polymorphism, in the vicinity of the gene in the family studied.     

Molecular cloning of a gene encoding a Chlamydia psittaci 57-kDa protein that shares antigenic determinants with ca. 60-kDa proteins present in many Gram-negative bacteria

In order to develop reagents to study the immune response of guinea pigs to infection by Chlamydia psittaci guinea pig inclusion conjunctivitis strain (GPIC), we constructed a plasmid clone bank with C. psittaci DNA. One of the recombinant clones isolated produced large amounts of a 57-kilodalton (kDa) protein that was immunoreactive with sera from GPIC infected guinea pigs. While investigating this recombinant protein, we discovered that all the Gram-negative bacteria analyzed so far have immunoreactive proteins of similar size. This protein seems to be a 'common antigen' already described in various Gram-negative bacteria.     

Theoretical study of the acidic strength of amino acid side chains

The acidic strengths in gas phase of three groups (NH₄⁺, H₂S, and HCOOH) that mimic the most common amino acid side chains of enzymes are studied by means of quantum mechanical methods. The results demonstrate that in gas phase the acidities of such groups change drastically with respect to those reported in aqueous phase. Moreover, the dependence between the energetics of the proton-transfer process and the distance separating the acid and base groups is stated. The biological implications of these results are discussed.     

Effect of 17β-estradiol on calcium response to phytohaemagglutinin in human lymphocytes

Pre-treatment of human lymphocytes with 17-estradiol diminishes the increase in concentration of cytosolic free calcium after stimulation with phytohaemagglutinin. The effect is dependent on 17-estradiol concentration and on the preincubation time. The effect is not due to an interaction between 17-estradiol and phytohaemagglutinin, but appears to be a consequence of the binding of the hormone to the cell surface. The effect is specific for 17-estradiol, since the isomer and other steroid hormones (progesterone, testosterone, diethylstilbestrol and 5-androstan), have no effect. Since the effect of the 17-estradiol can be suppressed by treatment of lymphocytes with ouabain, it appears that the effect of estradiol on the rise of cytosolic calcium induced by phytohaemagglutinin is mediated by the (Na, K)-ATPase.     

Plasma catecholamines and their physiologic thresholds during the first ten days of life in sheep

We studied serial plasma catecholamine levels in healthy newborn sheep over the first ten days of life. The results show that plasma norepinephrine values in newborn sheep are 3-4 fold higher, and plasma epinephrine values are two-fold higher than values in term fetal sheep. These elevations are sustained over the first 10 days of life. Cardiovascular (heart rate and blood pressure) and metabolic parameters (glucose and free fatty acids) are also significantly elevated above fetal levels. We performed graded catecholamine infusions in newborn animals and adult ewes to determine the minimum plasma catecholamine concentrations necessary for discernible physiologic effects. In response to step-wise increases in epinephrine or norepinephrine infusion rates, there were immediate increases in blood pressure and other physiologic responses. This pattern was seen in both newborn and adult animals, and differed from previous observations in fetal sheep where log-linear, dose response curves characteristic of a threshold response were seen. These results suggest that during the first two weeks of life plasma catecholamine levels are elevated above the threshold value for physiologic responses. These sustained elevations in circulating catecholamines are important in the maintenance of physiologic homeostasis.