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PubMed1985

Distribution of 64Cu in foetal and adult tissues in mice: influence of sodium diethyldithiocarbamate treatment.

64Cu (as 64CuCl2) was given intravenously to male C57BL mice and to pregnant C57BL mice at various stages of gestation. The disposition of the 64Cu in the adult animals and in the foetuses was studied by autoradiography and gamma spectrometry. The effects of treatments with diethyldithiocarbamate (DEDTC) on the disposition of the 64Cu in the animals were also examined. In addition, the ability of Cu to affect chondrogenesis was studied in an embryonic limb bud culture system. The results showed a strong uptake of 64Cu in the liver of the adult animals at all intervals (5 min.-24 hrs). At short survival intervals, there was also an uptake in the kidney cortex, the gastrointestinal mucosa, the adrenal, the pancreas, and the erythrocytes. Exposure to Cu may cause liver and kidney injuries, which may be related to the strong accumulation in these organs. 64Cu passed the placenta to the foetuses at all stages of gestation, although this occurred at a relatively slow rate. Within the foetuses the highest concentrations were found in the liver. Cu was observed to be toxic in the chick limb bud mesenchymal spot culture system although at relatively high concentrations. Foetal malformations and embryotoxicity may therefore be interpreted as a result of direct action of Cu on embryonic structures, although placental and/or maternal influence cannot be excluded. Pre- or posttreatment of the animals with DEDTC, which is a chelating agent, caused a very marked increase in the concentration of 64Cu in most tissues of the adult animals and also an increased foetal uptake of the metal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Pharmacokinetics and therapeutic efficacy of rimantadine in horses experimentally infected with influenza virus A2.

OBJECTIVE: To determine pharmacokinetics of single and multiple doses of rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of rimantadine in influenza virus-infected horses. ANIMALS: 5 clinically normal horses and 8 horses seronegative to influenza A. PROCEDURE: Horses were given rimantadine (7 mg/kg of body weight, i.v., once; 15 mg/kg, p.o., once; 30 mg/kg, p.o., once; and 30 mg/kg, p.o., q 12 h for 4 days) to determine disposition kinetics. Efficacy in induced infections was determined in horses seronegative to influenza virus A2. Rimantadine was administered (30 mg/kg, p.o., q 12 h for 7 days) beginning 12 hours before challenge-exposure to the virus. RESULTS: Estimated mean peak plasma concentration of rimantadine after i.v. administration was 2.0 micrograms/ml, volume of distribution (mean +/- SD) at steady-state (Vdss) was 7.1 +/- 1.7 L/kg, plasma clearance after i.v. administration was 51 +/- 7 ml/min/kg, and beta-phase half-life was 2.0 +/- 0.4 hours. Oral administration of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after 3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma concentrations of 500 ng/ml with mean bioavailability (F) of 25%, beta-phase half-life of 2.2 +/- 0.3 hours, and clearance of 340 +/- 255 ml/min/kg. Multiple doses of rimantadine provided steady-state concentrations in plasma with peak and trough concentrations (mean +/- SEM) of 811 +/- 97 and 161 +/- 12 ng/ml, respectively. Rimantadine used prophylactically for induced influenza virus A2 infection was associated with significant decreases in rectal temperature and lung sounds. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of rimantadine to horses can safely ameliorate clinical signs of influenza virus infection.

Administration, Oral↗
PubMed1980

Trophoblastic and uterine luminal epithelial surfaces at the time of blastocyst adhesion in the rat.

Fixed uteri from rats on the afternoon of day 6 of pregnancy were split to expose the implantation chambers, their enclosed blastocysts, and the imprints of the blastocyst on the adjacent epithelium of the chamber. Some of the implantation chambers were prepared for scanning electron microscopy; other chambers were treated with colloidal iron hydroxide, with cationized ferritin, or with the tannic acid method, and subsequently were prepared for transmission electron microscopy. In this manner, the disposition of the surface-coat markers on the surface of the blastocysts, surface of the uterus within the chamber, and the surface of the uterus that had been apposed to a blastocyst were compared. Despite the pronounced morphological differences between the microvilli of the uterine luminal epithelium in the imprint and those in the rest of the chamber, the binding of the markers was remarkably similar. No evidence of removal of surface coat could be found in that area of the uterus in contact with the blastocyst. In addition, in two instances in the cationized ferritin-treated material, and in another instance in tannic acid-stained material, regions of the apparently adhering trophoblastic cell membranes and uterine cell membranes had abundant coat materials and, possibly, even secretory materials interposed. When blastocyst-sized glass beads were introduced into uteri from animals made pseudopregnant or unilaterally pregnant, the beads failed to elicit a decidual response and made an imprint that did not resemble the imprint of a blastocyst in an implantation chamber. It was concluded that, at least in the initial stages of adhesion, the blastocyst does not bring about a physical removal of the demonstrable aspects of the surface coat of the uterus. It was concluded further, that glass beads are not a suitable object for mimicking a blastocyst in the rat uterus.

Animals↗
PubMed1997

Assessment of the developmental toxicity, metabolism, and placental transfer of N,N-dimethylformamide administered to pregnant rats.

This study evaluates the developmental toxicity and placental and milk transfer of N,N-dimethylformamide (DMF) in rats. Sprague-Dawley rats were given 0, 50, 100, 200, and 300 mg DMF/kg/day, by gavage, on Gestational Days (GD) 6 through 20. Maternal toxicity was indicated by depressions in weight gain and food consumption at doses >/=100 mg/kg. Fetal toxicity was indicated by decreased fetal body weight at doses >/=100 mg/kg, and by increased incidences of two skeletal variations (absent or poorly ossified supraoccipital and sternebrae) at 200 and 300 mg/kg. Thus, the maternal and developmental no-observed-adverse-effect level was 50 mg/kg/day. The time course disposition of [14C]DMF was examined over a 48-hr period in GD12- and GD18-pregnant rats after a single oral dose of 100 mg [14C]DMF/kg. Peak concentrations of radiocarbon occurred within 1 hr after dosing. Embryonic (GD12) and fetal (GD18) tissues accounted for 0.15 and 6% of the administered dose, respectively. Levels of radiocarbon in embryonic and fetal tissues were equal or slightly less than in maternal plasma up to 8 and 24 hr, respectively, and higher thereafter. HPLC analysis performed at intervals from 1 to 8 hr on GD12 and 1-24 hr on GD18 indicated that unchanged DMF and metabolites were readily transferred to the embryonic and fetal tissues, where their levels were generally equal to those in maternal plasma. The parent compound accounted for most of the radioactivity until 4-8 hr and then decreased. N-Hydroxymethyl-N-methylformamide (HMMF) and N-methylformamide (NMF) were the predominent metabolites and increased with time. Much lower concentrations were found for formamide and N-acetyl-S-(N-methylcarbamoyl)cysteine. Transfer of radioactivity into milk was studied in dams given a single oral administration of 100 mg [14C]DMF on Lactation Day 14. DMF, HMMF, and NMF were found in the milk at concentrations equal to those in plasma.

Abnormalities, Drug-Induced↗
PubMed1994

Development of the excitation-contraction coupling apparatus in skeletal muscle: peripheral and internal calcium release units are formed sequentially.

The development of calcium release units and of transverse tubules has been studied in skeletal muscle fibres from embryonal and newborn chicken. Three constituents of calcium release units: the tetrads, the feet and an internal protein directly associated with junctional surface of the sarcoplasmic reticulum are visualized by various electron microscope techniques. Evidence in the literature indicates that the three components correspond to the voltage sensors, the sarcoplasmic reticulum calcium release channels and the calcium binding protein calsequestrin respectively. We recognize two stages at which important events in membrane morphogenesis occur. The first stage coincides with early myofibrillogenesis (starting at approximately embryonal day E5.5), and it involves the assembly of calcium release units at the periphery of the muscle fibre in which feet and the internal protein are identified. Groups of tetrads also are present at very early stages and their disposition indicates a relation to the feet of peripheral couplings. Thus three major components of the excitation-contraction coupling pathway are in place as soon as myofibrils develop. The density of groups of tetrads in the surface membrane of primary and secondary fibres is similar, despite differences in developmental stages. The second stage involves the formation of a complex transverse tubule network and of internal sarcoplasmic reticulum-transverse tubule junctions, while peripheral couplings disappear. This stage starts abruptly (between E15 and E16) and simultaneously in primary and secondary fibres. It coincides with the myotube-to-myofibre transition. The two stages are separated by a relatively long intervening period (between E9 and E16). During the latter part of this period some primitive transverse tubules appear, and form junctions with the sarcoplasmic reticulum, but they remain strictly located at the periphery of the fibre and are not numerous. Finally, after the second stage there is a prolonged (up to 4 weeks) period of maturation, during which density of free sarcoplasmic reticulum increases, triads acquire a location at the A-I junction and fibre type differences appear. We conclude that a system for calcium uptake, storage and release exists at the periphery of the myotube during early myogenesis. The complexity of the system and its ability to deliver calcium through the entire fibre develop in parallel to the formation of myofibrils.

Animals↗
PubMed1995

Molecular architecture of membranes involved in excitation-contraction coupling of cardiac muscle.

Peripheral couplings are junctions between the sarcoplasmic reticulum (SR) and the surface membrane (SM). Feet occupy the SR/SM junctional gap and are identified as the SR calcium release channels, or ryanodine receptors (RyRs). In cardiac muscle, the activation of RyRs during excitation-contraction (e-c) coupling is initiated by surface membrane depolarization, followed by the opening of surface membrane calcium channels, the dihydropyridine receptors (DHPRs). We have studied the disposition of DHPRs and RyRs, and the structure of peripheral couplings in chick myocardium, a muscle that has no transverse tubules. Immunolabeling shows colocalization of RyRs and DHPRs in clusters at the fiber's periphery. The positions of DHPR and RyR clusters change coincidentally during development. Freeze-fracture of the surface membrane reveals the presence of domains (junctional domains) occupied by clusters of large particles. Junctional domains in the surface membrane and arrays of feet in the junctional gap have similar sizes and corresponding positions during development, suggesting that both are components of peripheral couplings. As opposed to skeletal muscle, membrane particles in junctional domains of cardiac muscle do not form tetrads. Thus, despite their proximity to the feet, they do not appear to be specifically associated with them. Two observations establish the identify of the structurally identified feet arrays/junctional domain complexes with the immunocytochemically defined RyRs/DHPRs coclusters: the concomitant changes during development and the identification of feet as the cytoplasmic domains of RyRs. We suggest that the large particles in junctional domains of the surface membrane represent DHPRs. These observations have two important functional consequences. First, the apposition of DHPRs and RyRs indicates that most of the inward calcium current flows into the restricted space where feet are located. Secondly, contrary to skeletal muscle, presumptive DHPRs do not show a specific association with the feet, which is consistent with a less direct role of charge movement in cardiac than in skeletal e-c coupling.

Animals↗
PubMed1990

Differences in the modulation of P450IA1 and epoxide hydratase expression by benz[a]anthracene and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse embryo versus mouse hepatoma-derived cell lines.

Polycyclic aromatic hydrocarbon (PAH)-induced C3H/10-T1/2/CL8 mouse embryo fibroblasts (10T1/2) and mouse hepatoma-derived Hepa 1c1c7 cells (Hepa-1), exhibit comparable total cytochrome P450 levels and total PAH-metabolizing activities but very different distributions of PAH metabolites. Based on anti-P450IA1-IgG inhibition data, P450IA1 contributes essentially all PAH metabolism in Hepa-1 microsomes but is not involved in PAH metabolism by 10T1/2 cells. In addition, the microsomal epoxide hydratase (EHm) in Hepa-1 cells is far less effective in dihydrodiol (diol) formation compared to that in 10T1/2 microsomes [Pottenger, L.H. and Jefcoate, C.R. Carcinogenesis, 11, 321-327 (1990)]. In the present study, the levels of expression of P450IA1 and EHm proteins and the corresponding mRNAs, both prior to and following exposure to benz[a]anthracene (BA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have been correlated with microsomal PAH metabolism by each cell type. In 10T1/2 cells, P450IA1 protein (56 kd) and mRNA (2.6 kb) were detectable at extremely low levels in only two of five cell preparations and then only after maximum induction by TCDD and BA. Thus although 10T1/2 cells contain functional Ah receptors, their capacity to induce P450IA1 is highly suppressed, representing at most 2% of the total P450. TCDD (10 nM) was 4-fold more effective than BA (10 microM) in inducing P450IA1 mRNA, while the levels of immunodetectable protein were comparable. An even greater discrepancy between P450IA1 mRNA and protein levels was seen in BA-induced Hepa-1 cells, where a 4-fold increase in mRNA was paralleled by a 20-fold increase in protein. This difference is probably due to the greater effect of BA depletion on mRNA compared to protein levels. In 10T1/2 cells, BA and TCDD were equally effective at increasing expression of an unidentified 1.9 kb mRNA sequence that blotted very weakly with the P450IA1 cDNA probe. The expression of this mRNA was independent from that of P450IA1. A similar band was visible in Hepa-1 cells less than 1% of the P450IA1 mRNA. EHm mRNA was almost 3-fold higher in 10T1/2 compared to Hepa-1 cells and was unaffected by cell treatments. In Hepa-1 cells, BA and TCDD elevated EHm protein and hydrating activity to levels comparable to those expressed in 10T1/2 cells. It is, therefore, suggested that the relative ineffectiveness of Hepa-1, compared to 10T1/2 EHm, to hydrate low levels of PAH-epoxides is due to differences between the two proteins or their disposition in the microsomal membrane.

Animals↗
PubMed1997

The values of life.

In Life's Dominion Dworkin aims at defusing the controversy about abortion and euthanasia by redefining its terms. Basically it is not a dispute about the right to life, but about its value. Liberals should grant that human life has not only a personal, but also an intrinsic value; conservatives should accept the principle of toleration which requires to let people decide for themselves about matters of intrinsic value. Dworkin fails, however, to distinguish between two kinds of personal value: (1) the value of something to a person, when he actually or dispositionally desires it, or finds it pleasant; and (2) the value of something to a person, when it's objectively contributes to his well-being, as defined by reference to his personal point of view, whether or not he ever perceives it as so contributing. He also fails to distinguish between two meanings of the concept of 'intrinsic value': (3) ultimate, i.e. non-instrumental personal value of kind (2); (4) the impersonal value of something which is not good-for-anybody, but simply good, i.e. not a constituent of someone's well-being. Dworkin argues that the human fetus from conception onwards has a value, that it is not a personal value of kind (1), and therefore must be an intrinsic value. But the value of the life of the fetus is not a personal value of kind (2) either and therefore not an intrinsic value of kind (3): it is normally a constituent of the well-being of the pregnant woman, but that doesn't constitute its value, and it is not good 'for' the fetus itself in the relevant sense, because it doesn't have a personal point of view. If, however, the fetus' life is allowed to have an intrinsic value of kind (4), the conservative cannot be refuted by appeal to the principle of toleration, for this only concerns intrinsic value of kind (3). The liberal, indeed, should recognize that the fetus' life has a value, but it is neither a personal value (1) or (2), nor an impersonal value (4), but rather a relational value which gradually develops from some point substantially later than conception.

Abortion, Induced↗
PubMed1982

Immunoelectron microscopic studies of the sites of cell-substratum and cell-cell contacts in cultured fibroblasts.

Our object was to obtain information about the molecular structures present at cell-substratum and cell-cell contact sites formed by cultured fibroblasts. We have carried out double immunoelectron-microscopic labeling experiments on ultrathin frozen sections cut through such contact sites to determine the absolute and relative dispositions of the three proteins fibronectin, vinculin, and alpha-actinin with respect to these sites. (a) Three types of cell-substratum and cell-cell contact sites familiar from plastic sections could also be discriminated in the frozen sections by morphological criteria alone, i.e., the gap distances between the two surfaces, and the presence of submembranous densities. These types were: (i) focal adhesions (FA); (ii) close contacts (CC); and (iii) extracellular matrix contacts (ECM). This morphological typing of the contact sites allowed us to recognize and assign distinctive immunolabeling patterns for the three proteins to each type of site on the frozen sections. (b) FA sites were immunolabeled intracellularly for vinculin and alpha-actinin, with vinculin labeling situated closer to the membrane than alpha-actinin. Fibronectin was not labeled in the narrow gap between the cell surface and the substratum, or between two cells, at FA sites. Control experiments showed that this could not be ascribed to inaccessibility of the FA narrow gap to the immunolabeling reagents but indicated an absence or severe depletion of fibronectin from these sites. (c) CC sites were labeled intracellularly for alpha-actinin but not vinculin and were labeled extracellularly for fibronectin. (d) ECM sites were characterized by large separations (often greater than 100 nm) between the cell and substratum or between two cells, which were connected by long cables of extracellular matrix components, including fibronectin. In late (24-36 h) cultures, ECM contacts predominated over the other types. ECM sites appeared to be of two kinds, one labeled intracellularly for both alpha-actinin and vinculin, the other for alpha-actinin alone. (e) From these and other results, a coherent but tentative scheme is proposed for the molecular ultrastructure of these contacts sites, and specific functional roles are suggested for fibronectin, vinculin, and alpha-actinin in cell adhesion and in the linkage of intracellular microfilaments to membranes at the different types of contact sites.

Actinin↗