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PubMed1990

Sodium channel blockers: the size/solubility hypothesis revisited.

The influence that drug size has on the rate of recovery of sodium channels in heart tissue has been reexamined. A drug dimension that looks at the end-on view of the molecule provides a substantially better explanation for the size dependence of repriming kinetics than does molecular weight. A quantitative model for the recovery time is provided that couples proton exchange kinetics with a drug size-dependent process that is related to recovery from inactivation. Drugs having a wider span at their aromatic end produce more slowing of the rate of recovery from inactivation.

Adrenergic beta-Antagonists↗
PubMed1990

Antimyoclonic effect of MK-801: a possible role for NMDA receptors in developmental myoclonus of the neonatal rat.

Rat pups exhibit transient "developmental dyskinesias," such as tremor and myoclonus, that are analogous to motor immaturities of the human neonate. Myoclonic jerks in the neonatal rat may reflect a developmental imbalance of excitatory and inhibitory neurotransmission. To test this hypothesis, spontaneous myoclonic jerks of naive rat pups (n = 200) were characterized behaviorally and pharmacologically. The frequency of myoclonus was high (154 +/- 14 jerks/30 min) in the first week. The distribution of jerks included limbs (47%) (27% in forelimbs and 20% in hindlimbs), tail (30%), trunk (12%), and head (11%). Myoclonus constituted the predominant neonatal adventitious movement (81%). Myoclonic jerks were variable in intensity, focal and multi-focal more often than generalized, and occurred when nonrespiratory movements were infrequent or absent, suggesting sleep. Myoclonic frequency significantly diminished after the second week; therefore, drug effects were studied in the first 7 days. Systemic injection of the novel noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocked neonatal myoclonus in a dose-dependent manner (ID50 = 0.67 mg/kg; r = 0.93). The nonselective excitatory amino acid (EAA) receptor antagonist kynurenic acid was ineffective. The EAA antagonist AP4 (1 and 10 mg/kg) also reduced myoclonic jerks, but other drugs, such as the selective glycine antagonist Iso-THAO (1 and 10 mg/kg), strychnine (0.5 mg/kg), clonazepam, and diazepam (1 mg/kg), were ineffective blockers. The putative agonists quisqualic acid (1-50 mg/kg) and NMDA (1-10 mg/kg) altered myoclonus only at behaviorally toxic doses. These data suggest that EAA receptors participate in developmental myoclonus of the neonatal rat and that development myoclonus may be a useful quantitative model of functional maturity of excitatory/inhibitory synapses. The efficacy of MK-801 also should be evaluated in drug- and lesion-induced myoclonus. Recognition of the high frequency and state dependence of spontaneous myoclonic jerks in neonatal rats may be important to neonatal antiepileptic drug studies.

Aminobutyrates↗
PubMed1990

Interferon-alpha and 3'-azido-3'-deoxythymidine are highly synergistic in mice and prevent viremia after acute retrovirus exposure.

This study was undertaken to calculate the in vivo drug interactions between recombinant human interferon-alpha A/D (rHuIFN-alpha A/D) and 3'-azido-3'-deoxythymidine (AZT) in a quantitative model for retroviral viremia. When given as single agents, both AZT and rHuIFN-alpha A/D suppressed virus-induced splenomegaly in a dose-dependent fashion in mice inoculated with Rauscher murine leukemia virus (RLV). However, suppressive doses of single-agent AZT caused anemia after 20 days of therapy. Combining rHuIFN-alpha A/D with AZT allowed drastic dose reductions for each agent while maintaining greater than or equal to 93% inhibition of splenomegaly. No clinically significant toxicity was seen. Computer analysis with the isobologram technique and combination index method showed that these combination regimens were highly synergistic. A 20-day course of AZT + rHuIFN-alpha A/D started 4 h after virus exposure was protective against RLV viremia and disease. After cessation of therapy, the animals were resistant to rechallenge with fully infectious RLV. We conclude that prompt initiation of effective combination therapy after retroviral exposure prevented viremia and disease and led to protective immunity.

Animals↗
PubMed1990

Incorporating dose-rate effects in Markov radiation cell survival models.

Markov models for the survival of cells subjected to ionizing radiation take stochastic fluctuations into account more systematically than do non-Markov counterparts. Albright's Markov RMR (repair-misrepair) model (Radiat. Res. 118, 1-20, 1989) and Curtis's Markov LPL (lethal-potentially lethal) model [in Quantitative Mathematical Models in Radiation Biology (J. Kiefer, Ed.), pp. 127-146. Springer, New York, 1989], which assume acute irradiation, are here generalized to finite dose rates. Instead of treating irradiation as an instantaneous event we introduce an irradiation period T and analyze processes during the interval T as well as afterward. Albright's RMR transition matrix is used throughout for computing the time development of repair and misrepair. During irradiation an additional matrix is added to describe the evolving radiation damage. Albright's and Curtis's Markov models are recovered as limiting cases by taking T----0 with total dose fixed; the opposite limit, of low dose rates, is also analyzed. Deviations from Poisson behavior in the statistical distributions of lesions are calculated. Other continuous-time Markov chain models ("compartmental models") are discussed briefly, for example, models which incorporate cell proliferation and saturable repair models. It is found that for low dose rates the Markov RMR and LPL models give lower survivals compared to the original non-Markov versions. For acute irradiation and high doses, the Markov models predict higher survivals. In general, theoretical extrapolations which neglect some random fluctuations have a systematic bias toward overoptimism when damage to irradiated tumors is compared with damage to surrounding tissues.

Cell Survival↗
PubMed1990

Identification of peripheral visual images in a laterally restricted gaze field.

When the peripheral visual field is restricted or distorted, as occurs with certain spectacle lenses, the identification of objects in the periphery requires a coordinated head and eye movement. Initial experiments on the identification of peripheral images under such restrictions show that the degradation in performance is defined by a consistent additional delay in the time required to identify the image correctly. An analysis of the motor movements shows that performance is solely determined by movements of the head; eye movements are sufficiently precise and fast so they do not limit performance. A quantitative model of the identification task was developed and model simulations confirmed the experimental findings that head movement variables, specifically response latency and movement duration, uniquely determine identification performance. Hence, improved performance under these conditions must come from modifications in head-movement control either through training or adaptive processes.

Adult↗
PubMed1990

Heterogeneity of high-affinity nicotinic [3H]acetylcholine binding sites.

Studies were conducted on high-affinity, nicotinic binding of 3H-labeled acetylcholine ([3H]ACh) to membrane preparations derived from the TE671 human clonal line and the PC12 rat pheochromocytoma. For comparative purposes and to extend results obtained by others in previous studies, [3H]ACh binding to membrane preparations derived from rat brain and from the electric tissue of Torpedo californica also was characterized. In each case, specific [3H]ACh binding (KD values of about 10 nM) could be fit by linear Scatchard and logit-log curves (slope of the latter of about 1.0) indicating that binding occurred to a single class of noninteracting sites, except that a better fit to PC12 cell membrane binding data was obtained using a two-site model. Quantitation of high-affinity binding sites for [3H]ACh and radiolabeled alpha-bungarotoxin and studies of unlabeled toxin competition for [3H]ACh binding indicated that toxin and agonist sites on TE671 cell or Torpedo membranes were closely related, but that toxin and agonist sites had limited or no physical overlap on PC12 cell or rat brain membranes. Generally, drugs of the bisonium and bis-choline series were more effective inhibitors of [3H]ACh binding to TE671 cell or Torpedo membranes, but nicotine and cytisine interacted with PC12 cell or rat brain sites with highest affinity. These results suggest that nicotinic agonists bind with high affinity to specific, membrane-bound sites on presumptive nicotinic ACh receptors expressed on each of these preparations. Moreover, the data are consistent with structural heterogeneity of these nicotinic receptor sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1985

The influence of locally administered ultraviolet light (UVB) on the allergic contact dermatitis in the mouse.

A quantitative model of contact allergy to picryl chloride in the mouse was used to evaluate the influence of locally administered ultraviolet light (UVB) on sensitization and challenge. UVB was given in three different doses immediately before and 24 h before sensitization and challenge, respectively. A suppressive effect was demonstrated on the afferent as well as on the efferent limb of the allergic reaction.

Animals↗
PubMed1986

Decreased anionic sites in Bruch's membrane of spontaneous and drug-induced diabetes.

The basal laminae of capillaries, glomeruli, and nerves are thickened in diabetes. Previous studies have shown that diabetic tissues produce increased levels of basal lamina collagen and reduced levels of proteoglycans. Since heparan sulfate and chondroitin sulfate proteoglycans are thought to act as anionic barriers regulating passage of proteins across Bruch's membrane of the eye, the cationic electron microscope tracers, polyethyleneimine (PEI) and ruthenium red, were used to study the distribution of anionic sites in Bruch's membrane of spontaneously diabetic Bio-Breeding/Worcester (BB-W) rats and streptozotocin-diabetic rats. The distribution of the two tracers is similar. In Bruch's membrane of control rats, electron dense particles are present at regular intervals along both sides of the basal laminae of the retinal pigment epithelium (RPE) and of the choriocapillary endothelium (CE), and along collagen fibers in the zone between the two basal laminae. Within 3-6 months after the onset of hyperglycemia in both diabetic rat models, quantitative analysis shows a significant reduction in binding sites along both RPE and CE basal laminae, while thickness of both basal laminae is significantly increased. Because reductions in anionic binding sites along basal laminae in the renal glomerulus have been found to accompany changes in glomerular filtration, these changes suggest that filtration through Bruch's membrane is altered in diabetes.

Animals↗
PubMed1989

[Operations research in group feeding programs: techniques for the identification and analysis of management problems].

The operations of the group feeding programs (PAG--"Programas de Alimentación a Grupos"--) can be viewed as a sequence of decisions and activities that according to their direction, order, relationship and dependency, will influence the quality and quantity of the service's delivery. While searching for the essential characteristics of a PAG: components, relationship, variables, pertinent parameters, restrictions, underlying criteria and objective functions, operations research can be useful for its analysis, the identification of its management problems, and to develop, evaluate and finally, implement solutions. Various operation research techniques are presented in this article, which are geared towards responding to those knowledge needs of the national technicians and program managers, in order to give a solid foundation to solutions for the management problems identified in a PAG. Failures of different quantitative models had been due, mainly, to the tendency to formulate models or investigate problems without users being prepared to implement the solutions. The techniques presented herein take into consideration the interaction between specialists and users.

Food Services↗
PubMed1989

[Effect of the Ca ionophore A-23187 on the plasmatic and mitochondrial potentials of the brain synaptosomes in rats: fluorescence measurements].

The applicability of the potential-sensitive dye diS-C3-(5) for the study of A23187 + Ca2+ induced plasma membrane hyperpolarization was tested in rat brain synaptosomes. An appropriate dye synaptosome ratio was chosen for the fluorescence titration dye in Ca-free Krebs-Ringer solution. The fluorescence intensity of the probe was increased upon the addition of Ca2+ (1 microM) to the synaptosomes in the presence of A23187 (1 microM). The effect of Ca2+ + A23187 persisted in a Na+-free medium or when Na+ channels were inhibited by tetrodotoxin as well as in high K+-depolarized synaptosomes (75 microM KCl). In the presence of oligomycin or a protonophore (1 microM) the effect of Ca2+ + A23187 was suppressed. This suggests that the A23187-induced fluorescence increase is due to a depolarization of intrasynaptosomal mitochondria. Therefore, the use of the dye diS-C3-(5) for the study of Ca-induced hyperpolarization does not seem to be feasible unless a quantitative model of changes in fluorescence related to the plasma and mitochondrial membrane potentials is elaborated.

Animals↗
PubMed1989

Cardiac pathology in the hypertensive diabetic rat. Biventricular damage with right ventricular predominance.

The hypertensive-diabetic rat is a new small animal model of cardiomyopathy characterized by ventricular damage. To determine the extent of pathology in this model, quantitation of light microscopic changes in hearts from 15 hypertensive-diabetic rats and 15 age-matched controls was performed. The fraction of myocardium involved by interstitial fibrosis, myocyte necrosis, replacement fibrosis, vascular sclerosis and perivascular fibrosis was computed separately for right and left ventricles. Spontaneously dying as well as deliberately killed hypertensive-diabetic rats were studied. Spontaneously dying animals had higher systolic blood pressures compared with rats killed deliberately. Body weights were lower and lung weights higher in the former group. Left and right ventricular necrosis and fibrosis were increased in spontaneously dying compared with deliberately killed rats. The degree of right ventricular necrosis and fibrosis paralleled that in the left ventricle, but was, unexpectedly, several times greater in magnitude. Thus, quantitative histology in the hypertensive-diabetic rat reveals more cardiac necrosis and fibrosis, in either ventricle, from spontaneously dying animals compared with deliberately killed rats. This damage, coupled with major functional alterations in the viable myocardium, may lead to congestive heart failure or arrhythmia.

Animals↗
PubMed1989

Nitric oxide and nitrous oxide production and cycling during dissimilatory nitrite reduction by Pseudomonas perfectomarina.

The denitrifier Pseudomonas perfectomarina reduced nitrite under conditions of kinetic competition between cells and gas sparging for extracellular dissolved nitric and nitrous oxides, NOaq and N2Oaq, in a chemically defined marine medium. Time courses of nitrite reduction and NOg and N2Og alpha removal were integrated to give NOg and N2Og yields. At high sparging rates, the NOg yield was greater than 50% of nitrite-N reduced, and the yield of NOg + N2Og was approximately 75%. Hence interrupted denitrification yields NOaq and N2Oaq as major products. The yields varied with sparging rates in agreement with a quantitative model of denitrification (Betlach, M. P., and Tiedje, J.M. (1981) Appl. Environ. Microbiol. 42, 1074-1084) that applies simplified Michaelis-Menten kinetics to NO2-----NOaq----N2Oaq----N2. The fit gave an estimate of the maximum scavengeable NOaq yield of 73 +/- 8% of nitrite-N. Thus a minor path independent of NOaq is also required. The fit of the model to data at lower sparging rates, where normal denitrification products predominate, implies that the extracellular NOaq pool yield is independent of gas sparging rate. Thus in P. perfectomarina NOaq and N2Oaq are intermediates, or facilely equilibrate with true intermediates, during complete denitrification. The recovery of most nitrite-N as NO and/or N2O under perturbed conditions is not an artifact of irreversible product removal, but an attribute of denitrification in this species, and most probably it is characteristic of denitrification in other species as well.

Kinetics↗
PubMed1988

Comparison of L-[1-11C]methionine and L-methyl-[11C]methionine for measuring in vivo protein synthesis rates with PET.

To evaluate the feasibility of using either L-[1-11C]-methionine or L-[methyl-11C]methionine for measuring protein synthesis rates by positron emission tomography (PET) in normal and neoplastic tissues, distribution and metabolic studies with 14C- and 11C-labeled methionines were carried out in rats bearing Walker 256 carcinosarcoma. The tissue distributions of the two 14C-labeled methionines were similar except for liver tissue. Similar distribution patterns were observed in vivo by PET using 11C-labeled methionines. The highest 14C incorporation rate into the protein-bound fraction was found in the liver followed by tumor, brain, and pancreas. The incorporation rates in liver and pancreas were different for the two methionines. By chloroform-methanol fractionation of these four tissues, in liver significantly different amounts of 14C were observed in macromolecules. Also in brain tissue slight differences were found. By HPLC analyses of the protein-free fractions of plasma, tumor, and brain tissue at 60 min after injection, for both methionines several 14C-labeled metabolites in different amounts, were detected. About half of the 14C-labeled material in the protein-free fraction was found to be methionine. In these three tissues the amount of nonprotein metabolites and [14C]bicarbonate amount ranged from 10% to 17% and 12% to 15% for L-[1-14C]methionine and L-[methyl-14C]methionine, respectively. From these results it can be concluded that the minor metabolic pathways have to be investigated in order to quantitatively model the protein synthesis by PET.

Animals↗
PubMed1987

Different binding forms of cadmium--implications for distribution and toxicity.

Our present understanding of mechanisms for induction of renal tubular damage by cadmium is summarized in Fig 1: Cadmium is taken up from various exposure routes into plasma where it is initially bound to albumin. Such cadmium is mainly taken up by the liver where it induces the synthesis of metallothionein, which is mainly kept intracellularly, but a small proportion escapes into blood plasma. Cadmium bound to metallothionein in plasma is quickly transported to the kidney tubule by glomerular filtration and subsequent uptake by pinocytosis into renal lysosomes. Uptake of cadmium bound to low mol. wt protein from hemolyzed blood cells may also contribute to cadmium accumulation in the renal tubule. Cadmium is released from metallothionein in the renal lysosomes, where proteins are catabolized. Non-metallothionein bound cadmium may then interact with sensitive sites in the renal cell and cause renal tubular damage. There is an internal synthesis of metallothionein in the renal cells and a balance is thus formed between metallothionein bound cadmium and non-metallothionein bound cadmium. Only in such situations when non-metallothionein bound cadmium reaches a sufficient concentration does the renal damage appear. This scheme has been based mainly on observations in animals and cellular systems. It is probable that similar conditions occur in humans; however, the amount of human evidence available to quantify the different pathways is limited. Nevertheless, based on several assumptions, a quantitative model has been designed for humans concerning relationships between exposure and development of renal damage. Available data have been summarized in two chapters of a recent publication (Nordberg et al 1985, Kjellström and Nordberg 1985). Much more data on humans would be desirable to make this kind of extrapolation with confidence.

Air↗
PubMed1987

The mechanisms of ATP hydrolysis accompanying the polymerization of Mg-actin and Ca-actin.

The hydrolysis of ATP that accompanies actin polymerization occurs on the F-actin subsequent to the elongation step. For Mg-actin, the rate of ATP hydrolysis is similar to the rate of elongation at low concentrations of G-actin but increases more slowly as the G-actin concentration is increased. This behavior can be quantitatively modeled by assuming that ATP hydrolysis occurs predominantly, but not exclusively, on a single subunit of Mg-F-actin at the interface between an ATP-subunit cap and an ADP-subunit core. The rates of elongation of Ca-actin and Mg-actin are similar but the rate of ATP hydrolysis on Ca-F-actin is appreciably slower than the rate of elongation at all concentrations of Ca-G-actin. The data for Ca-actin can be modeled by assuming that ATP hydrolysis occurs essentially randomly on Ca-F-actin within a large ATP cap which can be as long as 2,000 subunits in a 10,000-subunit long filament.

4-Chloro-7-nitrobenzofurazan↗
PubMed1986

Health assessment of exposure to developmental toxicants.

The U.S. EPA has taken an important step in developing these guidelines, the first of their kind. They more precisely delineate the hazard identification process and the factors important in supporting risk decisions for developmental toxicants than does any other document. Unfortunately, however, more precise estimates of risk are hampered by our lack of understanding of a number of factors, including the biological mechanisms underlying developmental toxicity, intra/interspecies differences, the influence of maternal effects on the dose-response curve, the likelihood of thresholds for certain of these end points, and the appropriate quantitative models for dose-response data and for low-dose extrapolation. To this extent, the Agency is supporting and conducting a number of investigations which will hopefully further our knowledge and improve our ability to assess risks for the developing human. The guidelines will be updated as such information becomes available.

Animals↗
PubMed1986

Decision making in laboratory test studies.

Evaluation of laboratory tests can be made at multiple levels. Evaluation at the levels of operational and decision making usefulness may be the most important but most neglected areas of analysis. Although quantitative models for such analysis are available, their application is often hindered by lack of precise probability measurements, unavailability of sensitivity and specificity data, and a poor understanding of the decision making process by physicians. A general understanding of such models and their mathematic principles have been presented with the hope that this will improve the diagnostic usefulness and application of the laboratory tests to be discussed in the remainder of this volume.

Clinical Laboratory Techniques↗
PubMed1985

Development of the lateral line system in Xenopus laevis. III. Development of the supraorbital system in triploid embryos and larvae.

During normal development of the supraorbital lateral line system of Xenopus, an elongated streak of primordial cells becomes subdivided into a linear series of cell groups containing only about eight cells each, thus forming a row of primary lateral line organs (Winklbauer & Hausen, 1983a,b). In triploid Xenopus embryos, cell size is 1.5 X normal. When the formation of lateral line organs occurs in triploid primordia, the nascent organs contain only about five or six cells each, i.e. about two thirds of normal. Thus, the increase in cell size is compensated for by a corresponding reduction in cell number, keeping constant the organ size in terms of total cell mass or volume. This result excludes a cell counting mechanism for determining organ size. In diploids, the primary organs, although being of equal size initially, differ vastly in their final size and exhibit a peculiar frequency distribution of organ sizes. A detailed quantitative model for supraorbital lateral line development has been proposed, which accounts for this characteristic frequency distribution (Winklbauer & Hausen, 1983b). This model makes precise predictions as to the frequency distribution of the final size of triploid lateral line organs, where the initial organ size is reduced to five or six cells. These predictions were verified experimentally.

Animals↗