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Biomedical subjects

D A Smith

Publications and source records attributed to D A Smith.

At least 343 records · Page 19Linked to original sources
PubMed1983

Immunocytochemical characterization of cloned cells from normal adult rat brain.

A cell clone, isolated from normal adult rat brain and maintained in culture for many passages, has been previously characterized by electron microscopy. Immunohistochemistry has now been shown that it possesses glutamine synthetase (GS) which supports its astrocytic origin. Cells failed, however, to express glial fibrillary acidic protein (GFAP) but did express the intermediate filament protein vimentin. The presence of fibronectin confirms the normal derivation of these cells and excludes the possibility of malignant transformation.

Animals↗
PubMed1983

A gene controlling condensation of heterochromatin in Drosophila melanogaster.

A temperature-sensitive lethal mutant of Drosophila melanogaster was used to identify an essential cell cycle function that is necessary for the mitotic condensation of heterochromatic but not of euchromatic portions of the genome. This mutant is an allele at a locus (mus-101) identified earlier by the use of mutagen-sensitive mutants. The data suggest that the mutagen-sensitive and repair-defective phenotypes of viable mus-101 mutants result from a disruption in chromosome organization.

Animals↗
PubMed1983

A case of combined Pick's disease and Alzheimer's disease.

The diagnosis of combined Pick's and Alzheimer's disease is rare, and over the years different authors have used different criteria to arrive at such a diagnosis. A case is reported of presenile dementia in which the histological changes of Pick's disease and Alzheimer's disease were mingled. The brain showed no focal atrophy, but the Pick changes were most numerous in the hippocampus and in the temporal lobe. An antibody against the 155 kilodalton component of neurofilaments demonstrated not only neurofibrillary tangles and components of senile plaques, but also Pick's inclusions.

Alzheimer Disease↗
PubMed1983

Four cases of Hodgkin's disease in striped skunks (Mephitis mephitis).

Twelve of 152 striped skunks (Mephitis mephitis) necropsied at the Ontario Veterinary College between 1970 and 1980 had neoplasms. Tumors occurred in one of 86 wild skunks, and 11 of 66 captive skunks. Captive skunks were primarily from one source and were older animals. Tumors in four skunks resembled those found in Hodgkin's disease of man. This diagnosis was based on the presence of Sternberg-Reed cells, the cellular pattern, and the malignant behavior of the neoplasms. In two of these skunks, a second neoplasm also was present. Other tumors diagnosed included pulmonary adenocarcinoma, pulmonary adenomatosis, undifferentiated adenocarcinoma, renal adenocarcinoma, thyroid adenoma, interstitial cell tumor, pheochromocytoma, pinealoma, squamous cell carcinoma, and spindle cell sarcoma.

Animal Diseases↗
PubMed1982

Afferent connections to the bed nucleus of the stria terminalis.

A systematic analysis of the distribution of cells containing horseradish peroxidase (HRP) end-product following HRP injections in the bed nucleus of the stria terminalis (BNST) revealed a topographic distribution of input from the amygdala. The appearance of HRP cells in the medial amygdaloid nucleus was associated with HRP injections in all parts of the amygdala except its most lateral portion. Injections of HRP confined to the anterolateral portion of the BNST resulted in extensive HRP labeling of cells in the basolateral amygdala, the central nucleus, and the amygdala hippocampal area. Labeling of the amygdala hippocampal area was also associated with HRP injections in the caudodorsal BNST or the supracommissural portion of the stria terminalis. Injections that labeled the commissural division of the stria terminalis produced labeling of cells in the anterior basolateral amygdala and in the nucleus of the lateral olfactory tract. The cortical and basomedial amygdaloid nuclei appear to project only weakly to the BNST. Several other regions that provide afferents to the BNST are described although their input is minor relative to that of the amygdala.

Afferent Pathways↗
PubMed1982

Conformational aspects of the actions of some piperidine dicarboxylic acids at excitatory amino acid receptors in the mammalian and amphibian spinal cord.

A series of piperidine dicarboxylates (PDA) has been tested for excitatory amino acid agonist and antagonist activity and for synaptic depressant properties of the spinal cords of frogs and immature rats in vitro and of cats in vivo. The substances tested comprised (+/-)-cis-2,3-PDA, (+/-)-cis-2,4-PDA, (+/-)-cis-2,5-PDA, (+/-)-cis-2,6-PDA, (+/-)-trans-2,3-PDA, (+/-)-trans-2,4-PDA and both (+) and (-) forms of cis-2,3-PDA. Peak excitatory amino acid agonist activity was observed with (+/-)-trans-2,3- and (+/-)-trans-2,4-PDA. Excitatory amino acid antagonism and synaptic depressant activity was observed only with cis-dicarboxylates, this activity being greatest in the 2,3-analogue. The agonist actions of piperidine dicarboxylates were effectively depressed by the specific NMDA receptor antagonist, (-)-2-amino-5-phosphonovalerate and, where tested, also by D-alpha-aminoadipate and low concentrations of Mg2+. It was concluded that the major part of these agonist actions were mediated by NMDA receptors. The main structural feature of the NMDA agonist actions of these substances was considered to be their close relationship to N-alkyl-aspartic and glutamic acid molecules, with the trans arrangement of the respective 2,3- and 2,4-situated carboxyl groups promoting most effective interaction with the active sites of the NMDA receptor. (+/-)-Cis-2,3-PDA depressed excitatory responses induced by NMDA, kainate, quisqualate, (+/-)-trans-2,3-PDA and (+/-)-trans-2,4-PDA, or evoked by dorsal root stimulation. Both monosynaptic and polysynaptic excitation were susceptible to the depressant action of this substance. The (-) isomer of cis-2,3-PDA carried both excitatory amino acid agonist and antagonist activity and also the synaptic depressant properties observed with the racemic form of this substance. The (+) isomer showed little pharmacological activity. It is proposed that the structure-activity features of these heterocyclic amino acids indicate some of the conformational requirements for interaction with physiological excitatory amino acid receptors.

Animals↗
PubMed1982

Effect of urethane on synaptic and amino acid-induced excitation in isolated spinal cord preparations.

Urethane (50 mM) produced a non-selective antagonism of depolarizations evoked by excitant amino acids or carbachol recorded from ventral roots of isolated spinal cord preparations of the frog or immature rat. Depolarizing responses to substance P or eledoisin-related-peptide were either unaffected or potentiated by this concentration of urethane. The threshold level for depression of dorsal to ventral root transmission was 10 mM urethane and transmission was completely blocked at 70-100 mM urethane. It is suggested that post-junctional blockade of the actions of excitant amino acids may be important in the anaesthetic action of urethane.

Animals↗
PubMed1982

Differential activation and blockade of excitatory amino acid receptors in the mammalian and amphibian central nervous systems.

1. Experiments were conducted in vitro on isolated spinal cords of frogs and immature rats and in vivo on cat spinal neurones. 2. The concept of two major types of excitatory amino acid receptors present in these preparations is summarized, one type (NMDA receptors) being activated specifically by N-methyl-D-aspartate (NMDA) and blocked by specific antagonists such as D(-)-2-amino-5-phosphonovalerate (APV), and a second type (non-NMDA receptors) characterized by insensitivity to specific NMDA antagonists. This second type may be comprised of two sub-types activated selectively by the agonists quisqualate and kainate. The putative transmitters L-glutamate and L-aspartate have mixed action on both NMDA and non-NMDA receptors. The major action of both transmitter candidates is considered to be on non-NMDA receptors, but the proportion of the composite responses mediated by NMDA receptors (at least for spinal neurones) appears to be greater for L-aspartate than for L-glutamate. 3. The preference of NMDA and non-NMDA receptors for a range of agonists is discussed. Some newer agonists are considered, in addition to several known agonists not previously discussed in terms of NMDA- and non-NMDA-receptor preference. Structure-activity relations of agonists are discussed. 4. The actions of some new amino acid antagonists are reported. Some of these have useful kainate and quisqualate blocking activity, in addition to their ability to block NMDA induced responses. 5. Evidence is presented suggesting that excitatory amino acid receptors are involved in both polysynaptic and monosynaptic excitation in the spinal cord, NMDA receptors mediating polysynaptic excitation and non-NMDA receptors monosynaptic excitation. 6. The unusual effect is reported of L-2-amino-4-phosphonobutyrate, which potently blocks spinal synaptic excitation in the absence of depressant action on excitatory amino acid-induced responses.

Amino Acids↗
PubMed1982

Region-specific effects on chromosome integrity of mutations at essential loci in Drosophila melanogaster.

Two mutagen-sensitive loci of Drosophila melanogaster, mus-105 and mus-109, previously identified by viable alleles, are shown to specify essential functions. Lethal alleles at the loci produce larvae that have degenerate imaginal discs and die at the larva-pupa boundary. Our data suggest that the causes of lethality are intolerable levels of cell death produced by high frequencies of chromosome aberrations (in excess of 0.5 aberration per cell per cycle). The pattern of aberrations is a locus-specific character. In mus-105 mutants the most common aberrations are breaks and exchanges in euchromatic portions of the genome whereas in mus-109 mutants the most common aberrations are breaks at heterochromatin-euchromatin junctions. The sensitivity of these junctions to breakage in mus-109 mutants is a property of all such junctions whether natural or produced by a rearrangement that juxtaposes heterochromatin and euchromatin. Larvae carrying the combination of two viable mutants, mus-105(A1) mus-109(D1), die at the larva-pupa boundary and display a high frequency of aberrations (0.7 per cell vs. 0.075 for either mutant alone) clustered at euchromatin-heterochromatin junctions. This synergistic interaction suggests there is a class of lesions that can be repaired by both mus-105(+) and mus-109(+). Thus, the apparent euchromatic specificity of mus-105(+), which was inferred from the pattern of predominantly euchromatic breakage observed in mus-105 mus-109(+) flies, is in fact generated by the wild-type function of mus-109(+) masking an effect of mus-105 in the heterochromatin. The fact that lethal mutants at the mus-105 and mus-109 loci have small imaginal discs coupled with the observation of a maternal effect of mus-105 suggests a paradigm for the control of cell division during the life cycle of Drosophila.

Alleles↗
PubMed1982

The effects of a series of omega-phosphonic alpha-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations.

1 The depressant actions on evoked electrical activity and the excitant amino acid antagonist properties of a range of omega-phosphonic alpha-carboxylic amino acids have been investigated in the isolated spinal cord preparations of the frog or immature rat. 2 When tested on dorsal root-evoked ventral root potentials, members of the homologous series from 2- amino-5-phosphonovaleric acid to 2-amino-8-phosphonooctanoic acid showed depressant actions which correlated with the ability of the substances to antagonize selectivity motoneuronal depolarizations induced by N-methyl-D-aspartate. 3 2-Amino-5-phosphonovalerate was the most potent substance of the series giving an apparent KD of 1.4 microM for the antagonism of responses to N-methyl-D-aspartate. 4 A comparison of the (+)- and (-)-forms of 2-amino-5-phosphonovalerate indicated that the N-methyl-D-aspartate antagonist activity and the neuronal depressant action of this substance were both due mainly to the (-)-isomer. 5 The (-)- and (+)-forms of 2-amino-4-phosphonobutyrate had different actions. The (-)-forms of this substance had a relatively weak and non-selective antagonist action on depolarizations induced by N-methyl-D-aspartate, quisqualate and kainate and a similarly weak depressant effect when tested on evoked electrical activity. The (+)-form was more potent than he (-)-form in depressing electrically evoked activity but did not antagonize responses to amino acid excitants. At concentrations higher than those required to depress electrically evoked activity, the (+)-form produced depolarization. This action was blocked by 2-amino-5-phosphonovalerate.

Amino Acids↗
PubMed1982

Metabolism and excretion of a chromone carboxylic acid (FPL 52757) in various animal species.

1. The disposition of the chromone carboxylic acid (FPL 52757) in several species has been investigated. The compound is extensively metabolized by hydroxylation in rat, mouse, ferret, squirrel monkey, cynomolgus monkey, rabbit, hamster, stumped-tailed macaque and baboon (e.g. 50-100% in rat, cynomolgus monkey and squirrel monkey). 2. The plasma clearance of the chromone in rat, rabbit and squirrel monkey was 138, 44 and 59 ml/kg per h respectively. Plasma clearance by the dog was slower (13 ml/kg per h) and due mainly to elimination of unchanged compound. 3. As the dog is particularly susceptible to FPL 52757-induced hepatotoxicity the parent compound may be responsible. Species which clear the compound rapidly compared with the dog did not show a hepatotoxic response. 4. Although metabolism occurs in man the clearance is still slow (15 ml/kg per h) and may be one reason for human susceptibility to a mild hepatotoxic effect with the compound.

Animals↗
PubMed1982

The mechanism of hepatotoxicity of a chromone carboxylic acid (FPL 52757) in the dog.

1. The chromone carboxylic acid (6,8-diethyl-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid) is hepatotoxic in dogs (at 40 mg/kg per day). This toxicity did not appear to be mediated by a reactive metabolite, as the compound was not metabolized by the dog, and phenobarbitone pretreatment (20 mg/kg per day) protected rather than potentiated. 2. Other studies in the dog showed that the chromone caused increases in the biliary excretion of alkaline phosphatase (17-fold), gamma-glutamyl-transpeptidase (9-fold), and 5'-nucleotidase (13-fold) which paralleled the biliary concentration of the drug (up to 1.3 mg/ml) and was accompanied by a reduction in bile flow. 3. The excretion of the chromone into the biliary tract of the dog was shown to be saturable, and therefore high hepatocellular concentrations of the drug and subsequent liver damage could result. 4. The toxicity of the chromone when administered to rat by retrograde biliary infusion, and the lysis of erythrocytes in vitro, are related to detergent properties of the drug and add confirmatory evidence for a mechanism of toxicity in the dog. 5. It is concluded that the chromone itself is responsible for the toxicity in the dog due to its detergent properties causing damage to the hepatobiliary tract. The protection by phenobarbitone and also by methionine may have been due to an increased bile flow reducing biliary concentrations.

Animals↗