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Biomedical subjects

G M Martin

Publications and source records attributed to G M Martin.

At least 109 records · Page 6Linked to original sources
PubMed1992

Conditioned taste aversions support drug discrimination learning at low dosages of morphine.

The present experiment shows that a conditioned taste aversion procedure can support discrimination learning at dosages of morphine comparable to those required to produce motivational effects. Sprague-Dawley rats were injected with 4.0 mg/kg morphine sulfate prior to a saccharin-lithium chloride pairing, and physiological saline prior to a saccharin-saline pairing. The rats avoided the saccharin solution following the administration of morphine and consumed significantly more saccharin following saline administration after four discrimination cycles. After this initial discrimination the subjects were trained with progressively lower doses of morphine. Discrimination learning was apparent at doses of 2.0, 1.5, 1.0, 0.75 and 0.5 mg/kg. Animals initially trained with 1.0 mg/kg morphine also learned the discrimination but required 10 training cycles. After this initial discrimination the subjects were trained with progressively lower dosages of morphine and showed a discrimination at a dosage of 0.5 mg/kg.

Animals↗
PubMed1992

Expression of a carboxy-terminal region of the beta-amyloid precursor protein in a heterogeneous culture of neuroblastoma cells: evidence for altered processing and selective neurotoxicity.

Six independent clonal isolates from a morphologically heterogeneous human neuroblastoma cell line stably expressed several products of the human amyloid precursor protein (APP) from an introduced DNA construct; the "substrate-adherent" phenotype (fibroblast-like cells) predominated in all 6; these displayed immunoreactivity of vimentin, but little to no reactivity of neuron-specific enolase. A stably transfected isolate which did not show any expression from the identical construct (presumably because of a position effect) exhibited the predominantly neuronal phenotype of the parental cells (neuron-specific enolase positive). These results suggest selective neurotoxicity of the expressed products. Two of the 6 stably expressing cell lines showed a decrease of native mRNA for APP to levels that were 1/4-1/3 that of the parental cells and a decrease of their growth rates to half that of the parental cells; these decreased growth rates were improved by conditioned medium from the parental cell line. Western blot analysis revealed at least four distinct fragments of the COOH-terminus of APP in the isolate which expressed protein and mRNA in greatest abundance, suggesting that overexpression of APP in a human neural cell line leads to aberrant cleavage of APP.

Amyloid beta-Protein Precursor↗
PubMed1992

Increased expression of beta-amyloid protein precursor and microtubule-associated protein tau during the differentiation of murine embryonal carcinoma cells.

Expression of the genes encoding the beta/A4 amyloid protein precursor (APP) and microtubule-associated protein tau was studied in an embryonal carcinoma cell line (P19) that differentiates in vitro into cholinergic neurons after treatment with retinoic acid. Expression of APP increased 34- (mRNA) and 50-fold (protein) during neuronal differentiation; APP-695 accounted for most of this increase. These remarkable increases in APP expression coincided with a proliferation of neuronal processes and with an increase in content of tau mRNA. Moreover, subsequent decreases in the levels of APP and tau mRNA coincided with the onset of the degeneration of the neuronal processes. Immunocytochemical staining suggested that greater than 85% of the P19-derived neurons are cholinergic and that APP is present in the neuronal processes and cell bodies. These results suggest that APP may play an important role in construction of neuronal networks and neuronal differentiation and also indicate that this embryonal carcinoma cell line provides an ideal model system to investigate biological functions of APP and the roles of APP and tau protein in development of Alzheimer's disease in cholinergic neurons.

Amyloid beta-Protein Precursor↗
PubMed1992

Survival curves, reproductive life span and age-related pathology of Mus caroli.

Although Mus caroli is being used in a number of laboratories as an experimental animal, basic information concerning its life span, reproductive ability, and age-related pathologies has been unavailable. Here we present this basic information, and discuss the similarities to and differences from the laboratory mouse, Mus musculus domesticus [strains A/StTrWo and (A/StTrWo x C57BL/6NNia)F1] and, from published data, wild-type Mus musculus.

Aging↗
PubMed1991

Multidrug resistance phenotype associated with selection of an aminopterin resistant dog kidney cell line.

A determination of the mechanisms of drug resistance in tumour cells is important for developing strategies to combat such resistance in persons receiving chemotherapy. This report describes a combined cellular, biochemical, and molecular analysis of a dog kidney cell line selected for resistance to increasing levels of the hydrophilic antifolate, aminopterin. Three distinct drug resistance phenotypes were observed in cells exhibiting high levels of aminopterin resistance. Two of these phenotypes were decreased aminopterin accumulation and increased levels of dihydrofolate reductase specific activity. The third drug resistance phenotype was noted initially as cross resistance to a variety of hydrophobic drugs indicating multidrug resistance. Biochemical assays demonstrated reduced accumulation of the hydrophobic fluorescent drug daunorubicin and of 3H-colchicine in the aminopterin resistant cells. These results were then correlated with increased levels of the multidrug resistance (mdr) gene product, P-glycoprotein, and mdr mRNA levels in the aminopterin resistant cells. However, experiments designed to prove a role for expression of the mdr gene in providing a degree of aminopterin resistance were unsuccessful. It is concluded that aminopterin selection in these dog kidney cells resulted in expression of at least three distinct drug resistance phenotypes and that one of these phenotypes, multidrug resistance, represented a secondary response to the aminopterin selection.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Genetic and environmental modulations of chromosomal stability: their roles in aging and oncogenesis.

The primary objective of this review is to suggest a major role of cytogenetic pathology in the genesis of both the neoplastic phenotype and the senescent phenotype of aging mammalian organisms. It is hypothesized that allelic variation at a number of genetic loci that have the potential to modulate various types of chromosomal mutation could account, in part, for species-specific variations in maximum life-span potentials and the times of onset of characteristic age-related neoplasms. As a corollary to this proposition, attention is directed to the potential importance of environmental clastogens and aneugens as both oncogenic and "gerontogenic" agents. By way of introduction, a series of definitions of our subject material is given (aging, oncogenesis, proliferative homeostasis, point mutation, chromosomal mutation, epimutation, mutagens, clastogens, aneugens, gerontogens). There follows a defense of the view that there is a tight coupling of abnormalities in proliferative homeostasis (including atrophies, hyperplasias, benign neoplasias and malignant neoplasias) with intrinsic biological aging. This view differs from those of other authors who either: 1) believe that, to qualify as a bona fide component of aging, the phenotype in question (in this case, neoplasia) must be "genetically programmed" or 2) insist that the rate of development of the neoplastic phenotype should parallel species-specific Gompertz kinetics for the survival of the population of organisms. After briefly reviewing the classification of chromosomal lesions, we consider evidence for constitutional genetic determinants of chromosomal stability, oncogenesis, and some other aspects of the senescent phenotype, both with respect to interspecific and intraspecific differences. The discussion will include the recent evidence characterizing a human segmental progeroid syndrome (Werner's syndrome) as a deletor mutator strain. A summary of research on environmental chemical clastogens and aneugens is given, showing both discordances and concordances of such assays with assays for point mutagens. An analysis of the literature indicates that there is no statistical evidence for the positive correlations when substances showing effects only at comparatively high concentrations (greater than 1 mM) are excluded from the analysis. Brief mention is also made of the roles of viral agents and ionizing radiation in the genesis of chromosomal mutations. Finally, some possible pathogenetic mechanisms common to chromosomal mutagenicity, oncogenicity and gerontogenicity are considered, including chemical free radicals (active oxygen species), DNA transposition, DNA amplification, DNA glycation, virally induced cell fusion, posttranslational modifications of centromeric and mitotic spindle proteins, and alterations in the metabolism of telomeric DNA.

Aging↗
PubMed1991

APP717, APP693, and PRIP gene mutations are rare in Alzheimer disease.

The amyloid precursor protein (APP) gene codes for the precursor to the beta-protein found in the amyloid deposits of Alzheimer disease (AD). Recently Goate et al. identified in codon 717 of this gene a missense mutation which segregates with AD in a familial AD (FAD) kindred. The same mutation was also found in affected subjects from a second FAD family but not in other FAD families or in normal controls. The following work was undertaken to determine the frequency of the codon 717 mutation in FAD and nonfamilial AD cases and in normal controls. We tested 76 FAD families, 127 "sporadic" AD subjects, 16 Down syndrome cases, and 256 normal controls for this mutation, and none were positive. We also tested for the APP codon 693 mutation associated with hereditary cerebral hemorrhage with amyloidosis-Dutch type, for PRIP gene missense mutations at codons 102, 117, and 200, and for the PRIP insertion mutations which are associated with Creutzfeld-Jakob disease and Gerstmann-Straussler Scheinker syndrome. No examples of these mutations were found in our population. Thus these APP and PRIP mutations are rare in both FAD and nonfamilial AD.

Adult↗
PubMed1990

Proliferative capacity of human peripheral blood lymphocytes sorted on the basis of glutathione content.

Glutathione (GSH) is important in defense against oxygen free radical damage, in detoxification of xenobiotics, and in mitogenesis. The reducing conditions provided by low molecular weight thiols such as 2-mercaptoethanol (ME) have been shown to promote the growth of lymphocytes in culture. We wished to determine the effects of 2-ME on GSH content, and to determine to what extent GSH status affected lymphocyte proliferation. GSH content was quantitated in human peripheral blood lymphocytes (PBL) using a flow cytometric assay with monochlorobimane. This analysis was performed on PBL as well as on the CD4+ T-cell subset, as identified with fluorescent anti-CD4 monoclonal antibodies (mAb). Cells were viably sorted on the basis of their GSH content, and incubated for 3 days with mitogenic concentrations of PHA (for PBL) or anti-CD3 mAb (for CD4+ cells) in the presence of bromodeoxyuridine (BrdU). BrdU/Hoechst cell cycle analysis was then performed on these cells. High GSH sorted cells had a higher percentage of cells capable of entering the cell cycle than low GSH sorted cells. This data indicates that some of the heterogeneity in proliferative capacity within PBL in culture is directly or indirectly related to GSH content. Incubation of cells in 2-ME prevented the loss of GSH that occurs when cells are cultured. 2-ME improved the proliferative capacity of unsorted cells, and of cells sorted for high and low GSH. Acridine orange staining of anti-CD3 mAb stimulated cells sorted for high and low GSH indicated that an early event in cell activation was affected by GSH content.

CD4 Antigens↗
PubMed1990

Increased frequency of 6-thioguanine-resistant peripheral blood lymphocytes in Werner syndrome patients.

The frequency of spontaneous 6-thioguanine (TG)-resistant peripheral blood lymphocytes in five unrelated Werner syndrome (WS) patients was determined using an autoradiographic labeling assay. The average frequency of TG-resistant lymphocytes was eightfold higher in WS patients than in sex- and age-matched normal control donors. This finding and previous identification of increased spontaneous chromosomal rearrangements and deletions in WS cells or cell lines suggest that WS is a human genomic instability or mutator syndrome.

Adult↗
PubMed1990

Discriminative properties of morphine that modulate associations between tastes and lithium chloride.

Wistar rats learned to withhold consumption of a target solution when morphine preceded presentation of the target solution and lithium chloride (LiCl) and to consume the same target solution when saline preceded the presentation of the solution. After this serial feature discrimination training, morphine did not block the formation of a Pavlovian association between saccharin and LiCl but did suppress consumption of familiar tap water. After Pavlovian conditioning, morphine blocked the formation of an association between saccharin and LiCl but did not suppress consumption of a familiar tap water solution. The roles of morphine and saline can be interchanged. It appears that the morphine discriminative stimulus is calling up a representation of neither the conditioned stimulus nor the unconditional stimulus alone, but rather a modified representation of some aspect of their association.

Animals↗
PubMed1989

A partial methylation profile for a CpG site is stably maintained in mammalian tissues and cultured cell lines.

We wished to determine if a partial methylation profile for a specific CpG site was stably maintained in both mammalian tissues and cultured cell lines. To accomplish this, we identified a CpG site with a partial methylation profile located upstream of the mouse adenine phosphoribosyltransferase promoter region. This site was found to be methylated at a level of approximately 25% in mouse brain, kidney, lung, and skeletal muscle tissues, at a level close to 50% in liver, and at level close to 0% in testis. These tissue-specific methylation profiles were not altered during aging. A methylation profile of approximately 25% at this CpG site was also observed in five mouse teratocarcinoma stem cell lines and one additional cultured cell line. This profile, however, was altered upon cellular differentiation, adenine phosphoribosyltransferase hemizygosity, and a loss of adenine phosphoribosyltransferase activity in some of the cultured cell lines. We conclude that partial methylation of a specific CpG site can be stably maintained both in vivo and in vitro and that a mechanism exists for its maintenance. The functional significance of a partial methylation profile remains to be determined.

Adenine Phosphoribosyltransferase↗
PubMed1989

Allelic variation linked to adenine phosphoribosyltransferase locus in mouse teratocarcinoma cell line and feral-derived mouse strains.

Southern blot analysis reveals two distinct adenine phosphoribosyltransferase (APRT) alleles in the P-19 mouse teratocarcinoma cell line. One allele is identical to that observed in common laboratory mouse strains (Mus musculus domesticus). The restriction enzyme site variations between the two alleles occur in sequences located both upstream and downstream of the APRT gene, but not within it. Although the P-19 cell line was established from a C3H strain embryo (Mus musculus domesticus), a sixth generation ancestor of this embryo was a feral mouse (Mus musculus musculus). The restriction pattern of the variant APRT allele in P-19 is identical to that of a feral-derived Mus musculus musculus animal, establishing the origin of this allele in the P-19 cell line. A third, distinct APRT allele was found in a Mus spretus feral-derived mouse. Exploiting the differences between the two APRT alleles in the P-19 cell line, we have demonstrated their sequential loss in APRT-deficient clones.

Adenine Phosphoribosyltransferase↗
PubMed1989

Mechanisms of conditioned meal initiation.

Three experiments investigate behavioral and biological mechanisms of meal initiation controlled by learning. Animals were classically conditioned to initiate a meal in response to a conditioned stimulus paired with food. We demonstrate that: a) aversion to the signalled food markedly reduces consumption but has no effect on eating-related behaviors anticipatory to ingestion; b) naloxone reduces the amount eaten but has no impact on food-anticipatory behaviors; c) dopamine antagonism attenuates food-anticipatory behaviors without influencing amount eaten, and d) satiety signals arising from food in the gut reduce both food-anticipatory behaviors and amount eaten. These results demonstrate that anticipatory (appetitive) and consummatory components of meal initiation can be dissociated and are controlled by different biological mechanisms. Cues conditioned to food elicit eating by selectively activating appetitive systems. The implications of the appetitive/consummatory distinction for contemporary theories of meal initiation are discussed.

Animals↗
PubMed1989

The genetics of Alzheimer's disease.

Genetic factors play a major role in some if not all cases of Alzheimer's disease (AD). In certain rare families, the disease is most likely inherited as an autosomal dominant trait. Identification of the genes involved in AD is in progress. One AD-related gene, which codes for the amyloid precursor protein (APP), has been cloned and characterized. This gene, though certainly involved in the pathogenesis of AD, is not defective in AD subjects. Genetic linkage analysis of familial Alzheimer's disease (FAD) should help to identify defective genes directly involved in initiating the pathogenesis of AD. In addition, the study of the genes responsible for the Down syndrome (DS) phenotype may yield information on the sequence of events leading to the dementia of AD.

Adolescent↗
PubMed1989

A flavor paired with lithium chloride blocks the formation of a pentobarbital-lithium chloride association.

Thirsty rats were used in order to determine whether a vinegar solution, which had been paired with an injection of lithium chloride, could block the formation of an association between a pentobarbital- and a lithium chloride-induced state. During phase 1 the rats in the blocking group had a 2.0% vinegar solution paired with an injection of 240 mg/kg of lithium chloride, during phase 2 these rats were reexposed to the vinegar prior to each injection of 20 mg/kg of pentobarbital and 240 mg/kg of lithium chloride, and during phase 3 these rats were given access to a novel 0.75% saccharin solution and were injected with pentobarbital after saccharin removal. Animals with this history did not form an association between the pentobarbital- and lithium chloride-induced states during phase 2 as evidenced by their refusal to consume the saccharin solution over repeated pairings of saccharin with pentobarbital during phase 3. Control groups that received forward pairings of pentobarbital and lithium chloride, in the absence of a previously conditioned vinegar solution during phase 2, formed an association between pentobarbital and lithium chloride. These findings indicate that drug states and flavors can interfere with each others' capacity to predict the occurrence of lithium chloride.

Acetates↗
PubMed1989

Mutator phenotype of Werner syndrome is characterized by extensive deletions.

Werner syndrome (WS) is a rare autosomal-recessive disorder characterized by the premature appearance of features of normal aging in young adults. The extensive phenotypic overlap between WS and normal aging suggests they may also share pathogenetic mechanisms. We reported previously that somatic cells from WS patients demonstrate a propensity to develop chromosomal aberrations, including translocations, inversions, and deletions, and that WS cell lines demonstrate a high spontaneous mutation rate to 6-thioguanine resistance. We report here the biochemical and molecular characterization of spontaneous mutations at the X chromosome-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in 6-thioguanine-resistant WS and control cells. Blot hybridization analysis of 89 independent spontaneous HPRT mutations in WS and control mutants lacking HPRT activity revealed an unusually high proportion of HPRT deletions in WS as compared with control cells (76% vs. 39%). Approximately half (58%) of the deletions in WS cells consisted of the loss of greater than 20 kilobases of DNA from the HPRT gene. These results suggest that an elevated somatic mutation rate, and particularly deletions, may play pathogenetically important roles in WS and in several associated age-dependent human disease processes.

Adolescent↗