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Biomedical subjects

M E Gaulden

Publications and source records attributed to M E Gaulden.

12 recordsLinked to original sources
PubMed1992

Maternal age effect: the enigma of Down syndrome and other trisomic conditions.

Aneuploidy is the most frequently observed chromosome abnormality in human liveborn, abortuses and oocytes. The only etiological factor that has been established is advanced maternal age for the occurrence of trisomies, particularly trisomy 21 which causes Down syndrome. The maternal age effect remains an enigma. Recent molecular data bearing on this question are reviewed as are the hypotheses that have been proposed linking nondisjunction and maternal age. Rationale is presented for a compromised microcirculation hypothesis that explains the cause of nondisjunction and why its occurrence changes with maternal age from menarche to menopause. It takes into account two facts: (1) 95% of Down syndrome children receive their extra chromosome from their mother, and in 80% or more of these the nondisjunction occurred in the first meiotic division, which is completed in the ovary. (2) The ovarian follicle containing the primary oocyte has no internal circulation. The hypothesis proposes that aneuploid oocytes arise from a concatenation of events. It begins with hormonal imbalance that causes a less-than-optimal microvasculature to develop around the maturing and mature follicles. The resulting decrease in the size of the perifollicular capillary bed reduces the volume of blood flow through the area, leading to an oxygen deficit and a concomitant increase inside the follicle of carbon dioxide and anaerobic products, such as lactic acid. This in turn causes a decrease in the intracellular pH of the oocyte that diminishes the size of the spindle, with consequent displacement and nondisjunction of a chromosome. The compromised microcirculation hypothesis explains the occurrence of aneuploidy in primary and secondary oocytes, sperm precursor cells, tumor and embryonic cells. It also explains why women of all reproductive ages may have a Down syndrome child.

Aneuploidy↗
PubMed1989

A model that explains the varying frequency of aneuploid children with maternal age (J-shaped curve) as well as aneuploidy of paternal origin.

A compromised microcirculation could account for aneuploidy incidence in women of any reproductive age, the frequency varying with the probability of events leading to reduced development and/or function of the critical perifollicular capillary bed. This would explain the J-shaped curve of changing frequency of Down syndrome children with maternal age (Erickson, 1978). The seminiferous tubule of the testis, like the follicle, has no internal circulation, so small localized regions of reduced circulation could occur and result in aneuploidy. From all that we know about the deficiency of regional microcirculation in tumors (see Hall, 1978), it is reasonable to speculate that reduced pH could be responsible for some of the aneuploidy that is seen in practically all advanced tumors. As a first step in testing the model proposed here, we are beginning studies with mouse oocytes, on the assumption that ovarian conditions are responsible for the maternal age effect rather than uterine conditions (reduced rejection of trisomic fetuses). Should our model for aneuploidy induction in both germ and somatic cells prove to be correct, the molecular mechanism(s) would still have to be ascertained.

Aneuploidy↗
PubMed1987

Hypothesis: some mutagens directly alter specific chromosomal proteins (DNA topoisomerase II and peripheral proteins) to produce chromosome stickiness, which causes chromosome aberrations.

Recent biochemical and molecular biological data on the composition and structure of the chromosome and the nucleus, combined with observations on the chromosomes of mutant yeast cells and grasshopper neuroblasts, offer new perspectives on mutagen-induced chromosome stickiness and its relation to chromosome breakage. A hypothesis consistent with these data states that chromosome stickiness (i) results from changes in specific non-histone proteins (topoisomerase II and the peripheral proteins) that are integral components of the chromosome and whose function is necessary for separation and segregation of chromatids, the changes being caused either by mutation in structural genes for the proteins (heritable stickiness) or by direct action of mutagens on the proteins (induced stickiness); (ii) occurs in various degrees (slight, moderate, severe, extreme) that are determined by the number of target protein molecules affected, a certain number (threshold) of affected molecules at a given site on a chromosome being required to resist the forces of anaphase movement in order to produce microscopically detectable stickiness; (iii) results from molecular events that can occur at several phases of the cell cycle (including interphase), but can only be recognized at prometaphase, metaphase and anaphase; and (iv) causes chromosome aberrations by the physical stretching and breaking of chromatids at the sticky sites; hence the breakage resulting from stickiness is a secondary effect that requires anaphase movement, in contrast to breakage resulting from direct action of mutagens on DNA.

Animals↗
PubMed1986

Formaldehyde-induced acentric chromosome fragments and chromosome stickiness in Chortophaga neuroblasts.

Embryos of the grasshopper Chortophaga viridifasciata were exposed in vitro to formaldehyde (FA), as formalin, at concentrations ranging from 10(-8)M (0.0003 ppm) to 10(-3) M (30 ppm) at 38 degrees C. A low frequency of distinct acentric chromosome fragments (0.02-0.04/cell) was observed in the neuroblasts after 1 hr exposure to 7.5 X 10(-4) or 10(-3) M FA plus 3 hr recovery, but not at lower concentrations, even with 4 hr exposure. There was no obvious relation between distinct fragment frequency and concentration of FA. Neuroblasts with sticky chromosomes were observed at 10(-4), 7.5 X 10(-4), and 10(-3) M FA, the percent of cells with slight, moderate, or severe stickiness varying with FA concentrations. Fragments were associated with the sticky chromosomes. The frequency of these sticky fragments at the two higher concentrations (0.15-0.30/cell) was greater than the frequency of distinct fragments. It is concluded that the distinct acentric fragments induced by FA result from breakage at a single sticky point (slight stickiness) between separating sister chromatids. The chromosome effects observed probably result from the action of daughter products that are formed by the interaction of FA with culture medium components, especially the fetal calf serum.

Animals↗
PubMed1986

Reactivity and fate of benzene and formaldehyde in culture medium with and without fetal calf serum; relevance to in vitro mutagenicity testing.

Gas chromatographic-mass spectrometric analyses were performed to determine the reactivity and fate of benzene (BEN) and formaldehyde (FA) in culture medium. BEN (solubility in water: approximately 500 ppm) does not react with culture medium, either with or without fetal calf serum, but its volatility, even in closed vials, is so great that 90% of a 250-ppm solution is lost to the head space after 1 h at 24 degrees C. FA, as a 37% aqueous solution, is a complex mixture that changes composition after 15-min incubation at 38 degrees C. FA is extremely reactive in culture medium containing fetal calf serum, and is much less reactive with medium components in the absence of serum. There is a dramatic increase in the number of daughter products in FA-treated medium over time, such that those seen immediately after FA is added to medium have been replaced after 60-min incubation (38 degrees C in closed vials) by many other interaction products. Methods ensuring maximum solubilization and minimal volatilization of BEN during exposure are essential for obtaining reproducible data on the mutagenic potential of BEN. The volatilization of FA from stock formalin solutions, and, more importantly, the interaction product(s) formed by this highly reactive compound with medium components, especially those in serum, are probably the critical aspects of an effective testing protocol for FA.

Animals↗
PubMed1985

Chromosome fragments and other abnormalities induced by mitomycin C in the neuroblast of Chortophaga viridifasciata.

Mitomycin C (MMC) induces acentric chromosome fragments in the neuroblast (Nb) of the grasshopper embryo (Chortophaga viridifasciata) after acute and chronic exposure to concentrations ranging from 10(-8) to 10(-4) M, the dose response being essentially linear up to 10(-5) M. Because Colcemid is not used in the Nb assay, it was possible to detect two additional effects of MMC: (1) Prolonged retardation of many cells occurs when they reach very late prophase; the chromosomes continue condensing and lose their orderly prophase orientation, and the nuclear envelope becomes increasingly fragile. Such cells, which were observed after both acute and chronic exposure, give the false impression of being c-metaphases when they are fixed and squashed. The frequency of retarded very late prophases and the duration of retardation are related to MMC concentration and time of exposure. A rationale is presented supporting the idea that the events associated with retarded very late prophase result from MMC effects on the nuclear envelope. (2) MMC significantly increases the frequency of Nb's with attenuated centromeres at the beginning of early anaphase, an effect that appears to be caused by a delay in the repulsion of sister chromatids that usually occurs immediately after centromere separation begins.

Anaphase↗
PubMed1985

Mitomycin C effects on cell cycle progression, including inhibition of very late prophase, as seen in living neuroblasts of Chortophaga viridifasciata, with some observations on mitomycin C purity.

Observations were made on living neuroblasts (Nbs) of the grasshopper (Chortophaga viridifasciata) embryo during a 4-h recovery period following 1-h in vitro exposure to 10(-8), 10(-6), and 10(-4) M mitomycin C (MMC). None of these concentrations affected the duration of mid-mitosis (prometaphase, metaphase, anaphase), but one as low as 10(-8) M causes a small reduction in the rate at which Nbs move through the remainder of the cell cycle, primarily by retarding their progress through S. As the concentration is increased there is slower movement through S and also prophase (there are no true G1 and G2 periods in the rapidly dividing Nb: 4-h cell cycle at 38 degrees C). A significant proportion of the cells exposed to 10(-4) M are blocked for 1 or more h at very late prophase, i.e., just before nuclear membrane breakdown. In such retarded prophases the chromosomes resemble c-metaphase chromosomes even though the nuclear membrane remains intact. Mass spectrometry data revealed that one lot of the MMC used contained one or more impurities.

Animals↗
PubMed1978

Linear dose-response of acentric chromosome fragments down to 1 R of x-rays in grasshopper neuroblasts, a potential mutagen-test system.

Grasshopper-embryo neuroblasts have no spontaneous chromosome breakage; therefore they permit easy detection of agents that break chromosomes. An X-ray exposure of 1 R induces in them a detectable number of chromosome fragments. The dose-response of acentric fragment frequency fits a linear model between 0 and 128 R. Thus another cell type is added to those previously demonstrated to have no threshold dose for the induction of chromosome or gene mutations.

Animals↗
PubMed1978

Use of the Y-body for identification of skin source on a successfully grafted burn patient.

The use of the interphase male Y-body (fluorescent Y chromosome segment) technique with cryostat sections of both fresh and frozen-stored skin biopsies is described. A female burn patient appeared to retain her donor homografts, thereby negating the need for autografts. Since a retained homograft of this sort challenged our understanding of immunologic barriers, we applied the Y-body technique to cutaneous biopsies obtained from the patient's burn area that had been homografted with skin from a male donor, as well as control biopsies from the patient's unburned skin and normal control male and female skin. Based on clinical and cytogenetic observations, it was concluded that the most reasonable explanation for this case was that the regenerating tissue at the graft site was that of the recipient and not that of the originally grafted male skin.

Burns↗
PubMedDate not supplied

Preferential decrease in thymus dependent lymphocytes during storage at 4 C in anticoagulant.

Human lymphocytes stored at 4 C either as leukocyte concentrates (LCs) in citrate-phosphate-dextrose (CPD) or as whole blood anticoagulated with CPD show a rapid and marked decrease in the relative and absolute numbers of thymus derived (T) lymphocytes. Determinations were made on cells recoverable on a Ficoll-Hypaque (F-H) gradient. In evacuated LCs, the relative percentage of T cells dropped to less than 10 per cent within 72 hours with a concomitant increase in the relative percentage of bone marrow derived (B) cells to 80 per cent or more. LCs opened to the air and subsequently stored at 4 C displayed an even more precipitous decline in the relative percentage of T cells, reaching a 10 per cent level within 72 hours. The relative percentage of T cells in CPD-anticoagulated whole blood samples stored at 4 C displayed similar decreases, reaching 20 per cent levels within 24 hours. The change in the relative percentage of T cells at the Ficoll-Hypaque interface was shown to reflect a decrease in the total numbers of T cells placed on the F-H gradient with time, since determinations of T and B cell numbers in NH4Cl-treated whole blood showed a 65 to 80 per cent decrease in the numbers of T cells within 24 hours in anticoagulated whole blood held at 4 C. Thus, it may be inferred that the T cell decrease is mediated via some interaction of anticoagulant, storage time, and some component(s) present in both LCs and whole blood.

Anticoagulants↗