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Biomedical subjects

S Guthrie

Publications and source records attributed to S Guthrie.

At least 55 records · Page 3Linked to original sources
PubMed1992

Motor neuron pathfinding following rhombomere reversals in the chick embryo hindbrain.

Motor neurons are segmentally organised in the developing chick hindbrain, with groups of neurons occupying pairs of hindbrain segments or rhombomeres. The branchiomotor nucleus of the trigeminal nerve occupies rhombomeres 2 and 3 (r2 and r3), that of the facial nerve r4 and r5, and that of the glossopharyngeal nerve r6 and r7. Branchiomotor neuron cell bodies lie within the basal plate, forming columns on either side of the ventral midline floor plate. Axons originating in rhombomeres 2, 4 and 6 grow laterally (dorsally) towards the exit points located in the alar plates of these rhombomeres, while axons originating in odd-numbered rhombomeres 3 and 5 grow laterally and then rostrally, crossing a rhombomere boundary to reach their exit point. Examination of the trajectories of motor axons in odd-numbered segments at late stages of development (19-25) showed stereotyped pathways, in which axons grew laterally before making a sharp turn rostrally. During the initial phase of outgrowth (stage 14-15), however, axons had meandering courses and did not grow in a directed fashion towards their exit point. When r3 or r5 was transplanted with reversed rostrocaudal polarity prior to motor axon outgrowth, the majority of axons grew to their appropriate, rostral exit point, despite the inverted neuroepithelial polarity. In r3 reversals, however, there was a considerable increase in the normally small number of axons that grew out via the caudal, r4 exit point. These findings are discussed with relevance to the factors involved in motor neuron specification and axon outgrowth in the developing hindbrain.

Animals↗
PubMed1991

Patterns of cell division and interkinetic nuclear migration in the chick embryo hindbrain.

Early in its development, the chick embryo hindbrain manifests an axial series of bulges, termed rhombomeres. Rhombomeres are units of cell lineage restriction, and both they and their intervening boundaries form a series that reiterates various features of neuronal differentiation, cytoarchitecture, and molecular character. The segmented nature of hindbrain morphology and cellular development may be related to early patterns of cell division. These were explored by labeling with BrdU to reveal S-phase nuclei, and staining with basic fuchsin to visualise mitotic cells. Whereas within rhombomeres, S-phase nuclei were located predominantly toward the pial surface of the neuroepithelium, at rhombomere boundaries S-phase nuclei were significantly closer to the ventricular surface. The density of mitotic figures was greater toward the centres of rhombomeres than in boundary regions. Mitotic cells did not show any consistent bias in the orientation of division, either in the centres of rhombomeres, or near boundaries. Our results are consistent with the idea that rhombomeres are centres of cell proliferation, while boundaries contain populations of relatively static cells with reduced rates of cell division.

Actins↗
PubMed1991

Formation and regeneration of rhombomere boundaries in the developing chick hindbrain.

Development in the chick hindbrain is founded on a segmented pattern. Groups of cells are allocated to particular segmental levels early in development, the cells of each segment (rhombomere) mixing freely with each other, but not with those of adjacent segments. After rhombomere formation, cells in the boundary regions become increasingly specialised. Rhombomeres are thus separate territories that will ultimately pursue different developmental fates. We are investigating the mechanisms that establish and maintain the pattern of rhombomeres and their boundaries. Donor-to-host transplantation experiments were used to confront tissue from different axial levels within the hindbrain. The frequency of boundary regeneration and patterning in the hindbrain was then assessed, based on gross morphology, arrangement of motor neurons and immunohistochemistry. We found that when rhombomeres from adjacent positions or positions three rhombomeres distant from one another were confronted, a normal boundary was invariably reconstructed. Juxtaposition of rhombomere 5 with 7 also yielded a new boundary. By contrast, donor and host tissue of the same positional origin combined without forming a boundary. The same result was obtained in combinations of rhombomeres 3 and 5. Confrontation of tissue from even-numbered rhombomeres 4 with 6 or 2 with 4 also failed to regenerate a boundary in the majority of cases. These results suggest that cell surface properties vary according to rhombomeric level in the hindbrain, and may support the idea of a two-segment periodicity.

Animals↗
PubMed1991

The impact of dexamethasone pharmacokinetics on the DST: a review.

Even though the DST has not proved successful as a marker for depression, it has stimulated a considerable amount of research into the interaction between neuroendocrine function and mood states. With the objective of perfecting the DST methodology, investigators have explored the interaction between dexamethasone plasma concentrations and cortisol response, and have found that there is a significant inverse correlation between dexamethasone concentrations and cortisol concentrations. Although this relationship is one of the factors that affects cortisol response in depressed patients, it usually explains less than 20 percent of the variance of cortisol response. One can only conclude that the affective state explains a certain amount of the remaining variance. Dexamethasone plasma concentrations may be altered by a variety of drug and disease interactions. Many enzyme inducers, including phenytoin, carbamazepine, and phenobarbital, increase dexamethasone CL, but some drugs that might be expected to alter dexamethasone CL, such as cimetidine and tobacco smoke, do not affect it. Any disease that causes hepatic dysfunction could be expected to decrease dexamethasone CL, whereas renal failure may increase dexamethasone CL. Neither Cushing's syndrome nor congenital adrenal hyperplasia appear to alter dexamethasone CL. Alcoholism has a dual effect on the DST. Chronic alcohol abuse may cause a cushingoid state, which could interfere with the DST interpretation. Also, chronic alcohol use may result in hepatic dysfunction, or an induction of P-450 enzymes. As a result of these different actions, alcohol could result in either an increase or decrease in dexamethasone CL. Studies of dexamethasone pharmacokinetics conducted in depressed patients are few, but they generally agree that DST nonsuppressors exhibit an increased dexamethasone CL when compared with suppressors. The only two studies to investigate this population longitudinally report somewhat contradictory results; one study reports an increase in dexamethasone CL following recovery from depression, and the other a decrease. Since only one of the studies was conducted using intravenous dexamethasone, differences in bioavailability might explain some of the differences in results between the two studies. In spite of the unresolved questions, these studies have stimulated research into an entirely new area: the possibility that affective diseases may alter the pharmacokinetics of some drugs.

Depressive Disorder↗
PubMed1991

Alternating patterns of cell surface properties and neural crest cell migration during segmentation of the chick hindbrain.

The developing chick hindbrain is transiently divided into a series of repeating units or rhombomeres. Recent work has shown that an alternating periodicity exists both in the cell surface properties of rhombomeres and in the segmental origin of hindbrain neural crest cells. Experiments in which rhombomeres from different axial levels were confronted in the absence of an interrhombomere boundary showed that odd-numbered segments 3 and 5 combined without generating a boundary, as did even-numbered segments 2, 4 and 6. When rhombomeres originating from adjacent positions, or three rhombomeres distant from one another were combined, a new boundary was regenerated. Mapping of the migration pathways of neural crest cells showed that odd-numbered and even-numbered rhombomeres share properties with respect to the production of neural crest cells. In the hindbrain region the neural crest is segregated into streams. Neural crest cells migrating from rhombomeres 1 and 2, rhombomere 4 and rhombomere 6 respectively populate distinct cranial nerve ganglia and branchial arches. In contrast, rhombomeres 3 and 5 are free of neural crest cells.

Animals↗
PubMed1990

Modulation of gap junction transcript and protein expression during pregnancy in the rat.

The expression of three different gap junction transcripts, alpha 1 (Cx43), beta 1 (Cx32), and beta 2 (Cx26) was examined in several organs during pregnancy in the rat. In all of the organs that were examined--uterus, ovary, heart, and liver--there was a strong correlation between levels of gap junction mRNA and gap junction antigens that were detected at different stages of pregnancy. A striking change in alpha 1 transcript levels (a 5.5-fold increase) was detected in the uterine myometrium on the day before parturition. This elevation of the alpha 1 transcript is thought to be associated with the formation of gap junctions that are required for synchronizing the contractility of the myometrial cells during parturition. 2 d before parturition, there was a detectable elevation of beta 2 transcripts and protein in the endometrial epithelium, which was then followed by a dramatic decrease in beta 2 gap junctional protein on the day before parturition. There was also a substantial elevation of alpha 1 transcripts (a 6.7-fold increase) in the stromal regions of the ovary on the day before parturition that was identical to the temporal pattern of alpha 1 expression in the myometrium. In all three instances--the alpha 1 transcripts in the myometrium, beta 2 transcripts in the endometrium, and alpha 1 transcripts in the ovary--the transcript modulation appeared to be cell specific, because the changes in transcript levels of these three gene products occurred independently of the poly(A) + RNA concentrations at the same pregnancy stages in the respective organs. There were no specific changes detected in gap junction transcript levels in the heart and liver during pregnancy. These observations indicate that a cell-specific modulation of gap junction expression occurs in two regions of the uterus and the ovary during pregnancy. Further, it appears that the same gap junction gene in different organs, such as the alpha 1 gene in the uterine myometrium and the heart, can be differentially regulated.

Animals↗
PubMed1988

High intercorrelations among urinary outputs of norepinephrine and its major metabolites. A replication in depressed patients and controls.

We examined the intercorrelations among urinary outputs of norepinephrine (NE) and its three major metabolites in unipolar depressed patients (n = 28) and normal controls (n = 24). Among the depressed patients, levels of NE correlated with normetanephrine (NM), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA), and VMA correlated with NM and MHPG. In the total group of depressed and control subjects (n = 52), the sum of NE and its major metabolites correlated with urinary outputs of NE, NM, MHPG, and VMA. These highly significant correlations among urinary outputs of NE and its major metabolites replicate a previous report of strong correlations among these same four urinary substances in a smaller group of depressed patients.

Adult↗
PubMed1988

Patterns of junctional communication during development of the early amphibian embryo.

Cell-cell communication through gap junctions was examined in Xenopus laevis embryos between the 16-cell and early blastula stages using Lucifer Yellow, Fluorescein, lead EDTA and dicyanoargentate as probes of junctional permeability. Injections were made into cells whose position was identified with respect to the primary cleavage axis and the grey crescent. FITC dextrans revealed cytoplasmic bridges between the injected cell and its sister only. In the animal pole at the 16-cell stage at the future dorsal side of the embryo, Lucifer Yellow was frequently and extensively transferred between cells through gap junctions. At the future ventral side gap junctional transfer of Lucifer Yellow was significantly less frequent and less extensive. The asymmetry of transfer between future dorsal and ventral sides of the animal pole was more marked at the 32-cell stage. In the vegetal pole also at the 32-cell stage, a dorsoventral difference in junctional permeability to Lucifer Yellow was observed. At the 64-cell stage the transfer of Lucifer Yellow was relatively frequent between cells lying in the same radial segment in the animal pole; transfer into cells outside each segment was infrequent, except at the grey crescent. At the 128-cell stage, Lucifer transfer between future dorsal or future ventral cells in the equatorial region was infrequent. A high incidence of transfer was restored at the future dorsal side at the 256-cell stage. At the 32-cell stage, fluorescein was infrequently transferred between animal pole cells although lead EDTA moved from cell to cell with high, comparable frequency in future dorsal and ventral regions. Dicyanoargentate always transferred extensively, both at the 32- and 64-cell stages. Treatment of embryos with methylamine raised intracellular pH by 0.15 units, increased the electrical conductance of the gap junction and produced a 10-fold increase in the frequency of Lucifer Yellow transfer through gap junctions in future ventral regions of the animal pole at the 32-cell stage.

Animals↗
PubMed1987

Plasma norepinephrine responses to cold challenge in depressed patients and normal controls.

Thirty depressed patients were compared with 39 controls for their plasma norepinephrine (NE) levels in relation to a cold challenge (placing a hand in ice cold water for 1 minute). Depressed patients showed significantly higher plasma NE levels than controls. Unipolar, but not bipolar patients, had significantly higher plasma NE levels than age- and sex-matched controls. Unipolar melancholic patients who were nonsuppressors on the dexamethasone suppression test showed a strong trend to have higher plasma NE levels than suppressors. These results are further evidence that the NE system is dysregulated in depression.

Bipolar Disorder↗
PubMed1987

Pharmacodynamics and pharmacokinetics of ethanol, diazepam and pentobarbital in young and aged rats.

Sleeping time was measured in groups of old and young rats following the intraperitoneal injection of pentobarbital (39.5 mg.kg-1), diazepam (30 mg.kg-1) and ethanol (3 g.kg-1). Concentrations of pentobarbital, and unbound and total diazepam in serum, and ethanol in breath were quantified; as well as whole brain concentrations of diazepam and N-demethyldiazepam. Healthy old rats slept significantly longer than young rats after receiving diazepam and ethanol but not pentobarbital. There were no significant differences in serum or whole brain concentrations of diazepam or N-demethyldiazepam between healthy young and old rats. There were also no changes in the serum pentobarbital or breath ethanol concentrations between the young and old rats. Increases in pharmacologic effect that occur with aging may be caused by alterations in pharmacokinetic parameters or changes at the site of drug action. The cause of an increased pharmacodynamic effect depends upon the specific drug, possibly because these compounds affect the same receptorionophore complex at different sites.

Aging↗
PubMed1986

Enhanced thyrotropin response to thyrotropin releasing hormone in boys at risk for development of alcoholism. Preliminary findings.

Alcoholism is three times more prevalent in men than in women. We studied responses of thyrotropin to protirelin (thyrotropin releasing hormone) in nine sons and eight daughters of patients with familial alcoholism and in eight control boys and seven control girls. Basal and protirelin stimulated triiodothyronine, prolactin, and growth hormone concentrations were also measured. The controls were matched for age, sex, and past alcohol exposure with the index children. The sons of familial alcoholics had significantly higher basal thyrotropin levels, peak thyrotropin levels, and thyrotropin areas under the curve than did the control boys. The daughters of patients with familial alcoholism showed no differences from the control girls. Analyses of triiodothyronine, prolactin, and growth hormone concentrations revealed no differences between the index children and controls. We believe that this is the first report of a male-limited neuroendocrine difference between children of alcoholics and control children. Further studies are needed to elucidate the clinical significance of our preliminary findings.

Adolescent↗