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Biomedical subjects

R J Walsh

Publications and source records attributed to R J Walsh.

At least 37 records · Page 2Linked to original sources
PubMed1988

In vivo autoradiographic analysis of prolactin binding in brain and choroid plexus of the domestic ring dove.

The binding of intravenously administered prolactin to choroid plexus and brain tissue was determined radioautographically in the ring dove, a species that exhibits prolactin-induced alterations in brain function. An intense autoradiographic reaction was detected over the epithelial cells of the choroid plexus 5 min after the intravenous injection of 125I-ovine prolactin. A significant reaction was also observed over the infundibulum but no significant uptake of prolactin occurred in other brain areas. The binding of radiolabelled prolactin to infundibulum appeared to be non-specific, since excess unlabelled hormone did not reduce silver grain density. In contrast, 125I-ovine prolactin binding in choroid plexus was significantly reduced by excess unlabelled ovine prolactin or human growth hormone, but not by ovine luteinizing hormone. Specific binding to choroid plexus was also detected in vitro. The lack of significant brain uptake of prolactin in vivo is discussed in relation to recent in vitro evidence for specific binding sites for prolactin in several dove brain regions. Similarities between the binding results obtained in this avian species and those reported previously in mammals suggest that the two vertebrate groups exhibit similar patterns of prolactin interaction with neural target tissues.

Animals↗
PubMed1987

Prolactin causes increased turnover of dopamine in 10-day-old rat median eminence.

The present work examines the ability of prolactin to enter the CNS of the rat and effect its feedback stimulation of dopamine release prior to the appearance of prolactin receptors in choroid plexus (i.e., 10 days postnatal). An inhibitor of tyrosine hydroxylase was used to allow the assessment of dopamine turnover separate from synthesis and transport of the amine. Chronic but not acute hyperprolactinemia resulted in increased dopamine release relative to vehicle-treated controls, as shown by diminished fluorescence intensity in the median eminence. These results indicate that activation of the prolactin short-loop feedback system occurs by 10 days postnatal, prior to the appearance of prolactin receptors at the choroid plexus.

Animals↗
PubMed1987

Antitumor imidazotetrazines. 14. Synthesis and antitumor activity of 6- and 8-substituted imidazo[5,1-d]-1,2,3,5-tetrazinones and 8-substituted pyrazolo[5,1-d]-1,2,3,5-tetrazinones.

The systematic variation of the potent antitumor agent mitozolomide (1) is extended to cover alteration of substituents at positions 6 and 8 and to change the imidazo[5,1-d]-1,2,3,5-tetrazinone (1) skeleton to the isomeric pyrazolo-[5,1-d]-1,2,3,5-tetrazinone (17) skeleton. The series of eight 6-alkyl and 6-aralkyl derivatives of 1 showed optimal antitumor activity when the group was small or linear, but activity diminished as size and branching of this substituent increased. This may reflect altered transport characteristics, or failure of the enlarged derivatives to fit a binding site, or possibly a reduced tendency for the derivatives having bulky groups at position 6 to hydrolytically generate the putatively active triazenes (21). Testing of 14 derivatives of 1 differently substituted at position 8 revealed a complex structure-activity relationship, with good antitumor activity obtained for carbamoyl and sulfamoyl groups bearing small substituents. The 8-methylsulfonyl compound had noteworthy activity, but the 8-cyano, 8-nitro, and 8-phenyl derivatives were devoid of useful antitumor activity in these tests. From the limited number of pyrazolotetrazinones (17) reported here, it is suggested that the same conclusions as regards activity also hold true for this ring system.

Animals↗
PubMed1987

A receptor-mediated mechanism for the transport of prolactin from blood to cerebrospinal fluid.

PRL interacts with areas of the central nervous system which reside behind the blood-brain barrier. While vascular PRL does not cross this barrier, it is readily accessible to the cerebrospinal fluid (CSF) from which it may gain access to the PRL-responsive areas of the brain. Studies were undertaken to characterize the mechanism responsible for the translocation of PRL from blood to CSF. Rats were given external jugular vein injections of [125-I]iodo-PRL in the presence or absence of an excess of unlabeled ovine PRL (oPRL), human GH, bovine GH, or porcine insulin. CSF and choroid plexus were removed 60 min later. CSF samples were electrophoresed on sodium dodecyl sulfate-polyacrylamide slab gels and resultant autoradiographs were analyzed with quantitative microdensitometry. The data revealed that unlabeled lactogenic hormones, viz. oPRL and human GH, caused a statistically significant inhibition of [125I]iodo-PRL transport from blood to CSF. In contrast, nonlactogenic hormones, viz bovine GH and insulin, had no effect on [125I]iodo-PRL transport into the CSF. An identical pattern of competition was observed in the binding of hormone to the choroid plexus. Furthermore, vascular injections of [125I]iodo-PRL administered with a range of concentrations of unlabeled oPRL revealed a dose-response inhibition in the transport of [125I]iodo-PRL from blood to CSF. The study demonstrates that PRL enters the CSF by a specific, PRL receptor-mediated transport mechanism. The data is consistent with the hypothesis that the transport mechanism resides at the choroid plexus. The existence of this transport mechanism reflects the importance of the cerebroventricular system in PRL-brain interactions.

Animals↗
PubMed1986

The ontogeny of specific prolactin binding sites in the rat choroid plexus.

The development of prolactin receptors in the choroid plexus of the rat was examined using the in vivo autoradiographic approach employing the principle of competitive binding. Experimental animals were injected with [125I]prolactin alone (total binding) while control animals received [125I]prolactin and a 500-fold excess of unlabelled prolactin (non-specific binding). Newborns as well as animals 10, 14 and 18 days postnatal were studied. Three minutes following hormone injection animals received an intracardiac perfusion with fixative and tissues were prepared for quantitative light microscopic autoradiography. The choroid plexus first demonstrated specific binding of prolactin, i.e. a statistically significant difference in the autoradiographic reactions between experimental and control animals, at 14 days postnatal. The lactogen specificity of these binding sites was further defined by the ability of [125I]prolactin to be displaced by unlabelled human growth hormone, which is lactogenic in rats, and not by unlabelled insulin, which is structurally dissimilar to prolactin. Morphometric analyses were performed on electron micrographs of choroid plexus from 10- and 14-day postnatal rats. The volume densities of constituents known to be enriched in polypeptide hormone receptors were measured and compared. Small cytoplasmic vesicles and tubules were statistically significantly more abundant in 10-day-old rats than in 14-day-old animals. It is conjectured that these vesicles and tubules contain an intracellular pool of prolactin receptors whose decrease at 14 days parallels the expression of specific binding sites at the cell surface.

Adrenal Cortex↗
PubMed1985

NH2-terminal specificity and axonal localization of adrenocorticotropin binding sites in rat median eminence.

Adrenocorticotropin binding sites in the rat median eminence have been localized in vivo. These binding sites occur in the basalar zone, which is rich in axonal endings. Using competitive binding and quantitative light-microscope radioautography, we found that the median-eminence binding site, in contradistinction to the adrenal receptor, binds specifically the residue 4-10 region of the adrenocorticotropin molecule. Using quantitative electron-microscope radioautography and median-eminence deafferentation, we localized the binding sites to axon terminals in this region. In time-delayed uptake studies using light-microscope radioautography, we failed to observe concentration of radiolabel in neurons of the medial basal hypothalamus after the direct injection of radioiodinated adrenocorticotropin(1-24) into the median eminence.

Adrenal Glands↗
PubMed1984

Binding and uptake of [125I]iodoprolactin by epithelial cells of the rat choroid plexus: an in vivo autoradiographic analysis.

Light and electron microscopic (EM) autoradiography were used to determine the subcellular fate of [125I] iodo-PRL that specifically binds to epithelial cells of the rat choroid plexus. Experimental animals (total binding) received an external jugular vein injection of ovine [125I]iodo-PRL, whereas control animals (nonspecific binding) received an identical dose of [125I]iodo-PRL plus a 500-fold excess of unlabeled PRL. Experimental and control animals were killed by vascular perfusion 3, 20, 40, 60, and 240 min after hormone injection. Choroid plexuses were removed, processed to Epon, and prepared for light and EM autoradiography. Quantification of silver grains at the light microscopic level revealed an intense autoradiographic reaction over the epithelial cells of experimental animals 3, 20, 40, and 60 min after hormone injection. The co-injection of unlabeled PRL resulted in a statistically significant reduction in the autoradiographic reaction throughout the initial 60 min of the test period, reflecting specific binding of PRL during this interval. Analysis of EM autoradiographs revealed that the initial binding of [125I]iodo-PRL occurred primarily at the basal and lateral plasmalemma of the epithelial cells. With time there was a dramatic reduction in the amount of radiolabel localized to the cell membrane and a concomitant increase in silver grains localized over the interior of the cells. Internalized [125I]iodo-PRL exhibited a preferential localization to small cytoplasmic vesicles, short tubules, multivesicular bodies, and dense bodies. Combined acid phosphatase cytochemistry and EM autoradiography revealed that only 11.2% of the internalized silver grains were localized over acid phosphatase-positive structures 40 min after injection. The results indicate that subsequent to the initial binding of [125I]iodo-PRL to the cell membrane, internalization and translocation occurs primarily to nonlysosomal cytoplasmic organelles. The study also demonstrates at least a partial or ultimate entrance of internalized PRL to the lysosomal system.

Acid Phosphatase↗
PubMed1983

Characterization of lactogen binding sites in choroid plexus.

Prolactin binding sites have been demonstrated previously in rat choroid plexus using in vivo radioautography (Walsh et al. 1978). In the present study we have employed this procedure to characterize further the binding specificity of these sites. Following the injection of 125I-hGH or 125I-oPRL an intense radioautographic reaction was observed over the choroid plexus. The reaction was significantly reduced by coinjecting excess unlabeled hGH or oPRL but not bGH. The specific binding of 125I-oPRL to choroid plexus from rat, rabbit, sheep and pig was demonstrated by in vitro assays. Subsequently a survey of 125I-oPRL specific binding in a number of regions of pig brain indicated that the highest binding was in choroid plexus. A detailed study of the characteristics of 125I-oPRL binding to pig choroid plexus was undertaken. Specific binding increased with choroid plexus homogenate protein to a maximum of 30% (3.0 mg protein/tube). Binding was maximum at 4 degrees C by 30-40 h of incubation. During the incubation the integrity of 125I-oPRL in the incubation medium declined steadily to 50% after 20 h and 35-40% after 48 h. Radioactivity eluted from binding sites was fully intact as judged by rebinding to lactogen receptor-enriched membranes. Binding showed a broad pH optimum of 5.5-7.5. On cell fractionation of choroid plexus binding sites were enriched in microsomes. The binding of 125I-oPRL and 125I-hGH was inhibited in a dose-dependent manner by unlabeled lactogens and was of high affinity. hGH and oPRL were equipotent inhibitors of the binding of both radioligands whereas bGH and a variety of structurally unrelated peptides were non-inhibitory.

Animals↗
PubMed1983

Acrosoxacin in the treatment of uncomplicated gonorrhoea.

Acrosoxacin was given as a single 300 mg oral dose to 105 patients with acute gonorrhoea. Of the 100 patients followed completely there was a 93% cure rate and 33% of men developed postgonococcal urethritis (PGU). This compared with a 97% cure and 30% PGU with 2 megaunits penicillin. The in vitro activity of acrosoxacin in Nottingham against strains of Neisseria gonorrhoeae showed that it was a highly active agent with 90% of strains inhibited by a concentration of 0.03 mg/l.

4-Quinolones↗
PubMed1983

Folate supplements and phenytoin-salicylate interaction.

We found biphasic fluctuations of serum phenytoin level when aspirin was added to chronic phenytoin therapy for an epileptic patient. The total serum phenytoin level was lowered initially by addition of aspirin. However, after 4 months on phenytoin-aspirin combination therapy, he showed elevated serum phenytoin levels, mild nystagmus, and serum folate deficiency.

Adult↗
PubMed1982

Response of tanycytes to aging in the median eminence of the rat.

Age-related changes in tanycytes of the median eminence were observed at both the light and electron microscopic level in male and female rats at ages 4 weeks to 14 months. The most obvious changes involved a marked progressive increase in number and size of droplets identified histochemically as neutral lipid and the development of complex degenerate bodies in the perivascular contact zone. These degenerate bodies consisted of large multiple complexes of myelin figures containing intercalated channels and pools of electron-dense material. They often occurred interspersed among large lipid droplets. The degenerate bodies (myelin figure complexes) and associated lipid droplets occupied much of the contact zone in the older animals. Evidence of axonal degeneration and tanycytic phagocytosis of deteriorating neural elements was also present. These age-related changes occurred independent of sex and were not affected by gonadectomy. This tanycyte response to aging in the median eminence is very similar to the response of neurohypophysial pituicytes to axonal degeneration, suggesting a phagocytic glial role for tanycytes.

Aging↗
PubMed1982

Early postnatal development of the arcuate nucleus in normal and sexually reversed male and female rats.

The ultrastructural characteristics of the arcuate nucleus in the rat were examined at days 2, 5, 10 and 15 postpartum in order to evaluate the cytological development of the nucleus during sexual differentiation of the hypothalamus. In an effort to accentuate potential steroid-dependent structural features, the nucleus in normal male and female rats was compared with that of rats in which sexual differentiation had been reversed, by subcutaneous injection of testosterone proprionate in neonatal female rats, and by bilateral castration of neonatal male rats. The arcuate nucleus did not reveal any evidence of sexual dimorphism nor any effects of neonatal castration or androgenisation. The nuclei of any animals exhibited an increase, with age, in morphologically mature neurons and synapses. At day 15, however, the nuclei still possessed features indicative of an immature neural system, including organelle-poor profiles of young neurons, growth cones, focal points of cellular degeneration, and a lack of myelinated axons and morphologically mature macroglial cells. Of particular interest was the observation that neonatally-castrated male rats failed to exhibit a quantitative increase in whorl bodies by day 15 post partum, in contrast to the characteristic increase in whorl bodies observed in male rats that were castrated in adulthood. The results indicate that the arcuate nucleus undergoes progressive structural maturation during sexual differentiation of the hypothalamus and that this development is not altered ultrastructurally by changes in the steroid environment. At day 15 postpartum, an age at which sexual differentiation is irreversibly fixed, the nucleus remains a partially developed neural system. Further structural maturation, both neuronal and glial, will undoubtedly contribute to changes in hypothalamic regulation of the pituitary-gonad axis which occur with age. The lack of whorl body proliferation in neonatally-castrated males indicates that the arcuate nucleus of developing animals does not respond morphologically to negative steroid feedback mechanisms in a manner comparable to that of adults. The proliferation of whorl bodies in response to steroid withdrawal is thus an age-dependent phenomenon.

Animals↗
PubMed1981

Directional dominance for low IgM and IgA levels.

A biometrical genetical analysis of IgG, IgM, and IgA levels in 134 sets of twins is reported. High heritabilities, around .8, are found for all three immunoglobulin levels, and possible reasons for lower heritabilities found in family studies are discussed. There is evidence for genetical dominance tending to decrease IgM and IgA levels, but there is no evidence for the importance of family environment although the presence of dominance may make its detection difficult. The causes of covariation in the three measurements are unclear in males but in females appear to be mainly environmental in correlations with IgA and equally genetical and environmental in the IgG-IgM correlation.

Adolescent↗
PubMed1980

Radioautographic identification of lactogen binding sites in rat median eminence using 125I-human growth hormone: evidence for a prolactin "short-loop" feedback site.

The binding characteristics of human growth hormone were exploited to identify radioautographically lactogen binding sites in the rat median eminence. Following systemic injection 125I-human growth hormone bound preferentially to the lateral palisade zone, a region of median eminence rich in dopamine and LHRH. Coinjection of 125I-human growth hormone with an excess of unlabeled human growth hormone or ovine prolactin, but not bovine grown hormone, competitively blocked 125I-human growth hormone binding to the external median eminence. These observation provide direct evidence of recognition sites for lactogenic hormones in a discrete region of the median eminence associated with hypothalamic regulation of hypophyseal prolactin and luteinizing hormone secretion. Median eminence lactogen binding sites may mediate presumed direct effect of lactogenic hormones on the reproductive functions of the hypophysiotropic hypothalamus.

Animals↗
PubMed1980

Sex differences in the inheritance of some anthropometric characters in twins.

Biometrical genetical techniques have been applied to the analysis of certain anthropometric characters measured in 134 pairs of adult twins. After allowing for assortative mating it appears that there is a family environment (E2) component for variation in height larger than previously reported. "Fatness" traits - weight, ponderal index, and skinfold thickness - all show higher heritabilities in males and substantial E2 components in females, and reasons for this are discussed. The same is true for cephalic index and forearm length but the reason for these differences is not so obvious. Head length shows a much higher heritability than head breadth. A larger sample of DZ opposite-sex pairs would allow more powerful discrimination, but the variety of patterns of variation revealed by the model-fitting approach used here justify its use over more traditional techniques.

Anthropometry↗