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Biomedical subjects

M Murray

Publications and source records attributed to M Murray.

At least 415 records · Page 23Linked to original sources
PubMed1986

Effects of portal vein ligation on sex hormone metabolism in male rats: relationship to lowered hepatic cytochrome P450 levels.

Hepatic cytochrome P450 levels in male rats fall after portal vein ligation, a procedure that produces total hepatic bypass of portal blood. The present study was undertaken to examine whether changes in sex hormone metabolism could account for these lowered cytochrome P450 levels. Portal vein ligation resulted in testicular atrophy and low serum testosterone concentrations. Serum luteinizing hormone levels were also reduced, suggesting that testicular atrophy was secondary to suppression of the hypothalamic-pituitary-gonadal axis. Serum estrone and estradiol concentrations were significantly increased after portal vein ligation, while the magnitude and delayed onset of increases in urinary total estrogen excretion suggested that this was due largely to increased estrogen production. In male rats, both castration (at 12 wk) and exogenous estrogen administration resulted in changes in hepatic cytochrome P450 levels and ethylmorphine N-demethylase activity that were qualitatively similar to those seen after portal vein ligation. In female and castrated male rats, however, cytochrome P450 was not affected by portal vein ligation. Testosterone supplementation corrected the changes of cytochrome P450 levels in castrated male rats but did not have this effect in portal vein-ligated male rats. It is concluded that changes in sex hormone metabolism do occur after portal vein ligation and may contribute to alterations in cytochrome P450 and drug-metabolizing enzyme activity. Decreased levels of serum testosterone, however, do not alone account for the changes in hepatic drug metabolism in this model, and suppression of a hypothalamic-pituitary factor appears to be important.

Animals↗
PubMed1986

Susceptibility and immune responses of zebu and taurine cattle of West Africa to infection with Trypanosoma congolense transmitted by Glossina morsitans centralis.

Following tsetse-transmitted infection with Trypanosoma congolense, major differences in development of localised skin reactions, the ability to control parasitaemia, the degree of anaemia and in antibody response to trypanosomes were found between the reputedly trypanotolerant breeds of cattle (N'Dama, N'Dama/Baoule crosses, Baoule) and the trypanosusceptible West African Zebu. The local skin reactions that developed in the Zebu were large and severe while those that occurred in the other breeds were smaller and less severe or mild. The timing of appearance of parasitaemia and the height of the first peaks were similar in all the animals, but the Zebu were less able to control subsequent waves of parasitaemia. Possibly reflecting these events, it was only in the Zebu that significant anaemia developed. Neutralizing antibody against homologous metacyclic trypanosomes developed between 14 to 18 days after infection in all breeds of cattle; however, marked differences were found when antibody to trypanosomes derived from first peak parasitaemias were tested in the Zebu and Baoule. Neutralizing antibody against these parasites appeared in the Baoule on day 24 but were not detected in Zebu until day 51. Furthermore, the antibody titres were 3 log2 higher in the Baoule. It was concluded that the trypanotolerance exhibited by the West African taurine cattle might be related to a) their ability to control trypanosome numbers in the skin and in the bloodstream, an outcome that was possibly brought about by the earlier and superior immune response and b) failure to develop anaemia which might be associated with their capacity to control parasitaemia.

Africa, Western↗
PubMed1986

Parasite kinetics and immune responses in efferent prefemoral lymph draining skin reactions induced by tsetse-transmitted Trypanosoma congolense.

Localised skin reactions (chancres) occurred on the flanks of cattle at the sites of deposition by tsetse flies of metacyclic forms of Trypanosoma congolense. Marked enlargement of the draining prefemoral lymph nodes accompanied the development of the skin reactions. Lymph from these nodes was collected through polyethylene cannulae inserted into the efferent lymphatics, and examined for trypanosomes, cells and antibody content. Within 6-9 days after infected tsetse fly bite, trypanosomes were detected in the efferent lymph; this preceded their appearance in the blood by 3-6 days, indicating that the lymphatic system acted as a major route for the passage of trypanosomes from the skin into the bloodstream. Responses induced in the draining lymph node as a result of trypanosome migration included a 2-3-fold increase in the volume of lymph and up to a 10-fold increase in lymphocyte output, including blast lymphocytes and plasma cells. Neutralising antibodies to metacyclic trypanosomes were detected in lymph and serum by Day 14 after infection, although in 2 out of 4 animals investigated, they were not demonstrated in serum until Day 18. Trypanosomes were also found in small numbers in efferent lymph of the prefemoral lymph node on the flank contralateral to the infected tsetse bites after development of parasitaemia. Increases in lymph flow and cellular output occurred about the same time in the ipsilateral and the contralateral efferent lymphatics, but were significantly less in the latter. Homologous challenge of immunised calves with tsetse-transmitted parasites revealed that trypanosomes were eliminated at the level of the skin or within the draining lymph node, as no parasites were detected in efferent lymph.

Animals↗
PubMed1986

Interference between different serodemes of Trypanosoma congolense in the establishment of superinfections in goats following transmission by tsetse.

When domestic ruminants cyclically infected with Trypanosoma congolense are superinfected with a different serodeme of the same species, an interference phenomenon occurs which delays the development of the second cyclical infection. Experiments were carried out to investigate the influence of the time interval between the two infections on the degree of interference and to follow the course of the superinfection clinically, serologically and histologically. Goats infected with tsetse-transmitted T. congolense IL 1587 were either infected simultaneously or 7, 14, 18, 28 or 35 days later with a different serodeme, T. congolense IL 1180. Skin reactions due to superinfection were either absent or smaller in size and delayed in onset compared with control animals undergoing a primary infection with T. congolense IL 1180 which had been initiated by tsetse fly bites. All animals were treated with the trypanocidal drug Berenil 21 days after superinfection and 3 weeks later challenged with T. congolense IL 1180 using tsetse flies. The goats that had been infected simultaneously with the two serodemes were immune to the homologous challenge, but 11 (85%) of the animals that had been superinfected were not. The effect of interference on the host immune response to T. congolense IL 1180 was most marked in animals superinfected at day 7; thereafter there was evidence that the ability to respond immunologically against secondary infection was gradually recovered. Histological examination of skin removed 7 days after a simultaneous infection of goats with two serodemes, showed trypanosomes and a cellular reaction similar to that following infection with a single serodeme. In skin removed 7 days after superinfection of goats that had been infected for 7 days, the cellular response was less pronounced and trypanosomes were not seen, although by 14 to 16 days numerous trypanosomes were present and there was a marked cellular infiltrate. It is postulated that the presence or absence of a factor induced shortly after initiation of a trypanosome infection in the skin of goats might delay parasite development when metacyclic trypanosomes are deposited by tsetse following superinfection.

Animals↗
PubMed1986

Inhibition of hepatic microsomal monooxygenase activity by cinchocaine: mechanistic studies and effects of ionization.

The quinoline-based local anaesthetic cinchocaine (dibucaine) was found to be a mixed-type inhibitor of microsomal aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities from control and phenobarbitone-induced rat liver in-vitro. Cinchocaine also elicited a characteristic type I optical difference spectrum in oxidized liver microsomes (Ks = 24 microM; delta Amax = 3.4 X 10(-3) absorbance units (nmol cytochrome P450)-1) but did not appear to bind to the reduced form of the cytochrome. Additional studies indicated that cinchocaine competitively inhibited the type I spectral binding of substrate (aminopyrine) to ferric cytochrome P450. Studies of monooxygenase inhibition by cinchocaine over a relatively narrow pH range (6.5-8.5) indicated that, as might be expected, the un-ionized form of the drug is associated with inhibitory potency superior to that of the ionized form. Thus 40% inhibition of aminopyrine N-demethylase activity was observed with 100 microM cinchocaine at pH 8.0 and 8.5 (24% and 50% un-ionized drug, respectively), whereas only 16% inhibition was observed at pH 6.5 (1% un-ionized drug). These findings suggest that the inhibitory action of cinchocaine is mediated exclusively via an interaction with ferric cytochrome P450 and that the extent of ionization is a determinant of mixed function oxidase inhibition.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1986

Infectivity to cattle of metacyclic forms of Trypanosoma (Nannomonas) congolense propagated in vitro. I. Development of localized skin reactions following intradermal inoculation.

Skin reactions similar to those induced by tsetse infected with Trypanosoma congolense were elicited in cattle at sites of intradermal inoculation of in vitro propagated parasites which morphologically resembled metacyclic trypanosomes. The time to detection of the reaction, the time to maximal size and the maximal size attained were dependent on the number of parasites inoculated, although it was possible to induce a skin reaction with as few as 20 trypanosomes. All cattle became infected with the initial detection of the skin reaction preceding parasitaemia by 3 to 7 days.

Animals↗
PubMed1986

Increase in melanin formation and promotion of cytotoxicity in cultured melanoma cells caused by phosphorylated isomers of L-dopa.

A new class of compounds, termed "dopa phosphates," is described. The compounds contain phosphate ester linkages at positions 3 and/or 4 of the phenylalanine ring. Dopa phosphates are highly soluble compounds which are stable over a wide range of pH values and are not hydrolyzed by boiling in concentrated acid. Synthetic yields of greater than 90% can be obtained using dopa as starting material. Exposure to alkaline phosphatase results in hydrolysis of the phosphate moieties and production of dopa. Dopa phosphates do not inhibit dopa oxidase (tyrosinase, EC 1.14.18.1) activity. Dopa oxidase does not catalyze the conversion of dopa phosphates into melanin unless the dopa phosphates are first treated with alkaline phosphatase. Dopa phosphates, when compared to L-dopa, are stable in the presence of O2 and are not oxidized by serum proteins. In the presence of cultured melanoma cells, dopa phosphates are readily converted into melanin, indicating that the cells are able to produce dopa from dopa phosphates. At high concentrations, dopa phosphates are cytotoxic toward melanoma cells in culture. The cytotoxicity is enhanced at least 3-fold by pretreatment of cells with melanotropin and is prevented by phenylthiourea, an inhibitor of dopa oxidase activity. These results, combined with studies on the uptake of radioactive forms of dopa phosphates (32P and 14C), indicate that phosphorylated isomers of dopa are efficiently taken up by Cloudman melanoma cells and are readily converted by the cells into a melanin precursor, presumably L-dopa.

Animals↗
PubMed1986

Replacement of synaptic terminals in lamina II and Clarke's nucleus after unilateral lumbosacral dorsal rhizotomy in adult cats.

Evidence from previous light-microscopic studies suggested that lumbosacral dorsal rhizotomy in cats elicits sprouting of converging undamaged systems into partially deafferented Clarke's nucleus and lamina II. We therefore applied quantitative electron-microscopic methods to determine whether this sprouting is associated with replacement of synaptic terminals (reactive reinnervation). We used stereological and morphometric methods to estimate terminal number per cross section in right and left lamina II and Clarke's nucleus in adult cats after acute and chronic unilateral (right-sided) lumbosacral deafferentation. Planimetric measurements of area indicated no significant shrinkage of either region as a result of the deafferentation; an increase in area occupied by glial cytoplasm (gliosis) equaled the decrease occupied by axonal components. The gliosis appears to persist indefinitely, although the degenerative debris stainable with conventional light-microscopic methods does not persist. Analysis of the synaptic population of lamina II reveals that the large central or "scalloped" terminals comprise a substantial fraction (greater than 40%) of the total area occupied by terminals in control material and that this population is largely lost upon deafferentation, leaving a large population of small terminals with spherical vesicles. Nevertheless, estimates of total terminal number indicate no difference between control and deafferented lamina II, suggesting a rapid and virtually complete replacement of lost dorsal root terminals by small terminals containing spherical vesicles. Terminal number in Clarke's nucleus also remains constant despite the loss of the dorsal root input. We conclude that there is also a virtually complete and rapid replacement of lost terminals in Clarke's nucleus by terminals containing spherical vesicles. These data provide an example of a case in which axonal sprouting demonstrated with light-microscopic methods is associated with electron-microscopic evidence of reactive reinnervation.

Animals↗
PubMed1986

Susceptibility of buffaloes, cattle and goats to infection with different stocks of Trypanosoma vivax transmitted by Glossina morsitans centralis.

A comparison was made of the susceptibility of buffaloes, cattle and goats to infection with Trypanosoma vivax transmitted either by Glossina morsitans centralis or by syringe inoculation. Three different isolates of T vivax (two from East Africa, one from West Africa) were used to compare skin reactions, parasitaemia, anaemia and the development of trypanosome-specific antibodies in buffaloes, cattle and goats. African buffaloes reared in captivity in an area free from trypanosomiasis proved to be highly resistant to infection with the three stocks of T vivax tested, irrespective of whether infection was by tsetse transmitted metacyclic forms or by intradermal or intravenous inoculation of bloodstream forms of the parasite. The bites of 19 tsetse infected with a West African T vivax stock did not cause local skin reactions, detectable bloodstream infections or antibody responses in two buffaloes. Following the bites of 120 tsetse flies infected with the same stock, two different buffaloes showed no local skin reactions, but had detectable bloodstream infections without showing signs of anaemia. Cattle and goats infected in a similar way showed severe local inflammatory skin reactions, high levels of parasitaemia and severe anaemia. The two East African stocks of T vivax caused no local skin reactions and only a transient parasitaemia in buffaloes following tsetse-transmitted infection or intradermal inoculation of bloodstream forms. On the other hand, cattle and goats infected with the East African stocks showed high parasitaemias but local skin reactions only occurred in the goats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Axonal transport of beta-receptors during the response to axonal injury and repair in locus coeruleus neurons.

Injections of the catecholamine neurotoxin, 6-hydroxydopamine, were placed in the ascending locus coeruleus (LC) pathway in the right cerebral cortex of rats partially destroying the noradrenergic projection to the somatosensory cortex. Norepinephrine (NE) levels fell to a nadir of 49% of control over the first 14 days, associated with a 40% increase in the number of beta-adrenoreceptor binding sites (labeled with [3H]dihydroalprenolol; [3H]DHA) in the denervated cortex. Both NE levels and cortical beta-receptor binding returned to control levels by 28 days. Similar changes, of lesser magnitude, also occurred in the unlesioned, left somatosensory cortex. Catecholamine histofluorescence studies supported these findings of denervation and reinnervation of the right cortex over a 3-month period. Anterograde axonal transport of beta-receptors was assessed by measuring the accumulation of beta-receptor binding sites ([3H]DHA) behind a second lesion placed in the more proximal portion of the ipsilateral LC pathway. Anterograde transport was completely blocked at 4 days, during the initial fall of NE levels, then was increased to 200% of control at 14-21 days, when recovery of cortical NE levels was beginning, and then returned towards control levels by 2-3 months when normal NE levels had been restored.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Halothane hepatitis. Detection of a constitutional susceptibility factor.

We studied susceptibility to halothane hepatitis with an in vitro test that detects cell damage from electrophilic drug intermediates. Metabolites of phenytoin were generated by incubation of phenytoin with rat hepatic microsomes in the presence of the epoxide hydrolase inhibitor 1,1,1-trichloropropene oxide (TCPO), which prevents the further metabolism of phenytoin to an inert metabolite. In lymphocytes exposed to this system, cytotoxicity was measured by trypan blue dye exclusion and was expressed as the percentage increase in trypan blue-positive cells after the addition of TCPO. In the presence of TCPO, lymphocytes from 11 patients with halothane hepatitis exhibited an increase in cytotoxicity at 0.06 mM phenytoin that was eight times greater than the increase in healthy controls (54 +/- 10 per cent [mean +/- S.E.M.] vs. 7.1 +/- 2.2 per cent, P less than 0.0001). Patients with other liver diseases and persons recently exposed to halothane without adverse effects did not differ from healthy controls. In three patients with halothane hepatitis who were studied serially, the lymphocyte abnormality was still present after 13 months. Family studies revealed abnormal results on 10 cytotoxicity tests among 19 members of four families. We propose that there is a familial, constitutional susceptibility factor that predisposes persons to halothane hepatitis.

Adult↗
PubMed1985

RNA content of normal and axotomized retinal ganglion cells of rat and goldfish.

The responses of rat and goldfish retinal ganglion cells to axotomy were examined by a quantitative cytochemical method for RNA and by morphometric measurement 1-60 (rat) and 3-90 (goldfish) days after interruption of one optic nerve or tract intracranially. Unoperated control animals were studied also. The RNA content of axotomized neurons of rat fell 7-60 days postoperatively. Additionally, atrophy of the axotomized somas occurred. Over time, neuronal atrophy approximately paralleled the loss of RNA, and mean cell area and RNA content were reduced by about 25% 60 days after axotomy. Incorporation of 3H-uridine by axotomized neurons declined also. Axotomized retinal ganglion cells of goldfish behaved differently from those of the rat and showed increases in RNA content, most conspicuously 14-60 days postoperatively. Enlargement of axotomized fish neurons occurred but was less proportionately than concomitant increases in RNA content. The nonaxotomized ganglion cells of goldfish displayed statistically significant increases in size and RNA content 14-49 days after unilateral optic nerve or tract lesions. In contrast, alterations in rat retinal ganglion cells contralateral to interruption of one optic nerve were of limited and questionable significance. The contrasting reactions to axotomy by the retinal ganglion cells of these two vertebrates, one of which regenerates optic axons and one of which does not, may support the proposition that the somal response to axon injury has an important bearing upon the success or failure of CNS regeneration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Sciatic nerve transection produces death of dorsal root ganglion cells and reversible loss of substance P in spinal cord.

Sciatic nerve section has been shown to reduce substance P (SP) in the dorsal horn of the spinal cord, but the mechanism which underlies the reduction is not understood. Whether SP levels subsequently recover as they do after dorsal rhizotomy has also been unknown. To test the hypothesis that transganglionic degeneration of primary afferents contributes to the reduction of SP, we have studied the changes in SP which result from section of the cat sciatic nerve and determined the extent of dorsal root ganglion (DRG) cell death. Sciatic nerve section resulted in DRG cell death, but the amount was variable and not seen in all animals. Reduction in dorsal horn and DRG SP was seen in all animals, and in the spinal cord it was followed by recovery. These sequelae resemble the changes which follow dorsal rhizotomy. After sciatic nerve section, the reduction in dorsal horn SP is smaller than after rhizotomy, the recovery more complete, and both the reduction and the recovery proceed more slowly. Evidence is presented that similar mechanisms may contribute to depletion of intraspinal SP after sciatic nerve section and after dorsal rhizotomy. The mechanisms contributing to recovery of spinal cord SP after sciatic nerve section may resemble known mechanisms of recovery that occur when the lesion is central.

Animals↗
PubMed1985

Selective retinal reinnervation of a surgically created tectal island in goldfish. I. Light microscopic analysis.

Through anatomical and physiological studies of the regenerating retinotectal projection of goldfish, we sought to determine whether the establishment of a topographic projection is attained through a refinement of an initially less precise pattern of innervation. A 1-mm-wide mediolateral strip of caudal tectum was removed so that a small island of tectal tissue was spared at the caudal pole, and the contralateral nerve was either crushed (TIX) or left intact (TI). The presence of regenerated axons in the ablated zone and the reinnervation of the caudal island were assessed with anterograde and retrograde labeling methods in the following postoperative intervals: early, 20-50 days; middle, 50-110 days; and late, more than 170 days. The anterograde radioautographic method revealed that the appropriate layers of the tectal island became reinnervated by optic axons during the early period. During the middle and late periods, one to several large, discrete bundles bridging the lesion zone along the surface of exposed subtectal structures were readily identified both by radioautography and by anterograde or retrograde labeling following application of horseradish peroxidase to the transected optic nerve or tectal island, respectively. In contrast, the anterograde horseradish peroxidase method did not reveal axon bundles extending caudal to the half-tectum in the absence of a tectal island. Among TIX cases, retrograde horseradish peroxidase labeling of the contralateral nasal retina was more widespread in the middle period than in the late period, a result we interpret as reflecting an improvement in topographical precision with time. The area of retinal labeling among TIX cases in the late period was similar to that following caudal tectal injection in cases with simple nerve crush, although it was still elevated above normal control values. Physiological maps indicated a focal representation of the nasal retina in the tectal island in both periods and did not reveal a transient extreme convergence of retinal input. These findings are discussed in relation to Sperry's chemoaffinity theory.

Animals↗
PubMed1985

Selective retinal reinnervation of a surgically created tectal island in goldfish. II. Electron microscopic analysis.

In the preceding study (Edwards et al., '85), we showed that regenerating optic axons reestablish a topographically restricted projection to a caudal tectal island created by surgical removal of a 1-mm-wide strip of caudal tectum in goldfish. In the present ultrastructural study, we evaluated the dependence of this axonal outgrowth on the presence of tectal target tissue caudal to the gap. Axon counts in the lesion zone were compared between cases with complete caudal tectal ablation and cases with ablation sparing a caudal tectal island (with and without optic nerve crush). During the postoperative interval of 20-50 days (early period), up to about 1,000 unmyelinated axons with features characteristic of optic axons were present in numerous small subpial bundles in both preparations. In the subsequent interval of 50-110 days (middle period), less than 200 axons were counted caudal to simple half-tecta, whereas 4,000-14,000 myelinated and unmyelinated axons were present in a few large bundles which crossed the lesion zone of tectal island cases. In this period, optic terminals could be demonstrated in the tectal island using the anterograde horseradish peroxidase method. At 170-300 days after surgery (late period), bridging bundles contained between 2,000 and 6,000 largely myelinated axons. We conclude that caudal tectal tissue is not necessary for the initial outgrowth of a small number of axons beyond a rostral half-tectum. The target is essential, however, for the maintenance of these axon fascicles and for the subsequent massive outgrowth of axons to the island. The contributions of glial guidance, diffuse exploratory outgrowth, and target-produced trophic factors to the formation of an initially exuberant projection to the island are discussed. A process of selective axon collateral withdrawal is proposed to account for the decrease in axon numbers within bridging bundles in the late period and for the late restriction in the retinal origin of the island projection indicated by results in the preceding study (Edwards et al., '85).

Animals↗
PubMed1985

Substance P in the interpeduncular nucleus of the rat: normal distribution and the effects of deafferentation.

The interpeduncular nucleus (IPN) is a midbrain structure that receives its major afferents from the medial habenulae via the fasciculi retroflexi. Among the axons projecting to the IPN is a population of substance P (SP)-containing axons. The IPN has been subdivided into the central, dorsal, intermediate, rostral, and lateral subnuclei using cytoarchitectonic criteria. The distribution of SP among these subnuclei was determined by using Sternberger's ('79) peroxidase-antiperoxidase technique. In the normal IPN the rostral subnucleus can be subdivided into two sectors on the basis of SP content. The ventral sector contains a moderate amount of SP and scattered SP positive perikarya. The dorsal cap of the rostral subnucleus contains denser SP than the ventral sector and it is continuous with the SP found in the dorsal subnucleus. The lateral subnuclei contain the densest SP found in the IPN and appear as laterally placed columns that expand in size caudally. The central and intermediate subnuclei contain very sparse SP. The fasciculus retroflexus was destroyed in 30 animals unilaterally or bilaterally and animals were perfused 4 days to 3 months postoperatively. After unilateral fascicular lesion, the SP in the rostral part of the ipsilateral lateral subnucleus is almost abolished, but caudally the decrease is confined to its lateral aspect. There is no visible decrease contralateral to the lesion. SP in the rostral part of the cap of the rostral subnucleus is decreased ipsilaterally but no loss is seen contralaterally or caudally. Animals with bilateral lesions show a great decrease in staining in the dorsal cap of the rostral subnucleus and the lateral subnuclei, with no decrease seen in the central, dorsal, or intermediate subnuclei. These results confirm that the origin of most of the SP in the IPN is fasciculus retroflexus fibers, but some of the SP arises from intrinsic SP perikarya located in the ventral sector of the rostral subnucleus and some may also arise from other sources. The areas of the IPN that receive bilateral SP projections from the fasciculus retroflexus (parts of the lateral and rostral subnuclei) show evidence for replacement of SP after lesion. This replacement implies sprouting or an increase in production of SP by remaining systems.

Afferent Pathways↗