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Biomedical subjects

M Murray

Publications and source records attributed to M Murray.

At least 325 records · Page 18Linked to original sources
PubMed1990

Structure-activity relationships in the in vitro modulation of rat hepatic microsomal androst-4-ene-3,17-dione hydroxylase activities by derivatives of 5 alpha- and 5 beta-androstane.

The relationships between structure and inhibitory potency toward microsomal cytochrome P-450 (P-450)-mediated androst-4-ene-3,17-dione hydroxylase activities were investigated in rat liver with a series of 5 alpha- and 5 beta-androstane derivatives. 5 beta-Reduced steroids (containing a cis-A/B ring junction) were more potent inhibitors than the 5 alpha-reduced epimers (containing a trans-A/B ring junction) except in the case of the 17 beta-hydroxy-substituted derivatives. The most effective inhibitor was 5 beta-androstane-3 beta-ol which exhibited I50 values of 7 and 27 microM against androstenedione 16 alpha- and 6 beta-hydroxylase activities, which are catalysed by P-450 IIC11 and IIIA2, respectively. In general, these two pathways of steroid hydroxylation were more susceptible to inhibition than the 7 alpha- and 16 beta-hydroxylase pathways. The 7 alpha-hydroxylase enzyme (P-450 IIA1) was only inhibited by 5 beta-reduced steroids that contained an oxygenated function at C17. All of the test compounds elicited type I spectral binding interactions with P-450 in oxidised microsomes. The most effective steroid inhibitors generally exhibited the greatest capacity to interact with P-450. Additional studies with one of the more potent compounds, 5 beta-androstane-3 beta-ol-17-one, revealed that the inhibition kinetics were competitive and that preincubation of the inhibitor with NADPH-supplemented microsomes prior to substrate (androstenedione) addition decreased the extent of inhibition observed. These findings are consistent with the assertion that the inhibition of hepatic steroid hydroxylases by 5 beta-androstanes involves an effective competitive interaction with the steroid substrate at the P-450 active site. Since the relative overproduction of 5 beta-reduced metabolites of certain androgens has been reported in clinical conditions, such as androgen insensitivity, it now appears important to investigate the hepatic drug oxidation capacity of patients with hormonal abnormalities.

Androstanes↗
PubMed1990

Susceptibility of African buffalo and Boran cattle to Trypanosoma congolense transmitted by Glossina morsitans centralis.

Four African buffalo (Syncerus caffer) and four Boran cattle (Bos indicus) were each exposed to the bites of 10 tsetse flies infected with Trypanosoma congolense. Although both groups of animals became infected, the buffalo showed no clinical signs of trypanosomiasis while the cattle suffered from the disease characterized by pronounced skin reactions, high parasitaemia and severe anaemia. The prepatent periods in the buffalo varied from 18 to 27 days in comparison with 11 to 14 days in the cattle. In the buffalo, skin reactions were only detectable by histological examination of skin biopsies, the peak of parasitaemia was at least a hundredfold below that in cattle and after 54 days parasites were no longer detected. In contrast, the cattle had a continuous high parasitaemia until they were treated with a trypanocidal drug 60 days after infection. Neutralizing antibody to metacyclic trypanosomes appeared in the buffalo during the prepatent period, 15-20 days after infection, whereas in cattle neutralizing antibody was not detected until 10 days after the first peak of the parasitaemia, 25-30 days after infection.

Animals↗
PubMed1990

Expression of beta-preprotachykinin mRNA and tachykinins in rat dorsal root ganglion cells following peripheral or central axotomy.

The changes in gene expression and protein synthesis induced in neurons by axotomy usually lead to increased production of axon constituents and decreased production of molecules related to neurotransmission. Exceptions to this generalization occur, however, and it is unclear whether the injury itself changes the pattern of synthesis or whether individual mechanisms regulate the synthesis of the various axonal components. We used in situ hybridization histochemistry and immunocytochemistry to compare the changes in L4 and L5 rat dorsal root ganglion neuron levels of preprotachykinin mRNA and tachykinin peptides caused by sciatic nerve injury with those caused by dorsal root injury. Both lesions elicit regeneration, although only the axotomized peripheral processes re-establish functional contact with their targets. In the contralateral, intact dorsal root ganglia approximately 17% of neurons contained detectable levels of both mRNAs and peptides. Sciatic nerve section decreased by 70% the number of neurons labeled for preprotachykinin mRNA at three days post-operatively. Not all cells in the ganglion are axotomized by the sciatic nerve lesion; grain counts over the cells spared by the lesion showed an increased level of labeling, possibly a result of collateral sprouting by these spared cells. By two weeks, the number of cells labeled for preprotachykinin mRNA had decreased to 80% of control levels. The numbers of neurons labeled for tachykinin peptides decreased more slowly and reached approximately 50% of control numbers at two weeks. By six months post-operatively, when regeneration is largely complete, the number of neurons containing both mRNAs and peptides returned to normal. In contrast, dorsal root section did not elicit a decrease in the number of neurons labeled either for the mRNAs or the peptides at any of the post-operative intervals examined. These results indicate that axotomy is not the stimulus that elicits changes in the expression of genes coding for tachykinins. Evidence is considered indicating that interruption of the supply of peripherally derived nerve growth factor may be responsible for the changes in gene expression for tachykinins after axotomy.

Animals↗
PubMed1990

Radiopaque acrylic resins containing miscible heavy-metal compounds.

Radiopacity is needed in order to facilitate diagnosis of polymeric appliances, which may be dislodged and become impacted in the upper respiratory or digestive tracts. In order for a stable, optically transparent, radiopaque material to be provided, heavy-metal compounds were investigated which we had previously shown to form homogeneous structures with methyl methacrylate-based systems. It was found that, when present in PMMA at 11 to 14%, several compounds of either bismuth or uranium or 35% of an organo-zirconium compound impart radiopacity equivalent to that of aluminum. A low level of cytotoxicity and lack of mutagenicity indicated that a high level of biocompatibility can be expected. Processing characteristics are somewhat altered, but formulations satisfactory for use in various dental devices were found.

Acrylic Resins↗
PubMed1990

When and why children first start to smoke.

Most investigations of smoking in children focus on prevalence in which uptake and maintenance are confounded. This paper reports an analysis of pure incidence data in a cohort of over 6000 Derbyshire schoolchildren followed for ten years investigated using survival data analysis techniques. Over 70% of the cohort tried at least one cigarette before the end of the fifth year of secondary school. Some 40% identified themselves as regular smokers while at school. The risks of taking up regular smoking were higher if, at the age of 11.7-12.7 years, the children had smoking siblings, opposite sex friends, were dismissive of the health hazards and susceptible to peer pressure. More girls than boys in that age range spent time with opposite sex companions and in organized social activities which in turn were significantly associated with the risk of taking up smoking. Thus the earlier physical and emotional development of girls may help explain recent findings that adolescent girls are now more likely to smoke than boys of the same age. The greatest incidence of regular smoking occurred when the average age was increasing from 14.2 to 15.2 years. This has very clear implications for the timing of anti-smoking interventions.

Adolescent↗
PubMed1990

Characteristics of students entering different forms of nurse training.

Developments in nurse training need to be based upon an understanding of the characteristics and aspirations of students. In this study, characteristics of a sample of registered nurses (n = 27) and students (n = 41) entering an undergraduate degree programme in nursing were compared with those of student nurses (n = 46) beginning training in a college of nursing. It was found that the three groups differed in terms of their social background, their reasons for becoming a nurse, their views on nursing, their perceived social competence and their views on the role of the nurse vis-à-vis the doctor. Certain sex and social class differences were also apparent. The findings are discussed with reference to the selection of students for different forms of training and the content of current nurse training programmes.

Adult↗
PubMed1990

Improved distribution of antigenic site specificity of poliovirus-neutralizing antibodies induced by a protease-cleaved immunogen in mice.

Previous studies showed that the distribution of antigenic site specificity of neutralizing antibodies to type 3 poliovirus obtained with the inactivated poliovirus vaccine can be deficient as compared with that obtained following poliovirus infection. This observation was shown by the relatively low capacity of sera from inactivated-poliovirus-vaccine-immunized persons to neutralize poliovirus cleaved at antigenic site 1. We investigated possibilities for improving the situation in a mouse model. Balb/c mice were immunized with intact or trypsin-cleaved type 3 poliovirus (Saukett strain). Sera from mice immunized with the intact virus readily neutralized the intact virus but neutralized the cleaved virus only rarely. In contrast, cleaved-virus-immunized mice produced antibodies that were able to neutralize the cleaved virus as well as the intact one. Mice immunized with a 100-fold-higher dose of the intact virus produced significant levels of antibodies to the cleaved virus, too. Somewhat surprisingly, mice immunized with high doses of the cleaved virus produced antibodies specific for the intact loop between beta sheets B and C of VP1 (virion protein 1), which should be cleaved in the immunogen. This was shown by a higher titer of antibodies to intact Saukett virus than to the corresponding cleaved virus, as well as to a type 1/type 3 hybrid poliovirus in which only the BC loop amino acids were derived from type 3 poliovirus. The cleavage-induced enhanced availability of antigenic determinants residing outside the BC loop was also shown by increased neutralization titers of monoclonal antibodies specific for some of these other determinants. These results indicate that by using a trypsin-cleaved type 3 poliovirus as a parenteral immunogen, it is possible to change the distribution of antigenic site specificities of neutralizing antibodies to resemble that following poliovirus infection.

Animals↗
PubMed1990

Randomized comparison of ofloxacin and doxycycline for chlamydia and ureaplasma urethritis and cervicitis.

Fifty-eight males and 34 females with nongonococcal urethritis and/or cervicitis were treated to compare the efficacy and safety of 7-day regimens of oral ofloxacin 300 mg twice daily and doxycycline hyclate 100 mg twice daily. Forty-seven patients were randomized to receive ofloxacin and 45 patients to receive doxycycline. The microbiologic response rate was 97% (32/33) for both ofloxacin and doxycycline; the combined microbiologic and clinical cure rates were 98% for both treatment groups (ofloxacin 46/47, doxycycline 44/45). Ofloxacin was as effective as doxycycline in the treatment of chlamydial infections (96% vs. 100%). In patients with Ureaplasma urealyticum, the initial response was complete with either drug, but recurrence of infection was observed with both treatment groups (1 of 4 patients in the ofloxacin group and 2 of 11 patients in the doxycycline group). In the treatment of mixed Chlamydia trachomatis and U. urealyticum infections, all 5 patients treated with ofloxacin and 3 of 4 patients treated with doxycycline were cured. In symptomatic patients whose initial cultures were negative, clinical cures were complete with both drugs, but Ureaplasma was isolated at 3 or more weeks post-treatment in 2 patients treated with ofloxacin. In a study of single-dose ofloxacin treatment of uncomplicated gonorrhea, Neisseria gonorrhoeae was eradicated in all subjects, but C. trachomatis was not reliably eradicated. Both drugs were well tolerated with only minimal adverse effects reported in either treatment group. A multiple-dose regimen of ofloxacin appears to be a highly effective and well-tolerated alternative to doxycycline in nongonococcal sexually transmitted disease.

Chlamydia Infections↗
PubMed1990

Trypanotolerance in cattle and prospects for the control of trypanosomiasis by selective breeding.

Tsetse-transmitted trypanosomiasis is one of the major constraints on the expansion of the livestock and agricultural industries in Africa. The disease affects animals and man, with direct and indirect losses estimated in billions of dollars annually. Because of the phenomenon of antigenic variation, no vaccine is available. Current prophylactic efforts must rely on tsetse control by the use of insecticides and on trypanocidal drugs. However, recent advances in our knowledge of tsetse and trypanosome biology are offering hope for alternative methods of trapping tsetse, new drugs and even vaccination. Possibly of even greater significance is the increasing sense that Africa herself might be able to contribute to the resolution of this problem. Over a period of several thousand years, she has generated cattle, such as the taurine N'Dama and West African Shorthorn breeds of West and Central Africa, that are now known to possess a significant degree of innate resistance to trypanosomiasis and several other important infectious diseases. These cattle are extremely well adapted to the environment and are now recognised as having considerable production potential. The ability to resist the development of anaemia in the face of infection, as assessed by packed red cell volume percent (PCV), has been shown to be correlated with the capacity to be productive, thereby identifying regulation of PCV as a key trait of trypanotolerance. Thus, an estimate of the ability of an infected animal to maintain PCV, following either experimental or field infection, could be used as a method for identifying trypanotolerant individuals. This could provide a means of estimating trypanotolerance heritability, thereby permitting rational breeding programmes to be instituted. Africa may thus provide the answer.

Animals↗
PubMed1990

Relative platelet-derived growth factor receptor subunit expression determines cell migration to different dimeric forms of PDGF.

Platelet-derived growth factor (PDGF) receptor transfectants of a fibroblastoid cell line (BHK) have been used to investigate the ability of the three dimeric forms of PDGF to elicit a chemotactic response. Cells transfected with the beta receptor subunit were only responsive to PDGF-BB, whereas cells expressing the alpha-receptor subunit were equally responsive to all three dimeric forms, PDGF-AA, PDGF-AB, and PDGF-BB. A positive chemotactic response correlated with rearrangement of actin organization. In a study of human arterial smooth muscle cells that express both PDGF receptor subunits endogenously, we again found that recombinant PDGF-AA could elicit a chemotactic response. However, the two smooth muscle cell isolates we examined differed in their chemotactic response to PDGF-AA. This difference correlated closely with their ability to respond mitogenically to this PDGF dimeric form, and the magnitude of both chemotactic and mitogenic responses was related to the proportion of the two receptor subunit species at the cell surface.

Animals↗
PubMed1990

Interferon down regulates the male-specific cytochrome P450IIIA2 in rat liver.

The aim of this study was to clarify the mechanism by which cytochrome P450 (P450)-mediated catalytic activity is decreased following interferon (IFN) administration. Microsomal steroid hydroxylation was assessed to test the hypothesis that IFN selectively decreases the activities of individual P450 isozymes in male rats. Thus, recombinant rat IFN gamma (r-rat IFN gamma) treatment produced 40% and 17% reductions in androst-4-ene-3,17-dione (androstenedione) 6 beta- and 16 beta-hydroxylation, respectively. Androstenedione 16 alpha- and 7 alpha-hydroxylation were unaltered following r-rat IFN gamma treatment. Similar changes in the androstenedione hydroxylation pathways were observed following administration of naturally derived rat IFN alpha/beta. Microsomal levels of P450IIIA2, the male-specific constitutive steroid 6 beta-hydroxylase, were lower after administration of r-rat IFN gamma (42% of control fractions). Furthermore, hepatic P450IIIA2 mRNA was found to be decreased to a similar extent by r-rat IFN gamma. These findings suggest that IFN selectively decreases the content of this isozyme by a mechanism involving altered mRNA regulation. Sex steroids were unlikely to have mediated the decrease in P450IIIA2 levels since serum estradiol and testosterone levels were unchanged by r-rat IFN gamma. In order to determine whether IFN alters the expression of P450IIIA1, a steroid-inducible member of the P450IIIA gene subfamily which is not expressed in untreated rat liver, adult female rats (which lack P450IIIA2) were coadministered pregnenolone 16 alpha-carbonitrile and r-rat IFN gamma. However, IFN failed to impair the induction of androstenedione 6 beta-hydroxylation produced by pregnenolone 16 alpha-carbonitrile. These findings suggest that although IFN decreases the expression of P450IIIA2, it may not down regulate the expression of other steroid-inducible P450IIIA proteins. In view of the existence of human P450IIIA orthologs which catalyze the metabolism of several important therapeutic agents, the findings of this study may help predict possible drug interactions in patients receiving IFN.

Animals↗
PubMed1989

In vitro inhibition of hepatic drug oxidation by thioridazine. Kinetic analysis of the inhibition of cytochrome P-450 isoform-specific reactions.

The phenothiazine tranquilizer thioridazine has been associated with drug interactions in man. This study investigated the capacity of the drug to inhibit hepatic drug oxidations mediated by cytochromes P-450 (P-450) in microsomes in vitro. Thioridazine was a potent linear mixed-type inhibitor of P-450b-dependent 7-pentoxyresorufin O-depentylase activity in phenobarbital-induced rat liver. The kinetic analysis revealed the enzyme-substrate dissociation constant (Ks) to be 1.6 microM whereas the dissociation constant of the enzyme-inhibitor complex (Ki) was 0.11 microM. In contrast, 7-ethoxyresorufin O-deethylase activity (mediated by P-450c) in beta-naphthoflavone-induced rat hepatic microsomes was inhibited to a lesser extent (Ki = 2.4 microM) in relation to the Ks value (0.5 microM). Spectral studies indicated that the efficiency of thioridazine binding in phenobarbital-induced microsomes was about 25-fold greater than in microsomes from beta-naphthoflavone-induced rat liver. This finding is consistent with the relative capacity of thioridazine to inhibit oxidase activities catalyzed by P-450b and P-450c. Mixed-function oxidase activities catalysed by other P-450s were also inhibited by thioridazine, although to a lesser extent than those catalysed by forms b and c. Thus, the 6 beta- and 16 beta-hydroxylations of androst-4-ene-3,17-dione in hepatic microsomes from untreated rats were inhibited to a similar extent (I50S = 52 and 43 microM, respectively). The 7 alpha- and 16 alpha-hydroxylase pathways were approximately only half as susceptible to inhibition by thioridazine. These findings demonstrate the capacity of thioridazine to inhibit a range of P-450-dependent drug oxidations, with those catalysed by forms b and c most susceptible. The present study strongly suggests that drug interactions elicited by thioridazine are most likely a consequence of inhibitory interactions with P-450 enzymes.

Animals↗
PubMed1989

In vitro inhibition of hepatic steroid hydroxylation by tamoxifen, a series of tamoxifen analogues and related compounds.

The in vitro inhibition of the cytochrome P-450 (P-450) isozyme specific positional hydroxylation of androst-4-ene-3,17-dione (androstenedione) by the alkylamino containing compounds trans- and cis-tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, SKF 525-A and the non-alkylamino containing compounds tamoxifen metabolite E, and tamoxifen analogue U-23469 was assessed in pooled hepatic microsomes isolated from untreated male rats. P-450 IIA 1-mediated androstenedione 7 alpha-hydroxylation appeared refractory to inhibition, with the lowest I50s being approximately 200 microM (cis- and and trans-tamoxifen, 4-hydroxytamoxifen). (According to the recently recommended nomenclature for cytochromes P-450 (Nebert DW and Gonzalez FJ, Ann Rev Biochem 56: 945-993, 1987), rat hepatic cytochromes P-450 UT-A, PB-B, PCN-E and UT-F are encoded by genes IIC 11, IIB 1, IIIA 1/2 and IIA 1, respectively. I50s toward the P-450 IIC 11-, IIB 1-, and IIIA 1/2-catalysed reactions, androstenedione 16 alpha-, 16 beta- and 6 beta-hydroxylations, respectively, were generally in the range 70-190 microM. However, metabolite E exhibited a rather specific and potent capacity to inhibit androstenedione 16 alpha-hydroxylase activity (I50 = 18 microM). Since a number of alkylamine compounds have been shown to sequester microsomal P-450 as an inactive metabolite intermediate (MI), the tamoxifen analogues were investigated for their in vitro MI complexation capacity. However, spectral binding studies revealed that the incubation of these compounds with NADPH-fortified microsomal fractions did not result in MI complex formation. In binding experiments conducted with oxidised microsomal fractions it was apparent that most of the tamoxifen analogues are type I ligands of quite high affinity for ferric P-450 (Ks range 10-60 microM). It seems unlikely that MI formation is involved in the observed inhibition of androstenedione hydroxylation by tamoxifen and congeners. Instead, and in contrast to the situation observed with SKF 525-A, it would appear that the inhibitory capacity of the tamoxifen analogues is more closely related to type I binding capacity with ferric P-450. A finding of particular interest is that metabolite E, in which the alkylamino side-chain is absent, elicited a type I interaction of high capacity. The maximal absorbance change of the type I interaction of this compound with microsomal P-450 was about three-fold greater than the other compounds.(ABSTRACT TRUNCATED AT 400 WORDS)

Androstenedione↗
PubMed1989

Determination of halofuginone in bovine plasma by competing-ion high performance liquid chromatography after solid phase extraction.

A high performance liquid chromatography (HPLC) method for the determination of the anticoccidial and antitheilerial drug halofuginone in bovine plasma was developed. Samples were diluted with acetic acid (10%, v/v) and cleaned up on a Bond Elut C8 column. The analyte was eluted from the extraction column and chromatographed by reversed-phase HPLC using decylamine as a competing-ion reagent. Detection was by UV at 243 nm. Recovery from plasma was 75%, and within-day and between-day coefficients of variation were 5.23 and 6.35% respectively. The specificity and sensitivity of this method (limit of detection in plasma, 1 ng/mL) were sufficiently high to enable us to characterize the time course of the drug in plasma after oral administration of therapeutic doses to cattle.

Administration, Oral↗
PubMed1989

Pulmonary disease following allogeneic bone marrow transplantation.

Bone marrow transplantation is the treatment of choice of many haematological disorders but its success is limited by two major complications, graft-versus-host disease (GVHD) and pulmonary disorders. Of the first 31 patients transplanted at St. James's Hospital (1984-1986) 16 (52%) had a successful outcome. Of the 15 patients who died, two died of GVHD and one of recurrent leukaemia. All others had severe pulmonary disease either causing death directly (9 cases) or contributing to death from toxic encephalopathy, carditis or recurrent leukaemia (1 case each). The principal forms of pulmonary disease were cytomegalovirus pneumonitis (4 cases), acute haemorrhagic pulmonary oedema (4 cases) and pneumocystis carinii pneumonia (2 cases). There were single cases of staphylococcal pneumonia and idiopathic pulmonary fibrosis. Aspergillus was a second pathogen in two cases. Pulmonary damage due to conditioning chemoradiotherapy and to GVHD probably underlies this high incidence of pulmonary disease. T-cell depletion to limit the incidence of GVHD together with increased prophylaxis against CMV and pneumocystis carinii will probably substantially reduce these complications in the near future.

Adolescent↗
PubMed1989

Interference in the establishment of tsetse-transmitted Trypanosoma congolense, T. brucei or T. vivax superinfections in goats already infected with T. congolense or T. vivax.

An interference phenomenon that delays superinfection with a trypanosome species different from that used for the initial infection has been found to occur in goats. Following tsetse transmission of Trypanosoma brucei to goats already infected with T. congolense, there was a delay in chancre development, as well as in the appearance of T. brucei and anti-T. brucei antibodies in the blood when compared to previously uninfected goats. However, there was no delay in the establishment of a tsetse-transmitted superinfection with T. vivax in goats already infected with either T. congolense or in animals already infected with a different serodeme of T. vivax.

Animals↗