Biomedical subjects

M Murray

Publications and source records attributed to M Murray.

At least 271 records · Page 15Linked to original sources

PubMed1993

Where are career ladders going in the 90s?

Information from 543 hospitals and 200,000 RNs was obtained through a National Nursing Compensation Survey. Analysis of the data showed that 239 hospitals had clinical nurse ladders and many others were planning to initiate some form of ladder program soon. Although the theoretical framework, the process and the compensation packages varied, it is clear that clinical ladders are quite effective in recruitment and retention of registered nurses.

Career Mobility↗

PubMed1992

Inhibition and induction of cytochrome P450 2B1 in rat liver by promazine and chlorpromazine.

Phenothiazine tranquilizers have been associated with pharmacokinetic drug interactions in man. In this study the in vivo and in vitro effects of the clinically important phenothiazines promazine (PZ) and chlorpromazine (CPZ) on drug oxidations catalysed by specific cytochrome P450 (P450) enzymes were investigated in the rat. In vitro, the two drugs were relatively ineffective inhibitors of constitutive P450 activities, but were inhibitory toward the principal phenobarbital-inducible P450 2B1 and, to a lesser extent, P450 1A1. Administration of PZ and CPZ to male rats did not markedly influence the total microsomal P450 content of the liver. However, the quantitatively important male-specific P450 2C11 was down-regulated by CPZ and concomitant induction of P450 2B1 and associated 7-pentylresorufin O-depentylase activity were noted. A small increase in the activity of microsomal 7-ethylresorufin O-deethylase was also observed following administration of both drugs to rats, suggesting induction of P450 1A1/2. Considered together, it is apparent that the two phenothiazines are preferential inhibitors and inducers of P450 2B1 in rat liver. Drug interactions in humans involving phenothiazines may reflect a combined effect of induction and inhibition processes as well as down-regulation of other P450s, such as that produced by CPZ on P450 2C11.

Animals↗

PubMed1992

Studies on the developmental and adrenal regulation of cytosolic and microsomal epoxide hydrolase activities in rat liver.

The present study was undertaken to ascertain developmental profiles of microsomal epoxide hydrolase (mEH) and cytosolic epoxide hydrolase (cEH) enzyme activities in rat liver. During development, mEH activity reached an optimum by 6 weeks of age (63 nmol/min/mg protein). Activities decreased thereafter in both sexes although in adult male liver the activity was twice that measured in adult female liver. Thus, the importance of pituitary maturation was suggested from these findings. Since glucocorticoids have been implicated in the regulation of mEH gene expression the effect of adrenalectomy on mEH activity was investigated in adult male rat liver. The procedure increased mEH activity almost two-fold and the increase was reversed by dexamethasone, but not deoxycorticosterone, administration. With respect to hepatic cEH activity, the developmental profiles indicated that enzyme activity was greatest in rats at 1 week of age (12-15 nmol/min/mg protein) and very little activity was detected beyond 4 weeks of age (approximately 5 nmol/min/mg protein); sex differences in cEH activity were not apparent at any age. Thus, the pituitary appears to be important in the developmental induction of mEH but not cEH. Glucocorticoids appear to provide the major hormonal influence on mEH expression. Thus, the hypothalamus-pituitary-adrenal axis is involved in the regulation of mEH but the regulation of the cEH enzyme remains unclear.

Adrenal Glands↗

PubMed1992

Inhibition and metabolite complexation of rat hepatic microsomal cytochrome P450 by tricyclic antidepressants.

Administration of imipramine (IMIP) and other tricyclic antidepressants to humans and experimental animals has been associated with inhibition of hepatic cytochrome P450 (P450)-mediated drug oxidation. This study investigated the capacity of several structurally related tricyclic antidepressants to inhibit microsomal P450 activity in vitro. It was found that IMIP, desipramine (DES), amitriptyline (AMIT) and nortriptyline (NOR) were poor inhibitors of P450 activity unless they were preincubated with microsomes and NADPH prior to transfer to flasks containing substrate. Thus, subsequent experiments characterized the time-dependent intensification of inhibition produced by the drugs. Preincubation of the N-methylaminoalkyl agents DES and NOR (200 microM) with NADPH-supplemented microsomes for 30 min led to an approximate 30% decrease in spectrally apparent P450 content; the N,N-dimethylaminoalkyl drugs IMIP and AMIT did not significantly decrease apparent P450 content. Analysis of optical difference spectra of microsomes during NADPH-mediated metabolism of these drugs revealed a prominent increase in absorbance at 454 nm with DES and NOR but not IMIP or AMIT. Monospecific antibodies to the male-specific P450 2C11 and, to a lesser extent, P450 3A2 were effective in preventing the formation of the DES metabolite 454 nm-Soret peak. In addition, the 454 nm absorbance was not produced by the incubation of DES with NADPH-fortified hepatic microsomes from adult female or immature male rats. Studies with the steroid substrate testosterone, which undergoes P450-specific positional hydroxylation, indicated that P450 2C11-mediated 2 alpha- and 16 alpha-hydroxylation were most susceptible to the time-dependent intensification of inhibition produced by DES (8.5 and 7.0 min preincubation required for loss of 50% activity, respectively) and NOR (4.0 and 4.0 min for loss of 50% of both activities). The 6 beta- (P450 3A2) and 7 alpha-hydroxylase (P450 2A1) pathways were somewhat less susceptible to inhibition than 2 alpha- and 16 alpha-hydroxylation. These findings suggest that DES and NOR form a metabolite intermediate (MI)-complex, characterized by a Soret region absorbance maximum near 454 nm in the optical difference spectrum, with microsomal P450 in male rat liver in vitro. Studies with the steroid substrate testosterone as well as immunoinhibition experiments are consistent with the proposition that this MI complex forms principally with the male-specific enzymes P450 2C11 and 3A2. Although a human orthologue of P450 2C11 has not yet been identified, P450s of the 3A subfamily are quantitatively important enzymes in human liver. MI complexation of such enzymes could be a feasible underlying mechanism for certain clinically important drug interactions involving tricyclic antidepressants.

Amitriptyline↗

PubMed1992

Subcurative chemotherapy and fatal post-treatment reactive encephalopathies in African trypanosomiasis.

The treatment of late-stage African sleeping sickness in man is often complicated by a post-treatment reactive encephalopathy. The bases of this pathological reaction was investigated in a mouse model of African trypanosomiasis. Subcurative treatment with diminazene aceturate, which did not clear parasites from the central nervous system, resulted in a post-treatment meningoencephalitis similar to that seen in man. By contrast, a curative regimen of melaminylthioarsenite and 5-nitroimidazole, which cleared parasites from the central nervous system, did not cause any pathological reaction in the mice. This result indicates that subcurative treatment leads to the development of the post-treatment encephalopathy. Evidence that this may also be the case in man was provided by the detection of trypanosome DNA with the polymerase chain reaction in the brains of 9 patients who had died as the result of a post-treatment reaction. Our findings suggest that more aggressive treatment regimens, which ensure the elimination of trypanosomes from the central nervous system, may prevent post-treatment reactions in patients.

Adolescent↗

PubMed1992

Interferon suppresses the isoform-specific activities of hepatic cytochrome P450 in female rats.

The results from the present study indicate that rat IFN-gamma decreases hepatic P450 levels and catalytic activities in female rats. The magnitude of the down-regulation of P450 is similar to that found in male rats. Furthermore, the activities of specific P450 isoforms (P4502A1 and P4502C6 and possibly P4502C12, and P4502B1 and 2) are decreased by IFN. Hence, the effect of IFN in female rats appears to involve several, but not all, hepatic P450 isoforms. Both hormone-dependent and hormone-independent isoforms are suppressed by IFN. The mechanism for this effect does not, however, appear to be mediated by changes in serum levels of sex steroids.

Animals↗

PubMed1992

Changes in atrial natriuretic factor and plasma renin activity in dogs infected with Trypanosoma brucei.

When beagle dogs were infected with Trypanosoma brucei, a marked reduction in the plasma concentration of atrial natriuretic factor (ANF) occurred in the terminal stage of the disease during weeks 3 and 4. At the same time there was an increase in plasma renin activity (PRA) after infection. Ultrastructural studies of the atria of these dogs demonstrated a reduction in ANF granules. The changes in ANF and PRA occurred in association with severe pancarditis and the development of heart failure. By impairing the ability of the heart and kidneys to regulate blood volume, the alterations in ANF and PRA could be involved in the pathogenesis of heart failure in T. brucei-infected dogs.

Animals↗

PubMed1992

Temporal and spatial patterns of expression of laminin, chondroitin sulphate proteoglycan and HNK-1 immunoreactivity during regeneration in the goldfish optic nerve.

Current views suggest that the extracellular environment is critically important for successful axonal regeneration in the CNS. The goldfish optic nerve readily regenerates, indicating the presence of an environment that supports regeneration. An analysis of changes that occur during regeneration in this model may help identify those molecules that contribute to a favourable environment for axonal regrowth. We examined the distribution and expression of two extracellular matrix molecules, laminin and chondroitin sulphate proteoglycan, and a carbohydrate epitope shared by a family of adhesion molecules (HNK-1), using immunocytochemical detection in sections from the normal adult goldfish optic nerve and in nerves from one hour to five months following optic nerve crush. We also used in vitro preparations to determine if neurites in retinal explants could express these same molecules. The linear distributions of laminin and chondroitin sulphate proteoglycan immunoreactivity in control optic nerves are co-extensive with the glia limitans, suggesting both are expressed by non-neuronal components surrounding the axon fascicles. Between one and three weeks postoperatively when axons elongate and reach their target, laminin and chondroitin sulphate proteoglycan immunoreactivity increases around the crush site and distally. At six weeks postoperatively the pattern of immunoreactivity has returned to normal. While the temporal pattern of changes in immunoreactivity is similar, the spatial pattern of these two extracellular proteins in the regenerating nerve differs. Chondroitin sulphate proteoglycan immunoreactivity is organized in discrete columns associated with regenerating axons while laminin immunoreactivity is more diffusely distributed. Examination of retinal explants reveals growing neurites express chondroitin sulphate proteoglycan but not laminin. Our results suggest that laminin is only associated with non-neuronal cells, while chondroitin sulphate proteoglycan is associated with axons as well as non-neuronal cells. HNK-1 immunoreactivity is co-extensive with both the glia limitans and axon fascicles and is more extensively distributed in the intact nerve than either laminin or chondroitin sulphate proteoglycan immunoreactivity. In contrast to laminin and chondroitin sulphate proteoglycan, HNK-1 immunoreactivity is substantially decreased at the crush site within one week following optic nerve crush. HNK-1 immunoreactivity reappears through the crush site during the next several weeks, although non-immunoreactive regions, co-extensive with areas predominantly containing non-neuronal cells, persist both proximal and distal to the crush, up to six weeks postoperatively. The pattern suggests that HNK-1 epitope expression by these non-neuronal cells is decreased during axonal regeneration.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Pathophysiology of ovine trypanosomiasis: ferrokinetics and erythrocyte survival studies.

The haematological changes, erythrokinetics and ferrokinetics of sheep were investigated after infection with Trypanosoma congolense. Following the detection of parasites in blood, the infected sheep developed macrocytic hypochromic anaemia. Studies with 51Cr-red cells, 125I-albumin and 59Fe as ferric citrate 11 weeks after infection revealed that infected sheep had significantly lower mean circulating red cell volumes but higher plasma and blood volumes than control sheep. The infected sheep also had enhanced erythropoietic activity as judged by significantly higher plasma iron turnover rates, faster disappearance of radio-labelled iron and higher iron incorporation rates than control sheep. The rate of disappearance of 51Cr-labelled red cells was greater in infected than in control sheep. It was concluded that the anaemia observed at this stage of infection was due to an increased rate of removal of red cells from the circulation coupled with haemodilution, with no evidence of dyshaemopoiesis.

Anemia↗

PubMed1992

Correlation of autoantibody titres with central nervous system pathology in experimental African trypanosomiasis.

CD-1 mice infected with the protozoan parasite Trypanosoma brucei brucei developed few signs of central nervous system pathology associated with the invasion of the central nervous system by these parasites and did not survive beyond 5-6 weeks with deaths common before this time point. However, use of the trypanocidal drug diminazene aceturate (40 mg/kg), which fails to cross the blood-brain barrier, on day 21 post-infection led to the development of central nervous system pathology similar to that seen in the fatal post-treatment reactive encephalopathies that can occur in human African trypanosomiasis. Enzyme-linked immunosorbent assays were used to measure autoantibody titres to double-stranded DNA, myelin basic protein and to the myelin-specific galactocerebrosides and gangliosides in groups of infected mice, with or without the post-treatment reaction, on day 30 post-infection and compared with uninfected controls. Infection with T. brucei brucei raised the titres of all of these autoantibodies. Treatment of infected mice with diminazene aceturate resulted in elevated levels of all of these autoantibodies compared to the untreated animals. There was a strong positive correlation between the central nervous system pathology and the levels of autoantibodies to myelin basic protein, galactocerebrosides and gangliosides, but not to double-stranded DNA. The elevated titres observed may be a consequence of the polyclonal B cell activation that is believed to occur in African trypanosomiasis, parasite epitopes that are cross-reactive with these central nervous system (CNS)-specific antigens or result from the CNS damage associated with sub-curative chemotherapy.

Animals↗

PubMed1992

The pathophysiology of ovine trypanosomosis: haematological and blood biochemical changes.

The course of Trypanosoma congolense infection in sheep was followed for 96 days. Infected animals developed fluctuating parasitaemia, macrocytic normochromic anaemia and leucocytosis which was principally a lymphocytosis. Following treatment with the trypanocidal drug, diminazene aceturate at 84 days after infection, the haematological values returned to normal within 12 days. Infected sheep developed hypocholesterolaemia and hypophospholipidaemia leading to a reduction in total serum lipids. This study has shown that sheep infected with T. congolense develop anaemia, the onset of which follows the first wave of parasitaemia. The changes in blood lipids observed in infected sheep appeared to be related to the intensity and duration of parasitaemia.

Animals↗

PubMed1992

Participation of a cytochrome P450 enzyme from the 2C subfamily in progesterone 21-hydroxylation in sheep liver.

Progesterone 21-hydroxylation in hepatic microsomes from adult male sheep is a quantitatively important metabolic pathway (0.27 +/- 0.08 nmol deoxycorticosterone formed/min/mg protein; representing 13-25% of total progesterone conversion). This study was undertaken to determine whether the ovine hepatic progesterone 21-hydroxylase may be another member of the P450 2C subfamily, normally associated with progesterone 21-hydroxylation in rodent liver. An IgG preparation raised in rabbits against purified rat liver microsomal cytochrome P450 2C6 was found to recognize a single antigen (MW 52 kDa) in sheep liver microsomes. This protein was present in sheep liver (apparent concentration 16 +/- 4 ng/micrograms microsomal protein) representing approx. 28% of the corresponding content of P450 2C6 in untreated rat liver. Preincubation of the anti-P450 2C6 IgG with hepatic microsomes was found to decrease the rate of progesterone 21-hydroxylation to 50-80% of uninhibited control. Taken together, from these findings it is apparent that a P450 enzyme, most likely from the 2C subfamily, catalyses deoxycorticosterone formation from progesterone in sheep liver and that this is a quantitatively important pathway of progesterone hydroxylation in these fractions.

Animals↗

PubMed1992

Immune response of elderly individuals to a live attenuated varicella vaccine.

The Oka strain live attenuated varicella-zoster virus (VZV) vaccine was administered subcutaneously to 202 VZV-immune individuals who were 55 to greater than 87 years old. The dose administered varied from 1100 to 12,000 pfu. One cohort received 3000 pfu with a 3000 pfu booster 3 months later. The vaccine was well tolerated. VZV-specific immunologic responses were evaluated over a 24-month period. The mean anti-VZV antibody level was significantly increased for 12 months after vaccination. Interferon-gamma production in vitro by peripheral blood mononuclear cells (PBMC) of vaccinees was also increased for 6 months after vaccination. Most significantly, VZV-specific proliferating T cells in PBMC of vaccinees were increased in frequency from 1 in 68,000 to 1 in 40,000. This vaccine-enhanced frequency of VZV-responding T cells is similar to the frequency observed in 35- to 40-year-old adults. Dose and age of the vaccinees did not significantly influence the magnitude of the mean cell-mediated immune response. The data indicate that VZV immunity in the elderly can be boosted by active immunization. If the increased incidence of herpes zoster that accompanies aging results from the natural waning of immunity, active immunization may prevent or attenuate zoster in the elderly.

Aged↗

PubMed1992

Acquired immunodeficiency syndrome: knowledge and attitudes of nurses in Northern Ireland.

The number of people suffering from conditions associated with HIV infection is growing steadily. These people require care from nurses who should be well trained to undertake all the various aspects of nursing care. Surveys have indicated that health professionals associate AIDS with minority groups such as homosexuals, drug-abusers and prostitutes. Incidents of sub-optimal nursing care of AIDS patients, or suspected AIDS patients belonging to these minority groups, have been well documented. Surveys have revealed much ignorance and confusion among the general public as well as among health professionals with regard to this controversial syndrome. This study aimed to measure nurses' knowledge and attitudes towards homosexuals, drug-abusers and prostitutes, who through their lifestyle are at increased risk for HIV infection. Questionnaires were distributed to a random sample of 800 nurses in Northern Ireland. The sample was stratified by several demographic variables. A response rate of almost 60% was achieved. Nurses appeared to have a moderate knowledge of issues related to HIV infection, but there were large gaps in their knowledge of the terminology used in HIV infection. Nurses were not extremely worried about AIDS itself. However, homosexuals, prostitutes and drug-abusers were seen to be at least partly responsible for their own illness. Implications for nursing care and for nurse education are discussed.

Acquired Immunodeficiency Syndrome↗

PubMed1992

The use of azathioprine to ameliorate post-treatment encephalopathy associated with African trypanosomiasis.

The treatment of human African sleeping sickness is complicated by a post-treatment meningoencephalitis that may be fatal. Using a mouse model this study assesses the use of the non-steroidal anti-inflammatory drug, azathioprine, in the management of this post-treatment reaction. Female NIH mice treated with the trypanocidal compound diminazene aceturate (40 mg/kg), 28 days after infection, developed a similar post-treatment reaction to that seen in humans. Administration of azathioprine (100 mg/kg) for 5 days before and 5 days after trypanocidal chemotherapy abrogated the pathology in the central nervous system although this returned approximately 15 days after cessation of azathioprine. Activated astrocytes associated with the later stages of the infection did not appear to be affected by the use of azathioprine.

Animals↗

PubMed1992

Detection of cytokine mRNA in the brains of mice with toxoplasmic encephalitis.

C57Bl/10 ScSn mice infected with Toxoplasma gondii developed a meningoencephalitis, characterized by areas of tissue destruction and cellular infiltration including foci of neutrophils. Large numbers of cyst stages were found throughout the brain but were not always associated with inflammation. The use of immunocytochemistry to detect glial fibrillary acidic protein, an astrocyte specific marker, showed a widespread astrocyte activation. This was particularly prominent in areas of intense inflammation but cysts were negative for glial fibrillary acidic protein, indicating that astrocytes were not host cells for the bradyzoites. The use of the polymerase chain reaction to assist in the amplification of total brain RNA allowed the characterization of the cytokines being produced locally within the brains of infected animals. beta-actin transcripts were detected in all of the uninfected and infected mice. In only one of the seven uninfected control mice were other transcripts found. Transcripts for tumour necrosis factor-alpha, interleukin-1 alpha and beta, interleukin-6, macrophage inflammatory protein-1 and interferon-gamma as well as the CD4 marker were detected in all of the infected mice. However, transcripts for IL-2 and IL-4 were not present. Several of the cytokines present are capable of initiating meningeal inflammation and may play a role in the immunopathogenesis of toxoplasmic encephalitis.

Animals↗

PubMed1992

Mutations in the principal neutralization determinant of human immunodeficiency virus type 1 affect syncytium formation, virus infectivity, growth kinetics, and neutralization.

The principal neutralization determinant (PND) of human immunodeficiency virus type 1 envelope glycoprotein gp120 contains a conserved GPG sequence. The effects of a 29-amino-acid deletion of most of the PND, a 3-amino-acid deletion in the GPG sequence, and 16 single-amino-acid substitutions in the GPG sequence were determined in a transient expression assay. All mutant envelope glycoproteins were expressed at levels comparable to that of the wild-type envelope, and mutations in the GPG sequence did not affect processing to gp120 or, except for the 29-amino-acid deletion, binding to CD4. Of all of the mutants, only the GHG and GFG mutants induced formation of syncytia similar in size and number to those induced by the wild-type envelope. When the envelope expression level was increased 10-fold or more, several additional mutants (APG, GAG, GSG, GQG, GVG, and GPF) also induced syncytium formation. Transfection with infectious proviral molecular clones containing the GHG, GFG, APG, GAG, GSG, or GPF mutations induced production of viral particles; however, only the GPG, GHG, and GFG viruses produced active infections in CD4-bearing cells. Furthermore, whereas the wild-type virus was efficiently neutralized by PND polyclonal and monoclonal antibodies, the GHG- and GFG-containing viruses were not. These results show that mutations in the GPG sequence found within the PND do not affect envelope expression and do not significantly affect CD4 binding or production of viral particles but that they do affect the ability of the envelope to induce syncytia and those of the viral particles to infect CD4 cells and be neutralized by PND antibodies.

Amino Acid Sequence↗

PubMed1992

Respiratory status and allergy after bronchiolitis.

As part of a long term prospective study, 73 children who had been admitted to hospital with viral bronchiolitis as infants, were reviewed 5.5 years later and compared with a carefully matched control group. In the postbronchiolitis group, there was a highly significant increase in respiratory symptoms including wheezing (42.5% v 15.0%, relative risk = 2.8). Although atopy in the family was not significantly increased in the index group, personal atopy was more prevalent. However, personal atopy was not significantly more prevalent in the symptomatic postbronchiolitis, compared with those who were symptom free, and so did not account for the high prevalence of postbronchiolitis wheezing in this cohort. In addition, in a stepwise logistic regressional model, bronchiolitis remained a significant predictor of wheezing after adjusting for potential confounding variables, including atopy. Bronchial responsiveness to histamine was significantly increased in the index group. However, no significant relationship of positive tests to wheezing could be demonstrated, and a high rate of positive responses was noted in the controls.

Bronchiolitis, Viral↗