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M Murray

Publications and source records attributed to M Murray.

At least 37 records · Page 2Linked to original sources
PubMed2000

Expression of yeast INM1 encoding inositol monophosphatase is regulated by inositol, carbon source and growth stage and is decreased by lithium and valproate.

Inositol monophosphatase plays a vital role in the de novo biosynthesis of inositol and in the phosphoinositide second messenger signalling pathway. We cloned the Saccharomyces cerevisiae open reading frame (ORF) YHR046c (termed INM1), which encodes inositol monophosphatase, characterized the protein Inm1p and analysed expression of the INM1 gene. INM1 was expressed in bacteria under the control of the lacZ promoter. The purified protein has inositol monophosphatase activity that is inhibited by the antibipolar drug lithium, but not valproate. In the inm1Delta:URA3 null mutant, inositol monophosphatase activity was reduced but not eliminated. The disruption had little effect on growth in the presence of lithium or valproate and no effect on growth in the absence of inositol. To characterize the regulation of INM1, we examined the effects of inositol, carbon source, growth phase, and the antibipolar drugs lithium and valproate on INM1 expression using an INM1-lacZ reporter gene. Unlike all other phospholipid biosynthetic enzyme-encoding genes studied, which contain the UASINO regulatory element, INM1 expression is increased in the presence of inositol. In addition, INM1 expression was repressed during growth in glycerol and derepressed as glucose-grown cells entered stationary. Both lithium and valproate, which cause a decrease in intracellular inositol, effect a decrease in INM1 expression. A model is presented to account for regulation of INM1 expression.

Amino Acid Sequence↗
PubMed2000

Haematological responses of repeated large volume blood collection in the horse.

The haematological response of regular, repeated blood harvesting was investigated in 40 Thoroughbred and non-Thoroughbred horses that donate 8 litres of blood every 3 weeks for the purposes of commercial blood production. When this volume of blood was removed on five occasions over 12 weeks, no adverse effect on packed cell volume (PCV), haemoglobin (HB), and red blood cell count (RCC) was observed. Although PCV, RCC and Hb values decreased during the first week after blood collection, followed by a gradual increase in values until the next harvest time, all values remained within published reference ranges. Derived red cell indices [mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and mean corpuscular haemoglobin concentration (MCHC)] also remained within reference range. We conclude that the removal of approximately 8 litres of blood (approximately 16 ml kg(-1)or 20 per cent of blood volume for a 500 kg horse) from blood donor horses every 3 weeks allows time for adequate recovery of haematological variables and does not result in adverse haematological changes.

Animals↗
PubMed2000

Metabolite-intermediate complexation and inhibition of microsomal CYP3A in rat liver by diltiazem.

1. The formation of metabolite intermediate (MI)-complexes between cytochrome P450 (CYP) and the alkylamine-substituted drugs diltiazem (DTZ) and desipramine (DES) and their effect on CYP activities was investigated in rat liver. 2. Dexamethasone and phenobarbitone pretreatment enhanced MI-complexation by DTZ (36% and 11% of total CYP complexed, respectively), whereas beta-naphthoflavone induction was without effect. All three treatments decreased MI-complexation produced by DES. 3. After a preincubation step in NADPH-supplemented microsomes DTZ and DES were effective inhibitors of the activities of CYPs 3A and 2C11 (testosterone 6beta- and 16alpha-hydroxylations, respectively). 4. Although MI-complexation by DTZ was more extensive in microsomes from dexamethasone-induced rats, the apparent inhibition potency of the drug toward CYP activity was unchanged. By comparison, inhibition of CYP activity by DES was less pronounced than in control liver. 5. These findings indicate that drug-mediated MI-complexation of CYPs does not necessarily potentiate the inhibitory effect on monooxygenase activity, although the duration of inhibition is longer. The extent of inhibition produced by stable drug metabolites may be similar to that from MI-complexation. but their duration of action is limited by diffusion from the active site of the enzyme.

Animals↗
PubMed2000

Comparison of the frequency of behavioral disinhibition on alprazolam, clonazepam, or no benzodiazepine in hospitalized psychiatric patients.

Several case reports have suggested that treatment with the benzodiazepine alprazolam can result in behavioral disinhibition. To address this question, the authors reviewed the medical records (blinded to all pharmacologic treatments the patients received) of 323 psychiatric inpatients treated with alprazolam (108 patients), clonazepam (111 patients), or no benzodiazepine (104 patients) between January 1989 and June 1990. During benzodiazepine treatment, there were no significant differences among the three groups on the following measures: (1) acts of self-injury (alprazolam, 1.9%; clonazepam, 1.8%; no benzodiazepine, 2.9%); (2) assaults on staff or other patients (alprazolam, 0%; clonazepam, 0.9%; no benzodiazepine, 1.0%); (3) need for seclusion or restraints (alprazolam, 3.7%; clonazepam, 6.3%; no benzodiazepine, 4.8%); (4) increased need for observation by hospital staff (alprazolam, 8.3%; clonazepam, 7.2%; no benzodiazepine, 6.7%); and (5) decrease in patient privileges (alprazolam, 11.1%; clonazepam, 12.6%; no benzodiazepine, 11.5%). The results indicate that in an inpatient psychiatric population, the frequency of behavioral disturbances with alprazolam, clonazepam, or no benzodiazepine does not differ. This suggests that alprazolam does not possess unique disinhibitory activity. Second, these data suggest that disinhibition may not be an important clinical problem associated with benzodiazepine use. The design of the study does not allow one to establish a relationship between the prescription of the benzodiazepine and worsening behaviors, and the findings need to be interpreted conservatively because it was a retrospective review of a heterogeneous population. However, it is noteworthy that the incidence of adverse events was low even in this high-risk population, and because the patients were in the hospital and under constant observation, the objective assessment of so-called paradoxical reactions was undertaken in a controlled setting.

Adolescent↗
PubMed2000

Single injections of a DNA plasmid that contains the human Bcl-2 gene prevent loss and atrophy of distinct neuronal populations after spinal cord injury in adult rats.

Spinal cord injury in adult mammals causes atrophy or loss of axotomized neurons. We have previously found that the product of the antiapoptotic gene Bcl-2, delivered by intraspinal injection of a DNA plasmid, reduces atrophy and loss of axotomized Clarke's nucleus neurons in adult rats. Here we studied whether the same treatment protects axotomized red nucleus (RN) neurons. Two months after the right dorsolateral funiculus was ablated in adult Sprague-Dawley rats by C3/C4 subtotal hemisection, there was approximately 48% loss of RN neurons in the magnocellular portion of the RN contralateral to the lesion and atrophy of many surviving neurons. When a DNA plasmid encoding the human Bcl-2 gene and the bacterial reporter gene LacZ, complexed with cationic lipids, was injected just rostral to the subtotal hemisection site, 87% of RN neurons survived, and there was partial, but robust, protection from atrophy. These and our previous results indicated that intraspinal administration of the Bcl-2 gene can prevent retrograde cell loss and reduce atrophy of axotomized RN and Clarke's nucleus neurons in adult rats and provide an effective means to rescue neurons whose survival depends on different growth factors.

Animals↗
PubMed2000

Glucocorticoid-dependent maintenance of CYP2C11-dependent oxidation in male rat liver in vivo.

1. Hormonal factors participate in the regulation of xenobiotic metabolising enzymes in liver. Hepatic xenobiotic oxidation capacity is decreased in adrenalectomised rats, which directly implicates adrenal hormones in the control of cytochrome P450 (CYP) expression. In addition, recent studies in cultured hepatocytes have demonstrated that low concentrations of glucocorticoid upregulate the male-specific CYP2C11, which is a major enzyme that catalyses xenobiotic and steroid hydroxylations in rat liver. The present study evaluated whether glucocorticoid or mineralocorticoid may be the adrenal factor that contributes to the in vivo expression of CYP2C11 in liver. 2. Adrenalectomy of male rats selectively decreased CYP2C11-dependent 2alpha-/16alpha-hydroxylation of testosterone and other steroid substrates to 60-70% of control, whereas activities mediated by other constitutive CYPs were unaffected. The decrease in CYP2C11 activity was due to impaired protein expression in liver after adrenalectomy. Administration of dexamethasone (DEX; 0.2 mg/kg i.p. daily for 6 days) restored CYP2C11 activity and protein, whereas the mineralocorticoid deoxycorticosterone (DOC) and adrenocorticotropic hormone (ACTH) were ineffective. 3. These findings establish that glucocorticoids have a partial role in the maintenance of CYP2C11 expression and associated microsomal oxidation in liver and provide a physiological correlate for similar observations made in vitro in hepatocyte culture.

Adrenalectomy↗
PubMed2000

Medicaid managed care reimbursement for HIV and its implications for access to care.

The rapid growth of managed care in state Medicaid programs has raised concerns about access to care for people living with HIV and AIDS (PLWH). Even the highest capitation rates that most programs pay to managed care organizations (MCOs) for disabled enrollees are substantially lower than the costs of care, especially when costly protease inhibitor therapy is taken into account. A national study has shown that Medicaid beneficiaries did not have the same level of access to protease inhibitors as did privately insured HIV patients in 1996 and 1997. Low capitation rates can limit access to care for PLWH by discouraging MCOs from having experienced HIV physicians on their provider panels and from enrolling PLWH. Since 1997, however, Medicaid programs in several states have adopted strategies to reduce the financial risks facing MCOs caring for PLWH and enrollees with other high-cost conditions. These strategies include global health-based (risk-adjusted) payment systems, AIDS-specific reimbursement rates, carve outs from capitation rates for medications and other services, risk pools for high-cost enrollees, risk corridors, and stop-loss insurance policies through which Medicaid programs share financial liability with MCOs for catastrophic losses. In addition, several programs have developed HIV centers of excellence. Most state Medicaid programs have yet to adopt any of these strategies. However, the growing numbers and types of experimental approaches to capitating services for PLWH may provide models for other states whose low reimbursement rates currently limit access to care.

Capitation Fee↗
PubMed2000

Simplifying modern wound management for nonprofessional caregivers.

Nonprofessional caregivers currently are participating in managing pressure ulcers at home. As this can be a stressful experience, innovative and easy-to-use products are needed to support caregiver confidence. A multicenter, randomized clinical trial was conducted to compare clinical performance and case of instruction of a change indicator dressing (SIG) and a hydrocolloid alginate dressing (HAD) in the management of pressure ulcers in the home and long-term care settings. SIG and HAD were randomized to 17 and 18 partial- or full-thickness pressure ulcers respectively. During five dressing changes, wound area, dressing application, maintenance, appearance, removal, wear time, ease of teaching, and caregiver understanding of each dressing's instructions were measured. Both dressings were rated highly regarding ease of teaching, ease of use, appearance, maintenance, and helpfulness in signaling the need for dressing change by both professional and nonprofessional wound caregivers. Average dressing wear time was 3.2 days for SIG and 2.7 days for HAD. Of these wounds managed in a moist environment, 6 of 17 (35%) subjects whose wounds were dressed with SIG, and 1 of 18 (6%) dressed with HAD healed during the course of the study (alpha < 0.04). Percent wound reduction in area per day of care was also greater for SIG (alpha < 0.01). Innovative dressings may help caregivers provide consistent quality pressure ulcer care and improve wound-healing outcomes.

Aged↗
PubMed1999

Red nucleus neurons of Bcl-2 over-expressing mice are protected from cell death induced by axotomy.

The Bcl-2 proto-oncogene regulates apoptosis and prevents cell death. We studied the effect of Bcl-2 gene over-expression on the survival of axotomized red nucleus (RN) neurons after unilateral hemisection at cervical segment 4/5 (C4/5) in mice. Seventy-five percent of RN neurons survived in Bcl-2 over-expressing mice 1 or 2 months after surgery compared with only 55% of RN neurons in wild-type mice. However, Bcl-2 gene over-expression does not prevent lesion-induced shrinkage of RN neurons.

Animals↗
PubMed1999

Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes.

Cytochromes P450 (CYPs) catalyze the 4-hydroxylation of all-trans-retinoic acid (ATRA), an agent used in the treatment of certain malignancies. Literature studies have implicated several CYPs in this reaction, but the relative importance of individual CYPs is unclear. Human microsomal CYPs that contribute to the activity were evaluated by correlation with activities of hepatic drug-metabolizing CYPs, the capacity of cDNA-derived CYPs to catalyze the reaction, and inhibition of the microsomal activity by chemicals. 4-HydroxyATRA formation in microsomes varied 7-fold (8.7 to 61 pmol/mg protein/min) and correlated partially with activities mediated by CYPs 3A, 2C, and 1A (p = 0.53 to 0.66). cDNA-derived CYPs 2C8, 2C9, and 3A4, but not 1A1 or 1A2, catalyzed ATRA 4-hydroxylation (2.53, 4.68, and 1.29 pmol/pmol CYP/hr). The Km for the reaction was 9 +/- 3 microM in hepatic microsomes (N = 3) and 6 microM in microsomes containing cDNA-derived CYP2C8; by comparison, Km values for the activity mediated by CYPs 2C9 and 3A4 were 100 and 74 microM, respectively. Inhibition of microsomal ATRA 4-hydroxylation was elicited by chemicals that interact with CYP2C8 (paclitaxel and diclofenac), but not those that interact with CYP2C9 (sulfaphenazole, tolbutamide, and torasemide). The CYP3A inhibitor troleandomycin and an anti-CYP3A IgG inhibited the activity slightly. Greater inhibition was produced by the less selective CYP3A inhibitors parathion, quinidine, and ketoconazole; CYP1A inhibitors were ineffective. These findings suggest that CYP2C8 is a major contributor to ATRA 4-hydroxylation in human liver and that 3A subfamily CYPs may be minor participants. Individual variation in CYP2C8 and 3A4 expression may influence ATRA pharmacokinetics and drug interactions during therapy.

Cytochrome P-450 CYP3A↗
PubMed1999

Pretranslational up-regulation of the hepatic microsomal delta4-3-oxosteroid 5alpha-oxidoreductase in male rat liver by all-trans-retinoic acid.

Administration of all-trans-retinoic acid (ATRA; 60 mg/kg daily for 3 days) to male rats increased the rate of 5alpha-dihydrotestosterone (5alpha-DHT) formation from testosterone in microsomal fractions in vitro. The formation of androstane-3alpha,17beta-diol from testosterone was also increased because of the higher concentration of 5alpha-DHT produced in microsomal incubations. Northern analysis confirmed that the increased rate of 5alpha-DHT formation was due to the pretranslational up-regulation in delta4-3-oxosteroid 5alpha-oxidoreductase (EC 1.3.99.5) mRNA expression in ATRA-treated male rat liver. Thus, ATRA elicited in male rat liver a partial feminization of the expression of this enzyme, which normally exhibits a female-selective distribution in the rat. Subsequent experiments evaluated whether the administration of human chorionic gonadotropin or thyroxine to ATRA-treated male rats decreases 5alpha-reductase activity to that observed in untreated male rat liver. Although these treatments did not decrease 5alpha-reductase to untreated male levels, it was found that administration of ATRA to gonadectomized male rats produced complete feminization of the enzyme. Again, up-regulation was confirmed at the mRNA level. The activity of the male-specific cytochrome P450 2C11 (as reflected by microsomal testosterone 16alpha-hydroxylation activity) was correspondingly decreased by treatments that increased steroid 5alpha-reductase activity. Thus, gonadectomy in combination with ATRA administration effected a more pronounced decrease in 16alpha-hydroxylation activity than either treatment alone. These findings suggest that ATRA is a novel positive regulator of the 5alpha-reductase that in combination with the removal of circulating androgen, which normally suppresses 5alpha-reductase levels, feminizes the expression of this enzyme in rat liver.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1999

Results of the Scoliosis Research Society instrument for evaluation of surgical outcome in adolescent idiopathic scoliosis. A multicenter study of 244 patients.

STUDY DESIGN: An outcome questionnaire was constructed to evaluate patient satisfaction and performance and to discriminate among patients with adolescent idiopathic scoliosis. OBJECTIVES: To determine reliability and validity in a new quality-of-life instrument for measuring progress among scoliosis patients. SUMMARY OF BACKGROUND DATA: Meta-analysis of the surgical treatment of adolescent idiopathic scoliosis determined that a uniform assessment of outcome did not exist. In addition, patient measures of well-being as opposed to process measures (e.g., radiographs) were not consistently reported. This established the need for a standardized questionnaire to assess patient measures in conjunction with process measures. METHODS: The instrument consists of 24 questions divided into seven equally weighted domains as determined by factor analysis: pain, general self-image, postoperative self-image, general function, overall level of activity, postoperative function, and satisfaction. The questionnaire takes approximately 5 minutes to complete and is taken at predetermined time intervals. A total of 244 of patients from three different sites responded to the questionnaire. RESULTS: The reliability based on internal consistency was confirmed with a Cronbach's alpha coefficient greater than 0.6 for each domain. In addition, acceptable correlation coefficient values greater than 0.68 were obtained for each domain by the test-retest method on normal controls. Similarly; to establish validity of the questionnaire, responses of normal high school students were compared with that of the patients. Consistent differences were noted in the domains between the two groups with P < 0.003. The largest differences were in pain (control, 29.96 +/- 0.20; patient, 13.23 +/- 5.55) and general level of activity (control, 14.96 +/- 0.20; patient, 12.16 +/- 3.23). Examination of the relationship between the domains and patient satisfaction showed that pain correlates with satisfaction to the greatest degree (Pearson's correlation co-efficient, r = -0.511; P < 0.001), followed by self-image (r = 0.412; P < 0.001). CONCLUSIONS: This questionnaire addresses patient measures for evaluation of outcome in adolescent idiopathic scoliosis surgery by examining several domains. It also allows for dynamic monitoring of scoliosis patients as they become adults. This is a validated instrument with good reliability measures.

Adolescent↗
PubMed1999

Direct agonists for serotonin receptors enhance locomotor function in rats that received neural transplants after neonatal spinal transection.

We analyzed whether acute treatment with serotonergic agonists would improve motor function in rats with transected spinal cords (spinal rats) and in rats that received transplants of fetal spinal cord into the transection site (transplant rats). Neonates received midthoracic spinal transections within 48 hr of birth; transplant rats received fetal (embryonic day 14) spinal cord grafts at the time of transection. At 3 weeks, rats began 1-2 months of training in treadmill locomotion. Rats in the transplant group developed better weight-supported stepping than spinal rats. Systemic administration of two directly acting agonists for serotonergic 5-HT(2) receptor subtypes, quipazine and (+/-)-1-[2, 5]-dimethoxy-4-iodophenyl-2-aminopropane), further increased weight-supported stepping in transplant rats. The improvement was dose-dependent and greatest in rats with poor to moderate baseline weight support. In contrast, indirectly acting serotonergic agonists, which block reuptake of 5-HT (sertraline) or release 5-HT and block its reuptake (D-fenfluramine), failed to enhance motor function. Neither direct nor indirect agonists significantly improved locomotion in spinal rats as a group, despite equivalent upregulation of 5-HT(2) receptors in the lumbar ventral horn of lesioned rats with and without transplants. The distribution of immunoreactive serotonergic fibers within and caudal to the transplant did not appear to correspond to restoration of motor function. Our results confirm our previous demonstration that transplants improve motor performance in spinal rats. Additional stimulation with agonists at subtypes of 5-HT receptors produces a beneficial interaction with transplants that further improves motor competence.

Amphetamines↗
PubMed1999

Reactions of lipid-derived malondialdehyde with collagen.

Malondialdehyde is a product of fatty acid oxidation (e.g. from low density lipoprotein) implicated in the damage of proteins such as collagen in the cardiovascular system (Chio, K. J., and Tappel, A. L. (1969) Biochemistry 8, 2821-2827). Its concentration is raised in diabetic subjects probably as a side effect of increased protein glycation. Collagen has enzyme-catalyzed cross-links formed between its individual molecules that are essential for maintaining the structure and flexibility of the collagen fiber. The cross-link dehydro-hydroxylysinonorleucine reacts irreversibly with 10 mM malondialdehyde at least 3 orders of magnitude faster than glucose reactions with lysine or arginine, such that there is little cross-link left after 1 h at 37 degrees C. Other cross-links and glycated elements of collagen are also vulnerable. Several possible products of malondialdehyde with collagen cross-links are proposed, and the potential involvement of collagenous histidine in these reactions is discussed. We have also isolated Ndelta-(2-pyrimidyl)-L-ornithine from collagenous arginine reacted with malondialdehyde. The yields of this product were considerably higher than those from model reactions, being approximately 2 molecules/collagen molecule after 1 day at 37 degrees C in 10 mM malondialdehyde. Collagenous lysine-derived malondialdehyde products may have been present but were not protected from protein acid hydrolysis by standard reduction techniques, thus resulting in a multitude of fragmented products.

Animals↗
PubMed1999

Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forelimb function.

Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been attributed to scar tissue and inhibitory molecules at the injury site that block the regenerating axons, a lack of trophic support for the axotomized neurons, and intrinsic neuronal changes that follow axotomy, including cell atrophy and death. We studied whether transplants of fibroblasts genetically engineered to produce brain-derived neurotrophic factor (BDNF) would promote rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were modified by retroviral-mediated transfer of a DNA construct encoding the human BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and neomycin resistance genes. The modified fibroblasts produce biologically active BDNF in vitro. These cells were grafted into a partial cervical hemisection cavity that completely interrupted one RST. One and two months after lesion and transplantation, RST regeneration was demonstrated with retrograde and anterograde tracing techniques. Retrograde tracing with fluorogold showed that approximately 7% of RST neurons regenerated axons at least three to four segments caudal to the transplants. Anterograde tracing with biotinylated dextran amine revealed that the RST axons regenerated through and around the transplants, grew for long distances within white matter caudal to the transplant, and terminated in spinal cord gray matter regions that are the normal targets of RST axons. Transplants of unmodified primary fibroblasts or Gelfoam alone did not elicit regeneration. Behavioral tests demonstrated that recipients of BDNF-producing fibroblasts showed significant recovery of forelimb usage, which was abolished by a second lesion that transected the regenerated axons.

Animals↗
PubMed1999

The parasites, predators, places and people I have known: a great adventure.

I am extremely proud to receive the WAAVP/Pfizer Animal Health award, and particularly so in Africa, the continent where I have spent a large part of my professional life. In the nearly 40 years in research I have had the privilege and excitement of being involved with many great parasites, predators, places and people. In my early days in Kenya I saw all the great wild animal predators, but soon came to appreciate that the greatest predator of all was disease, particularly parasitic disease, with the devastating effects of tsetse and ticks and the infections they transmitted, and of the all-prevailing roundworms. I learned several key lessons while working with research teams to develop better diagnostics, to improve epidemiological understanding as a basis for rational treatment and control, and to extend the understanding of disease processes with the view to developing novel methods of treatment or prevention. The Power of Pathology in diagnosing diseases, identifying new diseases and as a major tool for pathogenic diseases. The Power of Pathogenesis in identifying key mechanisms that led to new diagnostic techniques, improved methods of treatment, and possibly to future vaccines. The Power of Application of what we already know; while recognising that molecular biology will make a massive contribution to improving animal and human health, it is important to appreciate that we already have a very powerful armamentaria to diagnose, treat, control or prevent disease, and when used properly they have been successful and cost-effective. The Power of Genetic Resistance: the recognition that certain species, certain breeds, and certain individuals within breeds possess remarkable resistance to certain parasitic diseases such as trypanosomosis and helminthosis, and that this trait is genetically correlated with production, opens up a very powerful additional approach to improving animal health. The Importance of Measurement: I completely endorse the sentiments of Lord Kelvin, Professor of Natural Philosophy at Glasgow University who stated in 1846: "When you can measure what you are speaking about, and express it in numbers, you know something about it: but when you cannot measure it, your knowledge is of a meagre and unsatisfactory kind." This applies very much to Parasitology. The future is bright. The combination and integration of the new technologies of Biotechnology, Mathematical Methods and Bioinformatics coupled with advances in Computer Power will produce new standards in animal and human health in the 21st century. New methods of predicting, diagnosis, treating, controlling, prognosing and preventing disease will become available. WAAVP has a major role to play by ensuring that veterinary parasitologists are provided with the proper training, infrastructure and forum to advance new technologies and that the veterinary profession plays a leading role in the future direction they take.

Africa↗