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Biomedical subjects

M Murray

Publications and source records attributed to M Murray.

At least 145 records · Page 8Linked to original sources
PubMed1997

Pathophysiology of Trypanosoma congolense infection in two breeds of sheep, Scottish blackface and Finn Dorset.

The pathophysiology of Trypanosoma congolense infection was studied in two breeds of sheep, the Scottish Blackface (SB) and Finn Dorset (FD), which were known from previous studies to differ significantly in their susceptibility to haemonchosis, in which anaemia is also the primary pathophysiological effect. It was found that infected SB and FD lambs developed similar intensities of parasitaemia. However, infected SB lambs developed a higher degree of anaemia, more severe thrombocytopaenia and hypoalbuminaemia than infected FD. Following infection, the concentrations of plasma cholesterol, serum phospholipids and total lipids decreased. The decline in these lipid components appeared to be greater in infected SB than in infected FD lambs.

Animals↗
PubMed1997

Resistance of four sheep breeds to natural and subsequent artificial Haemonchus contortus infection.

The response of Red Maasai sheep to natural and artificial Haemonchus contortus infections was compared with sheep of Blackheaded Somali, Dorper and Romney Marsh breeds. Significant breed differences in egg count, packed cell volume (PCV), and mortality rates showed that the Red Maasai sheep were more resistant to natural H. contortus infection than sheep from the other three breeds. Of the initial groups of 15 wethers of each breed, two animals from each of the Dorper and Blackheaded Somali groups and nine from the Romney Marsh group died with haemonchosis during a 12 month field study. Following artificial infection of the Red Maasai, Dorpers and Blackheaded Somalis, with 10000 H. contortus L3, the Red Maasai sheep maintained a lower egg output and a higher PCV than animals of the other two breeds. The results clearly showed that breed substitution with the Red Maasai is a control option in areas where sheep are kept for meat and H. contortus is endemic.

Animals↗
PubMed1997

Response to artificial and subsequent natural infection with Haemonchus contortus in red Maasai and Dorper ewes.

Maiden Red Maasai and Dorper ewes were kept indoors and artificially infected with a single oral dose of 5000 infective larvae of Haemonchus contortus. Their faecal egg counts (FEC) and packed red cell volumes (PCV) were monitored for 9 weeks. They were then treated with an anthelmintic and turned out to graze together on a pasture contaminated with H. contortus. They grazed this pasture for 14 months and were allowed to mate and lamb. While at pasture the ewes were monitored for FEC, PCV and peripheral eosinophilia. Red Maasai ewes had significantly lower FEC, and for certain periods, significantly higher PCV and peripheral eosinophilia. During the periparturient period, FEC were about twice as high in the Dorper breed as the Red Maasai. These results confirm and extend previous reports on the superiority of the Red Maasai breed in East Africa.

Animals↗
PubMed1997

The influence of supplementation with cotton seed cake on the resistance of Ugandan goats to primary and secondary challenges with Trypanosoma congolense and on their response to treatment.

The present study investigated the influence of supplementation with cotton seed cake on the resistance of the Small East African breed of goats to primary and secondary challenges with Trypanosoma congolense and on their response to chemotherapy with diminazene aceturate. The supplemented group received 300 g of cotton seed cake per day in addition to about 500 g of fresh napier grass which was available to the unsupplemented group. It was observed that the supplemented infected (SI) group tended to sustain higher intensities of parasitaemia than the unsupplemented infected (USI) group particularly during the primary challenge and both groups showed longer prepatent periods to secondary challenge than to primary challenge. Infection caused a significant reduction in the rate of live body weight gain in the USI group compared with the unsupplemented control (USC) group whilst the SI group grew at the same rate as the supplemented control (SC) group. This effect was observed both during primary and secondary challenges. Following primary challenge, both infected groups developed similar degrees of anaemia, but the packed red cell volume (PCV) levels in the SI group improved towards the end of the first challenge and were also significantly higher than those of the USI group during the second challenge. After treatments at 56 and 126 days after infection (DAI), the greatest response was observed in PCV values. The response of the SI group was superior to that of the USI group and by 4 weeks after treatment the PCV values of the SI and SC groups were similar while those of the USI group were significantly lower than those of the USC group. It is concluded that supplementation with cotton seed cake plays an important role in the rate of live weight gain, and rate of recovery from anaemia produced by trypanosome infection in goats.

Animal Nutritional Physiological Phenomena↗
PubMed1997

Induction of cytochromes P450 2B and 2E1 in rat liver by isomeric picoline N-oxides.

Pyridine derivatives are widely used solvents and precursors for the synthesis of chemicals of industrial importance. Oxidized metabolites have been implicated in the observed toxicity of pyridines and are known to induce drug-metabolizing enzymes in rat liver. In this study the three isomeric picoline (methylpyridine) N-oxides, as major oxidized metabolites of 2-, 3- and 4-picoline, were evaluated as inducers of cytochrome P450 (CYP) enzymes in rat liver. After a single dose of 100 mg/kg 24 h before sacrifice the 3- and 4-isomers were effective inducers of microsomal substrate oxidations associated with the phenobarbital-inducible CYPs 2B; upregulation of CYP2B protein was confirmed by immunoblotting. In contrast, the 2-isomer did not increase CYP2B protein or activity in rat liver but CYP2E1 protein expression was upregulated by the isomers to 160-200% of control. The three chemicals increased aniline 4-hydroxylation activity in rat liver, which is consistent with induction of CYPs 2B or 2E1 and 4-nitrophenol 2-hydroxylation activity was increased in microsomal fractions from 3- and 4-picoline N-oxide-treated rats. The activities of several other CYPs were also determined and CYP1A-dependent 7-ethylresorufin O-deethylation was increased (to approximately 6- and 2-fold of control) by the 3- and 4-isomer, respectively, whereas the activity of CYP3A-mediated androstenedione 6beta-hydroxylation was decreased by the agents--most notably by the 2-isomer. During NADPH-supported oxidation of CCl4, lipid peroxidation was increased in microsomes from 3- and 4-picoline N-oxide-pretreated rats and was modulated in vitro by the CYP2B inhibitor orphenadrine, but not by the CYP2E1 inhibitor 4-methylpyrazole. These findings establish that particular isomers of picoline N-oxide rapidly upregulate CYP2B or, to a lesser extent, CYP2E1 and implicate CYP2B in the enhanced lipid peroxidation observed in microsomes from rats treated with 3- and 4-picoline N-oxides. Such induction process may contribute to the hepatotoxicity of pyridines by enhancing the capacity for microsomal lipid peroxidation.

Animals↗
PubMed1997

Effects of the incubation of long-chain polyunsaturated fatty acids on platelet lipids and thromboxane release.

Alterations of dietary lipids have been advocated to manipulate platelet release of thromboxane A2. We studied the effects of incubating platelets with several different polyunsaturated fatty acids on platelet-lipid profile and release of thromboxane A2 in response to platelet stimulation. Porcine platelets were isolated by centrifugation, washed three times in Tyrode's solution, and incubated with fatty acids (500 microM) in Tyrode's solution with albumin. Seven polyunsaturated fatty acids of varying lengths (18-, 20-, and 22-carbon chain) of the omega3 and omega6 families were incubated for 60 min at concentrations of 0, 10, 30, and 100 microM with saturated fatty acids comprising the remainder of the 500 microM fatty acids. The platelets were then stimulated for 5 min with A23187 (30 microM). Indomethacin was added, and the platelets were pelleted. Platelet lipids were extracted in hexane, transesterified and quantified by gas chromatography. Using radioimmunoassay, we measured thromboxane B2, the stable metabolite of thromboxane A2, in the platelets' supernatant. A 1-h incubation in each of the seven polyunsaturated fatty acids had no significant effect on platelet-lipid composition. We found a significant increase in thromboxane B2 production in arachidonic acid (100 microM) incubated platelets (324.0 +/- 63.8% of baseline) that was inhibited by eicosapentaenoic acid (81.0 +/- 26.8%, P < 0.01) and to a lesser extent by dihomogammalinolenic acid (189.8 +/- 28.3%, P < 0.03). We conclude that in altering diets to affect platelet release of thromboxane, the two fatty acids of interest are the 20-carbon chain fatty acids, dihomogammalinolenic acid and eicosapentaenoic acid. The ideal amount of each of these fatty acids to be incorporated entails supraphysiologic but pharmacologically achievable levels of fatty acids in plasma.

Animals↗
PubMed1997

The genetic basis of resistance to Ostertagia circumcincta in lambs.

The relationship between Ostertagia (Teladorsagia) circumcincta and sheep is one of the best understood host-parasite relationships in any species. The key components of resistance have been quantified, the extent of genetic control has been established for lambs, and methods now exist to breed lambs which will be both more resistant to worms and more productive than unselected lambs. A major gene for resistance has been identified within or around the major histocompatibility complex, and this gene appears to be the strongest yet identified for resistance to any parasite species. The most important mechanisms of resistance are local IgA responses which regulate worm fecundity and immediate hypersensitivity responses which regulate worm burdens. IgA responses develop before effective immediate hypersensitivity responses. Good simulation models now exist to predict, for example, outbreaks of disease and the response of sheep to selection. The challenge now is to use our improved understanding of the population biology to develop even better simulation models and to produce expert systems based on these models which can be used by veterinarians and others to determine optimal procedures for individual farms to control disease and reduce sub-clinical economic losses.

Animals↗
PubMed1997

Regulation of inositol monophosphatase in Saccharomyces cerevisiae.

Inositol monophosphatase is a key enzyme in the de novo biosynthesis of inositol and in the phosphoinositide second-messenger signalling pathway. Inhibition of this enzyme is a proposed mechanism for lithium's pharmacological action in bipolar illness (manic depression). Very little is known about how expression of this enzyme is regulated. Because the yeast Saccharomyces cerevisiae has been shown to be an excellent model system in which to understand the regulation of inositol metabolism, we characterized inositol monophosphatase in this yeast. Lithium inhibited monophosphatase activity in vitro. Growth in the presence of inositol resulted in increased expression of the enzyme in vivo, although inositol had no effect on enzyme activity in vitro. The inositol effect was apparent when cells were grown in glucose but not in glycerol/ethanol. Monophosphatase activity was derepressed as cells entered stationary phase. This effect was apparent only during growth in glucose plus inositol. The results demonstrate that S. cerevisiae monophosphatase is inhibited by lithium and regulated by factors affecting phospholipid biosynthesis.

Enzyme Inhibitors↗
PubMed1997

Nutrition support in clinical practice: review of published data and recommendations for future research directions. Summary of a conference sponsored by the National Institutes of Health, American Society for Parenteral and Enteral Nutrition, and American Society for Clinical Nutrition.

In the last 30 years, marked advances in enteral feeding techniques, venous access, and enteral and parenteral nutrient formulations have made it possible to provide nutrition support to almost all patients. Despite the abundant medical literature and widespread use of nutritional therapy, many areas of nutrition support remain controversial. Therefore, the leadership at the National Institutes of Health, The American Society for Parenteral and Enteral Nutrition, and The American Society for Clinical Nutrition convened an advisory committee to perform a critical review of the current medical literature evaluating the clinical use of nutrition support; the goal was to assess our current body of knowledge and to identify the issues that deserve further investigation. The panel was divided into five groups to evaluate the following areas: nutrition assessment, nutrition support in patients with gastrointestinal diseases, nutrition support in wasting diseases, nutrition support in critically ill patients, and perioperative nutrition support. The findings from each group are summarized in this report. This document is not meant to establish practice guidelines for nutrition support. The use of nutritional therapy requires a careful integration of data from pertinent clinical trials, clinical expertise in the illness or injury being treated, clinical expertise in nutritional therapy, and input from the patient and his/her family. (Journal of Parenteral and Enteral Nutrition 21:133-156, 1997).

Cachexia↗
PubMed1997

Drug-mediated inactivation of cytochrome P450.

1. Multiple forms of cytochrome P450 (CYP) catalyse the oxidation of chemicals of endogenous and exogenous origin, including drugs, carcinogens, steroids and eicosanoids. However, this unusual low substrate specificity also makes CYP susceptible to inhibition by a wide range of drugs, leading to pharmacokinetic interactions of potential clinical significance. 2. Some drugs are converted by CYP to reactive metabolites that bind covalently to sites within the active centre of the same CYP. Such mechanism-based inhibition leads to CYP inactivation or complexation. These processes give rise to long-term effects on drug pharmacokinetics, as the inactivated or complexed CYP must be replaced by newly synthesized CYP protein. 3. Drugs that inactivate CYP generally possess recognizable functional groups that are oxidized to reactive products. Thus, drugs with side chains containing unsaturated carbon-carbon bonds and furan ring systems are associated with CYP inactivation. Nitrogen-containing systems may also inactivate CYP. 4. Metabolites formed from drugs containing alkylamino and methylenedioxy functionalities can trap CYP as inert complexes without eliciting inactivation. However, the functional effects of inactivation and complexation on drug pharmacokinetics are indistinguishable. Drugs that elicit CYP complexation include the first generation macrolide antibiotics, but newer analogues appear much safer. Some antidepressants, antiepileptics and tuberculostatic agents have been associated with CYP complexation.

Animals↗
PubMed1997

Respiratory status and allergy nine to 10 years after acute bronchiolitis.

In order to evaluate further the relationship between acute bronchiolitis in infancy and subsequent respiratory problems, children prospectively followed up from the time of their admission to hospital were reviewed along with a group of matched controls recruited at the previous five and a half year assessment. Sixty one index children and 47 controls took part. The groups were well matched for age, height, parental smoking, and social class. Although the prevalence of respiratory symptoms had fallen when related to the previous review, there remained an excess of coughing (48 and 17% in index and control children respectively; odds ratio 4.02) and wheezing (34 and 13% in index and control children respectively; odds ratio 3.59). Bronchodilator therapy was used by 33% of index children compared with 3% of controls. Lung function tests revealed no significant differences in the measurements of lung growth-for example, forced vital capacity, functional residual capacity, and total lung capacity-but the index children had significant reductions in measurements of airways obstruction-for example, forced expiratory volume in one second, maximum expiratory flow at 75, 50 and 25% of vital capacity, and airways resistance. Family history and personal skin tests showed no excess of atopy in the index group. This study supports the claim that the excess respiratory symptoms after acute bronchiolitis are not due to familial or personal susceptibility to atopy.

Acute Disease↗
PubMed1997

A flexible and extensible object-oriented 3D architecture: application in the development of virtual anatomy lessons.

"Anatomic VisualizeR" represents the first application to be developed using a 3D architectural framework created at the University of California, San Diego, School of Medicine. This application combines 3D anatomic models (based on the Visible Human dataset) with supporting 2D media (e.g., diagnostic imagery, surgical videos, etc.) to establish a comprehensive learning environment for anatomy. "Guided lessons" are being created to address complex curricular and learning objectives. Faculty expertise is represented in these preconfigured lessons, in part through the specification of appropriate content and the incorporation of activities to enhance visualization. These lessons are an intellectual framework which ensures that clinically-relevant issues and ancillary learning opportunities are available. The curricular exercises are non-sequential and can be interrupted at any time; users are encouraged to freely explore the environment. At the core of Anatomic VisualizeR's object-oriented architecture is the ability to identify, access, view, and manipulate heterogeneous content. The capacity to query a database gateway to retrieve specified resources has been built into the application. Encapsulation of individual elements to form 3D display objects ("blocks") enables Anatomic VisualizeR to efficiently manage 3D models, 2D images, text, sound, and video. The "block" paradigm also allows Anatomic VisualizeR to associate contextually appropriate display characteristics and behaviors with the various content elements. For example, the anatomic model block provides the capability to "link" and "unlink" the anatomic models and to alter their transparencies. The anatomic models can be displayed concurrently with other blocks to facilitate structural comparisons. Anatomic VisualizeR marks a major milestone in our developmental efforts. While lessons and database content are still not complete, we are confident that it will become the first tangible realization of our vision.

Anatomy↗
PubMed1997

Embryonic spinal cord transplants enhance locomotor performance in spinalized newborn rats.

The results of the present experiments demonstrate that fetal spinal cord transplants placed into the site of a complete transection in newborn rats permit the development of complex patterns of locomotion. These patterns differ in some respects from normal, but include weight support, appropriate postural adjustment, and coordination between forelimbs and hindlimbs. 5-HT agonists administered to transplanted rats can further modify these motor patterns in ways that may prove able to enhance locomotion. When placed into lesion cavities in adult spinal cord, cells genetically modified to express neurotrophins can survive, differentiate, and mimic at least one consequence of fetal transplants, rescue of axotomized neurons from retrograde cell death.

Animals↗
PubMed1997

Biotransformation of parathion in human liver: participation of CYP3A4 and its inactivation during microsomal parathion oxidation.

Studies in rat liver have shown that cytochrome P450 (CYP) enzymes mediate the oxidative biotransformation of the phosphorothioate pesticide parathion to paraoxon and 4-nitrophenol. Transfer of the phosphorothioate thionosulfur atom to the CYP apoprotein results in amino acid modification and enzyme inactivation. Our study investigated the role of human hepatic CYP in parathion oxidation and their relative susceptibilities to inhibition and inactivation. Rates of parathion oxidation varied about 10-fold in microsomes from 23 individual livers (1.72-18.33 nmol total metabolites/mg protein/min). Linear regression of rates of parathion oxidation with those of other microsomal CYP reactions implicated CYP3A4 in the reaction. Thus, parathion oxidation was correlated strongly with testosterone 6beta-hydroxylation (r2 = 0.95, n = 11), but not with activities mediated by CYP 1A2, 2C9 or 2E1. CYP 3A4 expressed in lymphoblastoid cell lines was an efficient catalyst of parathion oxidation, although CYP 1A2 and 2B6 also catalyzed the activity. The CYP3A4 inhibitors ketoconazole and triacetyloleandomycin decreased the observed rate of microsomal parathion oxidation, but chemicals known to interact preferentially with other human CYP were essentially noninhibitory. P450 was lost during parathion biotransformation in human hepatic microsomes. Thus, incubation (10 min) of parathion (25 microM) with NADPH-supplemented microsomes led to an apparent 19 +/- 4% decrease in holo-P450 content. Several CYP-specific oxidation reactions were inhibited and inactivated by parathion. Testosterone 6beta-hydroxylation (mediated by CYP3A4), 7-ethylresorufin O-deethylation (CYP1A2) and tolbutamide methyl hydroxylation (CYP2C9/10), but not aniline 4-hydroxylation (CYP2E1), were inhibited effectively by parathion. Preincubation of microsomes with parathion and NADPH intensified the extent of inhibition (i.e., elicited inactivation) of reactions mediated by 3A4 and 1A2 and, to a lesser extent, 2C9. In summary, these findings strongly implicate CYP 3A4 as the principal catalyst of parathion oxidation in human liver, although other CYP may play a lesser role. During parathion oxidation CYP3A4 undergoes significant inactivation. In view of the role of this enzyme in the oxidation of many therapeutic agents, exposure to phosphorothioate pesticides may adversely affect drug elimination in humans.

Aniline Hydroxylase↗
PubMed1997

The role of the polyamine inhibitor eflornithine in the neuropathogenesis of experimental murine African trypanosomiasis.

The treatment of late-stage human African trypanosomiasis is complicated by a post-treatment reactive encephalopathy, also referred to as a 'reactive arsenical encephalopathy', that may be fatal. This study used a well established experimental mouse system to assess the use of the trypanostatic drug, eflornithine, in the management of this post-treatment reaction. Female CD-1 mice infected with an eflornithine-resistant trypanosome stabilate and treated with the trypanocidal compound diminazene aceturate on or after day 21 post-infection develop a reactive encephalopathy and relapsing parasitaemia. If these animals are re-treated with diminazene aceturate, a severe encephalopathy develops histologically comparable with that of human cases and characterized by a severe meningoencephalitis and astrogliosis. Histopathological and immunocytochemical examination shows that administration of eflornithine before or after the development of this reactive encephalopathy prevented or ameliorated the inflammatory reaction. Since an eflornithine resistant stabilate was used, this effect appears to be independent of the drug's trypanostatic action and illustrates an important, previously unrecognized, pharmacological property of eflornithine. Consideration can now be given to the use of eflornithine for the management of human trypanosomiasis cases, even where trypanosome resistance to eflornithine exists.

Animals↗
PubMed1997

Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites.

The antihypertensive agent diltiazem (DTZ) impairs hepatic drug metabolism by inhibition of cytochrome P450 (CYP). The accumulation of DTZ metabolites in serum occurs during prolonged therapy and leads to decreased DTZ elimination. Thus, DTZ metabolites may contribute to CYP inhibition. This study assessed the role of human CYPs in microsomal DTZ oxidation and the capacity of DTZ metabolites to inhibit specific CYP activities. DTZ N-demethylation varied 10-fold in microsomal fractions from 17 livers (0.33-3.31 nmol/mg of protein/min). DTZ oxidation was correlated with testosterone 6beta-hydroxylation (r = 0.82) and, to a lesser extent, tolbutamide hydroxylation (r = 0.59) but not with activities mediated by CYP1A2 or CYP2E1. CYP3A4 in lymphoblastoid cell microsomes catalyzed DTZ N-demethylation but CYP2C8 and CYP2C9 were also active (approximately 20% and 10% of the activity supported by CYP3A4); seven other CYPs produced little or no N-desmethyl DTZ from DTZ. The CYP3A4 inhibitors ketoconazole and troleandomycin decreased microsomal DTZ oxidation, but inhibitors or substrates of CYP2C, CYP2D and CYP2E1 produced no inhibition. Some inhibition was produced by alpha-naphthoflavone, a chemical that inhibits CYP1As and also interacts with CYP3A4. In further experiments, the capacities of DTZ and three metabolites to modulate human CYP 1A2, 2E1, 2C9 and 3A4 activities were evaluated in vitro. DTZ and its N-desmethyl and N,N-didesmethyl metabolites selectively inhibited CYP3A4 activity, whereas O-desmethyl DTZ was not inhibitory. The IC50 value of DTZ against CYP3A4-mediated testosterone 6beta-hydroxylation (substrate concentration, 50 microM) was 120 microM. The N-desmethyl (IC50 = 11 microM) and N,N-didesmethyl (IC50 = 0.6 microM) metabolites were 11 and 200 times, respectively, more potent. From kinetic studies, N-desmethyl DTZ and N,N-didesmethyl DTZ were potent competitive inhibitors of CYP3A4 (Ki = approximately 2 and 0.1 microM, respectively). CYP3A4 inhibition was enhanced when DTZ and N-desmethyl DTZ underwent biotransformation in NADPH-supplemented hepatic microsomes in vitro, supporting the contention that inhibitory metabolites may be generated in situ. These findings suggest that N-demethylated metabolites of DTZ may contribute to CYP3A4 inhibition in vivo, especially under conditions in which N-desmethyl DTZ accumulates, such as during prolonged DTZ therapy.

Biotransformation↗