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Biomedical subjects

M Murray

Publications and source records attributed to M Murray.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1999

DNA plasmid that codes for human Bcl-2 gene preserves axotomized Clarke's nucleus neurons and reduces atrophy after spinal cord hemisection in adult rats.

Spinal cord injury in adult mammals causes atrophy or death of some axotomized neurons. The product of the antiapoptotic gene Bcl-2 prevents neuron death in vivo. We delivered Bcl-2 by intraspinal injection of a DNA plasmid encoding this gene to determine if axotomized neurons destined to undergo retrograde death could be rescued. Axons of the right side Clarke's Nucleus (CN) were cut unilaterally in adult Sprague-Dawley rats by T8 hemisection, leaving the contralateral (left) CN as an intact control. Two months postoperatively, there was approximately 35% loss of total CN neurons in the right L1 segment. Only 15% of large CN neurons (>400 microm2), whose axons project to the cerebellum, survived--indicating atrophy and/or death of 85% of these cells. We injected a DNA plasmid encoding the human Bcl-2 gene and the bacterial reporter gene LacZ, which was complexed with cationic lipids, into the right side of segment T8 of the normal spinal cord, or just caudal to the hemisection site. The reporter gene was expressed in the perikarya of right CN neurons at L1 for up to 7 days, but not 14 days. Two months following T8 hemisection and Bcl-2/LacZ DNA injection, there was no significant loss of CN neurons ipsilateral to the lesion. Surprisingly, 61% of large neurons survived, indicating partial protection from atrophy. In contrast, a DNA plasmid that codes for the LacZ reporter gene, but not Bcl-2, did not prevent CN neuron death or atrophy. Administration of the Bcl-2 gene in adult rats and its expression in these CNS neurons prevents retrograde cell death, and also minimizes atrophy. These results may serve as the basis for developing novel gene therapy strategies for patients with spinal cord injury.

Animals↗
PubMed1999

Intraspinal delivery of neurotrophin-3 using neural stem cells genetically modified by recombinant retrovirus.

Neural stem cells have been shown to participate in the repair of experimental CNS disorders. To examine their potential in spinal cord repair, we used retroviral vectors to genetically modify a clone of neural stem cells, C17, to overproduce neurotrophin-3 (NT-3). The cells were infected with a retrovirus construct containing the NT-3.IRES.lacZ/neo sequence and cloned by limiting dilution and selection for lacZ expression. We studied the characteristics of the modified neural stem cells in vitro and after transplantation into the intact spinal cord of immunosuppressed adult rats. Our results show that: (i) most of the genetically modified cells express both NT-3 and lacZ genes with a high coexpression ratio in vitro and after transplantation; and (ii) large numbers of the xenografted cells survive in the spinal cord of adult rats for at least 2 months, differentiate into neuronal and glial phenotypes, and migrate for long distances. We conclude that genetically modified neural stem cells, acting as a source of neurotrophic factors, have the potential to participate in spinal cord repair.

Animals↗
PubMed1999

Varying features of early age-of-onset "sporadic" and hereditary nonpolyposis colorectal cancer patients.

PURPOSE: Although the criteria for clinical diagnosis of hereditary nonpolyposis colorectal cancer are not fully agreed on, young age seems to be a common trait. The purpose of this study is to identify clinicopathologic features of hereditary nonpolyposis colorectal cancer in early age-of-onset colorectal cancer patients stratified as a function of family cancer history. METHODS: Two hundred thirty consecutive colorectal cancer patients 40 years or older at time of diagnosis were registered into an ongoing database during a ten-year period. Accurate family history was obtained via medical records, telephone calls, and questionnaires on 146 patients. According to extent of family history of cancer, patients were stratified into seven groups: 1) fulfilling Amsterdam criteria, 2) fulfilling less strict criteria, 3) having at least one first-degree relative with colorectal cancer, 4) having at least one distant relative with colorectal cancer, 5) having at least one first-degree relative with any cancer, 6) having at least one distant relative with any cancer, 7) having no family history of cancer. RESULTS: Twenty-two of 146 patients fulfilled Amsterdam and less strict hereditary nonpolyposis colorectal cancer criteria (15 percent). These hereditary nonpolyposis colorectal cancer patients were significantly younger (31 vs. 35 years; P = 0.0003) and had more metachronous colorectal cancer (27 percent vs. 2 percent; P = 0.007) and less colorectal cancer with nodal or metastatic spread than the non-hereditary nonpolyposis colorectal cancer patients (35 percent vs. 65 percent; P = 0.01). CONCLUSION: Precise familial cancer assessment in early age-of-onset colorectal cancer increases the yield of hereditary nonpolyposis colorectal cancer diagnosis. Because of the frequent development of metachronous colorectal cancer and favorable prognosis, extensive rather than segmental surgery should be considered in early age-of-onset colorectal cancer patients belonging to hereditary nonpolyposis colorectal cancer families.

Adolescent↗
PubMed1999

The influence of energy intake on some blood biochemical parameters in Scottish Blackface sheep infected with Trypanosoma congolense.

The intensity of parasitaemia, degree of anaemia, live body weight gains and blood biochemical changes were measured in two groups of Scottish Blackface sheep infected experimentally with Trypanosoma congolense and allowed either a high (9.9 MJ metabolisable energy (ME) per day) or a low (6.1 MJ ME per day) energy intake. It was observed that infected animals on the low energy intake had a longer mean prepatent period, but following patency they developed more severe anaemia and greater growth retardation than those on the high energy intake. Both infected groups exhibited significant reductions in serum total lipids, phospholipids, plasma cholesterol and albumin. However, these changes were more severe in the animals on the low energy intake than in those on the high energy intake. It was concluded that adequate energy nutrition enhances the ability of infected animals to withstand the adverse effects of infection by promoting body weight gains and moderating the severity of the pathophysiological changes associated with ovine trypanosomosis.

3-Hydroxybutyric Acid↗
PubMed1999

Hepatic microsomal enzyme activity in the koala and tammar wallaby: high 17beta-hydroxysteroid oxidoreductase activity in koala liver microsomes.

We have studied the hepatic microsomal xenobiotic metabolising capacity of koala (Phascolarctos cinereus) and tammar wallaby (Macropus eugenii). Total cytochrome P450 content in hepatic microsomes from koala (0.87 +/- 0.18 nmol/mg protein, n = 4, mean (S.D.) and rat were comparable while tammar wallaby displayed reduced P450 content (0.24 +/- 0.04 nmol/mg protein). Associated microsomal activities (NADPH cytochrome P450 reductase, aminopyrine N-demethylation, aniline hydroxylation, and androstenedione 6beta- and 16alpha-hydroxylation) in koala liver were similar to or reduced relative to rat. Hepatic microsomal NADPH-supported 17beta-hydroxysteroid oxidoreductase (17beta-HSOR) activity was significantly higher in koala (9.99+/-3.08 nmol/mg protein/min) than in tammar wallaby liver (0.86 +/- 0.16 nmol/mg protein/min). However, when NADH was utilised as cofactor the activity was similar in both marsupial species (koala, 1.44 +/- 0.84 nmol/mg protein/min; tammar wallaby, 1.52 +/- 0.44 nmol/mg protein/min). Michaelis-Menten parameters for the kinetics of 17beta-HSOR androstenedione reduction by NADPH and NADH were determined in the koala. The Km for androstenedione was of the order of 1.9-4 microM (n = 4) irrespective of the cofactor used, whilst the Km for NADPH was 0.04-0.05 microM (n = 2) and for NADH was 134-430 microM (n = 2). Potential inhibitors were evaluated for their effects on NADPH-mediated 17beta-HSOR activity with menadione and, to lesser extents, menthone, benzaldehyde and metyrapone eliciting significant inhibition. From detailed kinetic studies menthone was found to be an uncompetitive inhibitor of the activity in koala liver (Ki 220 microM).

Animals↗
PubMed1999

Modeling of a roller-compaction process using neural networks and genetic algorithms.

In this study, roller-compaction of acetaminophene was studied to model the effect of binder type (hydroxypropyl methyl cellulose (HPMC), polyethylene glycol (PEG), Carbopol), binder concentration (5, 10 and 20%), number of roller-compaction passes (one or two), and extragranular microcrystalline cellulose addition on the properties of compressed tablets. Forty-two batches resulted from the experimental design. The artificial neural network methodology (ANN) along with genetic algorithms were used for data analysis and optimization. ANN and genetic models provided R2 values between 0.3593 and 0.9991 for measured responses. When a set of validation experiments was analyzed, genetic algorithm predictions of tablet characteristics were much better than the ANN. Optimization based on genetic algorithm showed that using HPMC at 20%, with two roller-compaction passes would produce mechanically acceptable acetaminophene tablets. PEG and carbopol would also produce acceptable tablets perhaps more suitable for sustained release applications. Using PEG as a binder had the additional advantage of not requiring an external lubricant during tablet manufacturing.

Acetaminophen↗
PubMed1999

Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure.

BACKGROUND: Patients with acute renal failure (ARF) have high morbidity and mortality rates, particularly if they have serious comorbid conditions. Several studies indicate that in rats with ARF caused by ischemia or certain nephrotoxins, insulin-like growth factor-I (IGF-I) enhances the recovery of renal function and suppresses protein catabolism. METHODS: Our objective was to determine whether injections of recombinant human IGF-I (rhIGF-I) would enhance the recovery of renal function and is safe in patients with ARF. The study was designed as a randomized, double-blind, placebo-controlled trial in intensive care units in 20 teaching hospitals. Seventy-two patients with ARF were randomized to receive rhIGF-I (35 patients) or placebo (37 patients). The most common causes of ARF in the rhIGF-I and placebo groups were, respectively, sepsis (37 and 35% of patients) and hypotension or hemodynamic shock (42 and 27% of patients). At baseline, the mean (+/- SD) APACHE II scores in the rhIGF-I and placebo-treated groups were 24 +/- 5 and 25 +/- 8, respectively. In the rhIGF-I and placebo groups, the mean (median) urine volume and urinary iothalamate clearances (glomerular filtration rate) were 1116 +/- 1037 (887) and 1402 +/- 1183 (1430) ml/24 hr and 6.4 +/- 5.9 (4.3) and 8.7 +/- 7.2 (4.4) ml/min and did not differ between the two groups. Patients were injected subcutaneously every 12 hours with rhIGF-I, 100 microgram/kg desirable body weight, or placebo for up to 14 days. Injections were started within six days of the onset of ARF. The primary end-point was a change in glomerular filtration rate from baseline. Other end points included changes from baseline in urine volume, creatinine clearance and serum urea, creatinine, albumin and transferrin, frequency of hemodialysis or ultrafiltration, and mortality rate. RESULTS: During the treatment period, which averaged 10.7 +/- 4.1 and 10.6 +/- 4.5 days in the rhIGF-I and placebo groups, there were no differences in the changes from baseline values of the glomerular filtration rate, creatinine clearance, daily urine volume, or serum urea nitrogen, creatinine, albumin or transferrin. In patients who did not receive renal replacement therapy, there was also no significant difference in serum creatinine and urea between the two groups. Twenty patients in the rhIGF-I group and 17 placebo-treated patients underwent dialysis or ultrafiltration. Twelve rhIGF-I-treated patients and 12 placebo-treated patients died during the 28 days after the onset of treatment. CONCLUSIONS: rhIGF-I does not accelerate the recovery of renal function in ARF patients with substantial comorbidity.

Acute Kidney Injury↗
PubMed1999

Serum fructosamine concentrations in hyperthyroid cats.

Serum fructosamine concentrations were measured in 35 healthy cats and in 30 hyperthyroid cats before and 30 days after curative radioiodine ((131)I) treatment. Hyperthyroid cats were divided into those with 30 day post-treatment total thyroxine (T4) concentrations within (EuT4) or below (HypoT4) the reference range. The median (semi-interquartile range, SIR) fructosamine concentration was significantly lower in hyperthyroid compared with healthy cats (295. 0 (18.5) micromol l(-1)) both before (254.0 (27.6) micromol l(-1)) and after (268.5 (28.0) micromol l(-1)) treatment (P < 0.001 in each case). (131)I therapy was associated with increases in serum fructosamine (mean increase 20.4 micromol l(-1), P = 0.039) and total protein (6.3 g l(-1), P < 0.002) in the HypoT4 group and in globulin concentration in both EuT4 (5.9 g l(-), P < 0.002) and HypoT4 (5.2 g l(-1), P = 0.023) groups. There were no direct relationships between the observed elevations in fructosamine concentration and those in total protein or globulin concentrations suggesting that the effect may be due to reduced rates of protein turnover. Reduced values may need to be considered when interpreting serum fructosamine concentrations for monitoring the degree of glycaemic control in diabetic cats with concurrent hyperthyroidism.

Animals↗
PubMed1999

Classifying psychiatric inpatients: seeking better measures.

BACKGROUND: Use of case-mix reimbursement in psychiatric inpatients has been limited as a result of a lack of systems which effectively group patients according to required resource needs. In recognition of the fact that many patient factors, in addition to diagnosis influence delivery of care in psychiatry, new measures of patient need are emerging. OBJECTIVE: This study compared improvement realized by using a multidimensional measure of patient severity, the Computerized Severity Index (CSI), to predict length of stay (LOS) in psychiatric inpatients over that achieved by using patient variables routinely collected in the discharge abstract. METHOD: Through retrospective chart review, severity ratings were made on 355 psychiatric discharges with primary diagnoses of psychotic or major depressive disorders. Those ratings were combined with demographic and diagnostic data available in discharge abstracts and were then entered into multivariate regression analyses to model LOS. RESULT: CSI ratings significantly contributed to prediction models, which accounted for an additional 9% to 11% of variation in LOS over discharge abstract data. Among patients with psychotic disorders, maximum severity during hospitalization was the best predictor of LOS, whereas among patients with depressive disorders, it was an increase in severity following admission. CONCLUSION: Severity ratings, based on chart review, improved prediction of LOS over discharge abstract variables for psychiatric inpatients in two diagnostic groups. Further research is needed to estimate the impact of incorporating severity ratings into a grouping system for all psychiatric inpatients. Estimation of predictive accuracy is important to determine the amount of risk passed on to providers in a payment system based on psychiatric case mix.

Comorbidity↗
PubMed1999

Mechanisms and significance of inhibitory drug interactions involving cytochrome P450 enzymes (review).

The cytochrome P450 (CYP) superfamily of enzymes are catalytically competent toward an unusually diverse array of lipophilic chemicals. The major microsomal CYP in human liver, CYP3A4, participates in the oxidative biotransformation of most drugs. Accordingly, it is not surprising that CYP activity is also readily inhibited by many drugs. Such interactions may elicit adverse toxic effects in patients and this situation is exacerbated by the practise of polypharmacy. Clinical studies have suggested that the judicious selection of drugs for combination therapy may be a relatively simple means by which drug interactions can be avoided. Such studies will rely heavily on basic information obtained from biochemical studies that describe the substrate preferences of CYPs and molecular studies on the factors that determine CYP levels in subjects. This review focuses on the information that is emerging on CYP substrate and inhibitor specificity, protein structure from homology modelling approaches and CYP expression in liver as it emerges from molecular analyses. With information of this type, drawn from several different sources, it will eventually be possible to reconcile the likelihood of drug interactions produced by specific combinations of drugs and predict those individuals who are at risk from such interactions, as a consequence of their genetic makeup.

Animals↗
PubMed1999

Anatomic VisualizeR: realizing the vision of a VR-based learning environment.

The University of California, San Diego's Anatomic VisualizeR project has reached another milestone. As the period of DARPA-funded research and development comes to a close, UCSD's VR-based learning environment has matured to the point where curricular implementation is now underway. In this presentation, we will reflect on the process by which lessons in this virtual environment are realized, highlight the results of ongoing 3-D perception studies, and describe examples of how Anatomic VisualizeR is being used in medical school anatomy and high school biology classes. To conclude, we will outline the future of this project which will include full scale curricular implementation, learning outcomes assessment, and dissemination through industrial and academic partnerships.

Anatomy↗
PubMed1999

Down-regulation of rat hepatic microsomal cytochromes P-450 in microvesicular steatosis induced by orotic acid.

Microvesicular steatosis is an important component of the overall pathogenesis of drug-mediated liver injury. Although mitochondrial damage has a role in the development of microvesicular steatosis, the consequences of fatty change for hepatic gene function are unclear. The present study was undertaken to evaluate hepatic cytochrome P-450 (CYP) function in a rat model of microvesicular steatosis produced by the intake of diets containing 1% orotic acid (OA) that were administered for 5, 10, or 21 days. Hepatic triglyceride levels were increased to 3-fold of control after 5 days and were elevated further at 10 and 21 days. Cholesterol and phospholipid contents were increased after 10 and 21 days but not by 5 days of feeding. Microsomal androst-4-ene-3,17-dione hydroxylation activities mediated by CYP2C11 (16alpha-hydroxylation) and CYP3A2 (6beta-hydroxylation) were decreased in liver from OA-fed rats for only 5 days, whereas CYP2A1/2-mediated steroid 7alpha-hydroxylation was decreased after 10 days; these observations were complemented by immunoblot analysis that demonstrated the impaired expression of the corresponding CYP proteins. CYP2C11 mRNA, the major CYP in male rat liver, was down-regulated in steatotic liver to 52 +/- 4% of control. Thus, microvesicular steatosis induced by short-term intake of OA-containing diets is histologically similar to that produced by hepatotoxic drugs and produces the rapid down-regulation of constitutive CYPs in rat liver. Analogous processes of lipid deposition in human liver after drug- or disease-related injury could precipitate adverse effects during subsequent drug therapy.

Androstenedione↗
PubMed1999

Redefining open access to primary care.

Over the last decade the term access has been used to describe the ease with which insured populations receive care. This has become a significant market issue and continues to be an important clinical issue. This article suggests that relying on clinical definitions of good access is no longer useful. The authors recommend a definition based on the patient's perspective: "The ability to seek and receive care from the provider of choice at the time the patient chooses." The authors describe a model for analyzing access systems and identify three major types. The strengths and weaknesses of each are described and the most successful access system is described in detail. This Second Generation Open Access system offers an appointment today for any problem, exceeds all regulatory requirements for access, matches patients with their PCP at unprecedented rates, reduces overall utilization, and improves patient, staff, and physician satisfaction.

Emergency Treatment↗
PubMed1999

Audit of the nutritional content of patient meals in Ayrshire and Arran.

Recent studies have indicated an unacceptably high prevalence of malnutrition in hospital patients and inadequacies in the diets offered to patients. In 1995 the Health of the Nation Nutrition Guidelines for Hospital Catering were produced with the aim of raising standards in hospital catering. An audit was conducted to compare the nutritional adequacy of patient meals provided by three NHS Trusts within Ayrshire, with the Health of the Nation Guidelines. Across the three Trusts approximately 45% of days failed to provide the recommended minimum amount of energy. NSP, folate and vitamin C provision was adequate in all three Trusts. However there were some inadequacies in the provision of calcium, iron and zinc. In two of the Trusts approximately, half, and in the other Trust one third, of the main meals failed to provide the recommended 300 kcals. In all three Trusts approximately one third of vegetarian meals failed to provide the recommended amount of protein. It has been recommended that the current menus in the three Trusts are altered to ensure that the nutritional standards in the Guidelines are met. Additionally a menu coding system, which indicates the suitability of dishes for different diets, should be used. The three Trusts have agreed to collaborate to produce a core set of menus that meet the recommendations. These recommendations will be implemented along with those from the National Food and Health Best Practice Guide.

Female↗