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Biomedical subjects

C Grant

Publications and source records attributed to C Grant.

At least 73 records · Page 4Linked to original sources
PubMed1997

Glucose kinetics of the Virginia opossum: possible implications for predicting glucose turnover in mammals.

Primed continuous infusions of 6-3H-glucose, respirometry and measurements of nitrogen excretion were carried out in adult Virginia opossums (Didelphis virginiana). Our goals were to determine resting glucose turnover rate, to establish the relative importance of this oxidative fuel in the energy budget of this species, to assess whether metabolic rate is a better predictor of glucose turnover rate than body mass and to demonstrate that glucose kinetics can be measured in the opossum for future use of this animal model in studies of mammalian glucoregulation. Results show that the resting glucose turnover rate of opossums averages 17.5 +/- 0.9 mumol/kg.min (n = 9), that 31% of total glucose flux is oxidized and that glucose oxidation represents 9% of their metabolic rate. An allometric equation predicting glucose turnover rate from body mass for placental mammals overestimates the measured turnover rate of this marsupial by 30%, suggesting that turnover rate is better predicted from metabolic rate than from body mass. Finally, this study demonstrates that the Virginia opossum is a convenient model to study glucose metabolism in vivo, and we propose that the very rapid aging characteristics of this species should be exploited to investigate the effects of aging on glucose homeostasis.

Aging↗
PubMed1997

Mapping ESTs to the TSC1 candidate interval by use of the 'Science 96' transcript map.

The transcription map of the human genome published by Schuler et al. (1996) is a valuable resource in which approximately one quarter of all human genes have been mapped with respect to genetic framework markers using radiation hybrids. We have taken information from this map to provide potential genes within the TSC1 candidate region on chromosome 9q34. In so doing we have been able to provide an independent assay of the quality of the radiation hybrid mapping by using somatic cell hybrids and a 2 Mb cosmid contig covering the TSC1 region as mapping tools. In addition, we have built sequence contigs of ESTs for 25 clusters. This has shown that about 20% of the relevant EST clusters in the Unigene resource (Boguski & Schuler 1995) contain chimaeric clones.

Animals↗
PubMed1997

The cerebral pharmacokinetics of meperidine and alfentanil in conscious sheep.

BACKGROUND: Different opioids have different delays (hysteresis) between their concentrations in blood and their cerebral effects. Possible mechanisms include differences in their rate of penetration into the brain and differences in their distribution volume in the brain. There have been few in vivo studies of the cerebral kinetics of opioids to differentiate these mechanisms. METHODS: The cerebral kinetics of meperidine and alfentanil were examined using conscious sheep that were fitted with long-term monitoring equipment to measure relative changes in cerebral blood flow and opioid concentration gradients across the brain through frequent sampling of arterial and sagittal sinus blood. The data were compared using hybrid physiologic modeling with membrane-limited (consistent with mechanism 1) and flow-limited (consistent with mechanism 2) models of cerebral kinetics. RESULTS: Alfentanil had a variable effect on relative cerebral blood flow, whereas meperidine induced a transient increase. The arteriovenous concentration gradients were small after alfentanil but large after meperidine. The flow-limited model gave acceptable descriptions of observed sagittal sinus concentrations for alfentanil and meperidine, whereas the membrane-limited model collapsed to a flow-limited model. The half-lives of equilibrium between blood and brain were 6.3 and 0.8 min for meperidine and alfentanil, respectively: CONCLUSIONS: The rate of penetration of both opioids into the brain was rapid and not rate-limiting. Large differences in the cerebral distribution volume of meperidine and alfentanil accounted for the respective delays in their peak brain concentration relative to blood.

Alfentanil↗
PubMed1997

The effects of short intravenous infusions of thiopentone on myocardial function, blood flow and oxygen consumption in sheep.

The cardiovascular effects of slow (over two minutes) intravenous infusions of thiopentone 750 mg in conscious instrumented sheep breathing 100% oxygen were examined for 30 minutes following the start of the infusion. The maximum rate of rise of left ventricular pressure (an index of myocardial contractility) decreased significantly from 1 to 10 minutes, to a minimum of 45% of baseline. Heart rate increased by up to 33% above baseline from 0.5 min onwards. Both mean arterial pressure and cardiac output were decreased from between 1 and 7 min. Left ventricular minute work was transiently decreased, but left coronary blood flow and myocardial oxygen consumption showed little or no change from baseline. We conclude that in vivo, thiopentone administered at a relatively slow rate caused large reductions in myocardial contractility, and therefore cardiac reserve, in the absence of significant changes in myocardial blood flow or oxygen consumption.

Anesthetics, Intravenous↗
PubMed1996

A prespore-specific gene of Dictyostelium discoideum encodes the small subunit of ribonucleotide reductase.

We have isolated the gene. rnrB, that encodes the ribonucleotide reductase small subunit of Dictyostelium discoideum. The deduced amino acid sequence of rnrB exhibits about 60% sequence identity with its homologues in other eukaryotes. As demonstrated by RNA blot analysis the rnrB transcript is detected in growing cells and decreases dramatically at the onset of development. The rnrB transcript reappears after the cells have formed multicellular aggregates. To further examine the pattern of expression, we have fused the rnrB promoter and part of its coding sequence to lacZ. The transgenic strain bearing such a reporter construct expresses the fusion gene with a biphasic profile, which is indistinguishable from that of the endogenous rnrB. The multicellular aggregates of Dictyostelium are differentiated along the anterior-posterior axis. Cells in the anterior give rise to the stalk of the fruiting body while cells in the posterior are precursors of spores. Results from histochemical staining show that beta-galactosidase activity is detected exclusively in the posterior two-thirds of the aggregates. These data suggest that rnrB is expressed in prespore cells during postaggregative development and in vegetative cells.

Amino Acid Sequence↗
PubMed1996

Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication.

Despite the widespread abuse of marijuana, knowledge about its effects in the human brain is limited. Brain glucose metabolism with and without delta 9 tetrahydrocannabinol (THC) (main psychoactive component of marijuana) was evaluated in eight normal subjects and eight chronic marijuana abusers with positron emission tomography. At baseline, marijuana abusers showed lower relative cerebellar metabolism than normal subjects. THC increased relative cerebellar metabolism in all subjects, but only abusers showed increases in orbitofrontal cortex, prefrontal cortex, and basal ganglia. Cerebellar metabolism during THC intoxication was significantly correlated with the subjective sense of intoxication. The decreased cerebellar metabolism in marijuana abusers at baseline could account for the motor deficits previously reported in these subjects. The activation of orbitofrontal cortex and basal ganglia by THC in the abusers but not in the normal subjects could underlie one of the mechanisms leading to the drive and the compulsion to self-administer the drug observed in addicted individuals.

Basal Ganglia↗
PubMed1996

In vivo relationships between the cerebral pharmacokinetics and pharmacodynamics of thiopentone in sheep after short-term administration.

The cerebral kinetics and dynamics of thiopentone after infusions of 250, 500, and 750 mg over 2 min were examined in chronically instrumented sheep (6, 6, and 5 sheep per dose, respectively). The cerebral kinetics were studied by rapid sampling of arterial and dorsal sagittal sinus blood (afferent and efferent blood for the brain, respectively) for 40 min, and could be described by a single flow-limited compartment when arterial concentrations and cerebral blood flow were used as forcing input functions. The half-lives of equilibration between blood and the brain were estimated to be 0.67 (SEM = 0.07), 0.57 (0.03) and 0.74 (0.05) min for the 250-, 500- and 750-mg doses, respectively, showing that the cerebral concentrations of thiopentone rapidly equilibrate with the afferent blood concentration. Simultaneous pharmacodynamic measurements included cerebral blood flow via a Doppler flowmeter on the sagittal sinus, and an index of the depth of anesthesia based on an algesimetry method. Thiopentone transiently reduced cerebral blood flow to 82 (SEM = 3), 80% (7), and 74% (10) of baseline for the 250-, 500-, and 750-mg doses, respectively, and failure to account for drug-induced changes in cerebral blood flow in the model overestimated the apparent volume of the brain by 12% for the 500-mg dose. For the 500-mg dose, the changes in cerebral blood flow could be accounted for by an effect compartment with a half-life of 0.82 min for arterial blood, and 0.00 min for sagittal sinus blood, showing the effluent brain concentrations were in equilibrium with this drug effect. The time course of the depth of anesthesia for the 250-mg dose could be accounted for by an effect compartment with a half-life of 1.33 min for arterial blood, and 0.41 min for sagittal sinus blood. Thus, the rate of equilibration between blood and brain could not account for all of this delay. It is concluded that after short-term administration thiopentone equilibrated rapidly with the brain, and that this is consistent with the observation that the magnitude of its clinically relevant effects closely follow the time course of the arterial blood concentrations.

Animals↗
PubMed1996

Impact of incomplete coverage of neonatal dried blood spot screening on estimating HIV-1 seroprevalence.

The aim of this study was to determine the extent to which selective under-coverage of births to mothers more likely to be at risk of HIV-1 infection will result in a significant under-estimation of the true neonatal seroprevalence. Census data, local birth statistics, maternity data and data from the prevalence monitoring programme were used to produce a model to predict the effects of under-coverage in the uptake of neonatal metabolic screening which has been observed in babies with a mother of ethnic group black African. The adjustment factor which allows for under-coverage is the relative inclusion ratio (RIR); the probability that samples from a group at different risk of HIV infection were included in the survey divided by the probability of inclusion for samples from all other babies. The RIR was found to be close to unity (0.97), indicating a minimal bias. Under usual conditions only if the relative inclusion ratio (RIR) declined to values of 0.87 or below would there be a substantial bias. Despite some selective under representation, the results obtained from the Unlinked Anonymous HIV Monitoring Programme Dried Blood Spot Survey would seem to identify levels of prevalence in the population of child-bearing women with a good degree of accuracy and remains a useful tool for resource allocation, planning of services, provision of care and counselling.

Adolescent↗
PubMed1996

Myocardial pharmacokinetics of thiopental in sheep after short-term administration: relationship to thiopental-induced reductions in myocardial contractility.

The myocardial kinetics and dynamics of thiopental (750 mg over 2 min) were examined in chronically instrumented sheep (five studies in four sheep). The myocardial kinetics were studied by simultaneous rapid sampling of arterial and coronary sinus blood for 30 min. The myocardial kinetics for four of the five studies were best described by a single flow-limited compartment with apparent volumes of between 42 and 113 mL. These volumes equated to half-lives of equilibration between blood and myocardium of between 0.49 and 1.00 min when baseline blood flow was taken into account. The remaining study was better described by a model with a slight membrane limitation (permeability/flow ratio of approximately 2). Myocardial contractility was studied as a measure of myocardial pharmacodynamics and was reduced to 53% of baseline at approximately 2.5 min after the start of the dose. Effect compartment analysis showed that there was hysteresis between the time course of these contractility changes and the time course of the arterial concentrations, with effect compartment half-lives between 0.08 and 0.87 min. There was significantly less hysteresis for the coronary sinus concentrations. It is concluded that thiopental equilibrated rapidly with a component of the myocardium, and that consequently its effects on myocardial contractillity also rapidly equilibrated with both afferent and effluent myocardial blood.

Animals↗
PubMed1996

Glucose tolerance, insulin secretion, insulin sensitivity and glucose effectiveness in normal and overweight hyperthyroid women.

OBJECTIVE: Inter-relationships between insulin sensitivity and body weight in patients with hyperthyroidism remain incompletely understood. We have examined whether a mild excess of body weight exacerbates the metabolic abnormalities of spontaneous hyperthyroidism. DESIGN AND PATIENTS: Insulin-modified intravenous glucose tolerance tests were performed on 14 hyperthyroid women with body mass indices (BMI) ranging from 21 to 31 kg/m2. A control group of 19 healthy women matched for age and BMI was also studied. MEASUREMENTS: Intravenous glucose tolerance (KG), first and second-phase integrated insulin responses to glucose, the integrated glucose area under the curve (AUC), and minimal model parameters of insulin sensitivity (SI) and glucose effectiveness (SG) were determined. RESULTS: Hyperthyroid women had mean KG, glucose-induced insulin secretion and SG values similar to those in control women. The mean glucose AUC was higher in hyperthyroid patients (P < 0.05). Lower insulin sensitivity was observed in hyperthyroid patients than in control women (SI = 0.38 +/- 0.07 vs 0.59 +/- 0.07 l/min pmol 10(4) (mean +/- SEM), P < 0.05). A steeper decline in insulin sensitivity with increase in body mass index was found in hyperthyroid women when compared with the control group, after adjusting for age. When groups were compared according to their BMI, hyperthyroid women with normal weight (BMI < or = 25 kg/m2, n = 8) had mean KG, insulin response to glucose, glucose AUC, SG and SI values similar to those in normal weight control women (n = 11). Overweight hyperthyroid patients (BMI > 25 kg/m2, n = 6) had a higher (P < 0.05) second-phase insulin response to glucose than normal weight patients, a higher glucose AUC (P < 0.05) than normal weight patients and overweight controls (n = 8), and a lower SI (P < 0.05) than normal weight patients and overweight controls. SG was not influenced by BMI in hyperthyroid patients. CONCLUSIONS: These results suggest that overall glucose tolerance was not significantly affected in normal weight hyperthyroid women. However, when a moderate excess of weight is also present, a state of clear insulin resistance occurs.

Adult↗
PubMed1996

Efficacy of intra-muscular analgesics for acute pain in sheep.

The analgesic action of intramuscularly injected buprenorphine, methadone, flunixin meglumine and xylazine was examined in sheep, using algesimetry based on a leg withdrawal response to an electrical stimulus. No analgesic response was detected for buprenorphine, methadone or flunixin meglumine. Only the alpha 2-adrenoceptor agonist, xylazine, produced an analgesic response. The current required to elicit a response increased by 170% (4.5 +/- 0.43 mA to 12.23 +/- 1.14 mA; mean +/- SE) after a dose of 0.05 mg/kg xylazine; by 180% (4.73 +/- 0.3 mA to 13.28 +/- 2.35 mA) after 0.1 mg/kg and by 510% (4.52 +/- 0.29 mA to 27.63 +/- 3.89 mA) after 0.2 mg/kg. Intramuscular xylazine appears to be an effective analgesic agent for acute pain in the sheep and further investigation into ideal administration regimens and dosage may provide more detailed information on relationships between dose, analgesic and sedative effects. The findings also suggest that some common analgesic agents, and opioids in particular, may be ineffective for the management of acute pain in sheep and that any analgesic should be administered only on the basis of its proven efficacy in that species.

Acute Disease↗
PubMed1996

Cerebral effects of propofol following bolus administration in sheep.

The effects of bolus administration of propofol (50 mg, 100 mg and 200 mg) on cerebral blood flow and cerebral metabolic rate for oxygen were examined in a chronically catheterized sheep preparation. Depth of anaesthesia was simultaneously measured using a withdrawal response to a noxious electrical stimulus and it was demonstrated that the 100 mg dose induced moderate sedation while the 200 mg dose induced relatively deep anaesthesia. Propofol caused transient dose-dependent decreases in cerebral blood flow, despite minimal changes in blood pressure. These were accompanied by parallel decreases in cerebral metabolic rate but no change in cerebral oxygen extraction. As cerebrovascular responses in the sheep appear similar to those in man, the parallel changes in cerebral blood flow and metabolic rate demonstrated in this study supports the suitability of propofol as a neuroanaesthetic agent.

Anesthesia, Intravenous↗
PubMed1996

Brain and blood concentrations of propofol after rapid intravenous injection in sheep, and their relationships to cerebral effects.

The time-course of propofol concentrations in the blood and brain following rapid administration of three doses were examined using a sheep preparation and regional pharmacokinetic techniques. These were compared to the time-course of cerebral effects of propofol reported previously. There were marked differences between the time-course of propofol concentrations in arterial blood and the brain, with a close relationship between the time-course of brain concentrations and effects on depth of anaesthesia and CBF. There was evidence that the effect of propofol on cerebral blood flow altered its own rate of elution from the brain. Hysteresis between arterial propofol concentrations and cerebral effects following rapid i.v. administration therefore appears to have a pharmacokinetic basis, and conventional compartmental pharmacokinetic analysis using blood concentrations alone may fail to accurately predict the time-course of both brain propofol concentrations and depth of anaesthesia.

Anesthetics, Intravenous↗
PubMed1996

A review of problems of universal access to prenatal care.

Despite the preponderance of evidence that points to the advantages of prenatal care, the number of women who receive adequate prenatal care has remained at a plateau or actually decreased since 1980. Over the past decades, many demographic and structural barriers to receiving prenatal care have been identified; financial obstacles have been cited as the major barrier. The assumption has generally been made that if financial barriers to prenatal care were removed, problems with access to prenatal care would be solved. Recent appreciation of the significance of nonfinancial barriers to prenatal care has resulted in recognition that even if all financial barriers were removed, there would still be access problems.

Attitude to Health↗
PubMed1996

The systemic and cerebral kinetics of thiopental in sheep: enantiomeric analysis.

Thiopental is used as a racemate (rac-thiopental). Enantiomeric pharmacokinetic differences could therefore influence the onset and duration of anesthesia of rac-thiopental. We studied the systemic and cerebral kinetics of R(+)- and S(-)-thiopental in five adult ewes after a 2-min intravenous infusion of 500 mg rac-thiopental sodium. Systemic kinetic values were determined from the time course of concentrations in arterial plasma; cerebral kinetic values were deduced from the time course of the concentration differences between arterial and superior sagittal sinus blood plasma. Enantiomeric differences were found in both sites, with the (R:S) ratio of thiopental enantiomer blood concentrations initially being > or = 1 then decreasing to < 1 after approximately 60 min. This is consistent with the finding of the mean total body clearance of R(+)-thiopental being 17% (SD 12%) greater than that of S(-)-thiopental (P = .04). Sagittal sinus plasma concentrations of both enantiomers followed closely behind those in arterial plasma and this is consistent with facile bidirectional exchange of thiopental between plasma and brain. No significant differences were found between enantiomers in the rates of brain influx or efflux. Onset and regression of anesthesia occurred while the enantiomer blood concentrations were similar. Hence published pharmacokinetic-pharmacodynamic models of the onset of thiopental effects probably are not significantly compromised by neglecting the enantiomeric duality of thiopental, but models based on its elimination kinetics could be compromised if enantiomeric differences are neglected.

Anesthetics, Intravenous↗
PubMed1995

Brain glucose metabolism in violent psychiatric patients: a preliminary study.

Positron emission tomography with 18F-deoxyglucose was used to evaluate regional brain glucose metabolism in eight normal subjects and eight psychiatric patients with a history of repetitive violent behavior. Seven of the patients showed widespread areas of low brain metabolism. Although the location of the abnormal regions varied among patients, they showed significantly lower relative metabolic values in medial temporal and prefrontal cortices than did normal comparison subjects. These regions have been implicated as substrates for aggression and impulsivity, and their dysfunction may have contributed to the patients' violent behavior.

Adult↗