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Biomedical subjects

C Grant

Publications and source records attributed to C Grant.

At least 55 records · Page 3Linked to original sources
PubMed2000

The effect of altered cerebral blood flow on the cerebral kinetics of thiopental and propofol in sheep.

BACKGROUND: Thiopental and propofol are highly lipid-soluble, and their entry into the brain often is assumed to be limited by cerebral blood flow rather than by a diffusion barrier. However, there is little direct experimental evidence for this assumption. METHODS: The cerebral kinetics of thiopental and propofol were examined over a range of cerebral blood flows using five and six chronically instrumented sheep, respectively. Using anesthesia (2.0% halothane), three steady state levels of cerebral blood flow (low, medium, and high) were achieved in random order by altering arterial carbon dioxide tension. For each flow state, 250 mg thiopental or 100 mg propofol was infused intravenously over 2 min. To quantify cerebral kinetics, arterial and sagittal sinus blood was sampled rapidly for 20 min from the start of the infusion, and 1.5 h was allowed between consecutive infusions. Various models of cerebral kinetics were examined for their ability to account for the data. RESULTS: The mean baseline cerebral blood flows for the "high" flow state were over threefold greater than those for the low. For the high-flow state the normalized arteriovenous concentration difference across the brain was smaller than for the low-flow state, for both drugs. The data were better described by a model with partial membrane limitation than those with only flow limitation or dispersion. CONCLUSIONS: The cerebral kinetics of thiopental and propofol after bolus injection were dependent on cerebral blood flow, despite partial diffusion limitation. Higher flows produce higher peak cerebral concentrations.

Anesthetics, Intravenous↗
PubMed2000

Management of menorrhagia in primary care-impact on referral and hysterectomy: data from the Somerset Morbidity Project.

OBJECTIVE: To investigate the management of menorrhagia in primary care and its impact on referral and hysterectomy rates. DESIGN: Prospective observational study. SETTING: 11 general practices from the Somerset Morbidity Project. SUBJECTS: 885 women consulting their general practitioner with menorrhagia over four years. MAIN OUTCOME MEASURES: Proportions of these women investigated and treated with drugs in primary care, referred to a gynaecologist and undergoing operative procedures. The relation between investigation and prescribing in primary care and referral to and surgery in secondary care. RESULTS: Less than half of women had a vaginal examination (42%, 95% CI 39% to 45%), or a full blood count (39%, 95% CI 36% to 43%). Almost a quarter of women, 23% (95% CI 20% to 26%), received no drugs and 37% (95% CI 34% to 40%) received norethisterone. Over a third, 38% (95% CI 34% to 40%), of women were referred, and once referred 43% (95% CI 38% to 48%) of women were operated on. Women referred to a gynaecologist were significantly more likely to have received tranexamic acid and/or mefenamic acid in primary care (chi(2)=16.4, df=1, p<0.001). There were substantial between practice variations in management, for example in prescribing of tranexamic acid and/or mefenamic acid (range 16% to 72%) and referral to gynaecology (range 24% to 52%). There was a significant association between high referral and high operative rates (Spearman's correlation coefficient=0.86, p=0.001). CONCLUSIONS: Substantial differences in management exist between practices when investigating and prescribing for menorrhagia in primary care. Rates of prescribing of effective medical treatment remain low. The decision to refer a woman impacts markedly on her chances of subsequently being operated on. Effective management in primary care may not reduce referral or hysterectomy rates.

Adult↗
PubMed2000

Development and validation of a recirculatory physiological model of the myocardial concentrations of lignocaine after intravenous administration in sheep.

A recirculatory physiological model of the determinants of the myocardial concentrations of lignocaine after intravenous administration was developed in sheep and validated with the intention of analysing and predicting the outcome of altered dose regimens and various pathophysiological states on the initial myocardial concentrations of lignocaine. The structure and parameters of the model were determined by hybrid modelling of the time-courses of the pulmonary artery, arterial and coronary sinus concentrations of lignocaine after the intravenous administration of 100 mg of lignocaine over 5 min to 5 chronically instrumented sheep. The model accounted for the determinants of the myocardial concentrations via compartments for venous mixing, the lung (a single-compartment model with a first-order loss) and the heart (a single flow-limited compartment). Recirculation and the remainder of the body were represented as a single tissue pool with a clearance term. The distribution volume of the heart was 0.42+/-0.009 L, which gave a half-time of myocardium:blood equilibration of 2.37 min. The distribution volume of the lungs was 5.40+/-0.23 L, with an apparent first-order loss of 1.02 L min(-1) representing deep distribution or metabolism. The validity of the model was tested by comparing the predictions of the model with the equivalent data collected in 6 sheep when lignocaine (89 mg) was administered via a complex dose regimen with a faster initial rate of infusion (39.1 mg min(-1)), declining exponentially to basal infusion rate (7.02 mg min(-1)) over 8 min. The predictions of the model were in general agreement with these data. It is concluded that the model was sufficient to account for the effect of altered dose regimens of lignocaine on the time-course of its myocardial concentrations.

Anesthetics, Local↗
PubMed2000

Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains: elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-alpha and IL-10 define a unique cytokine profile in macrophages from young nonobese diabetic mice.

Cytokines derived from macrophages (Mø) play a critical role in the development of type 1 diabetes in the nonobese diabetic (NOD) mouse. Based on earlier findings from lupus-prone strains of inherent cytokine defects in Mø , NOD Mø were evaluated for intrinsically dysregulated cytokine production with the potential to initiate or exacerbate disease. Endotoxin-activated peritoneal Mø from young prediseased NOD mice produced interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha levels similar to those of Mø from a panel of control strains but reduced compared with the congenic diabetes-resistant NOR strain. IL-6 and IL-10 production were similar in NOD and NOR Mø, indicating that reduction in NOD IL-1 and TNF-alpha expression was selective. Nevertheless, the ratio of TNF-alpha and IL-10 production, a stringent index of normal Mø function, distinguished NOD from all normal strains. The most striking feature of NOD Mø, however, was their substantially elevated IL-12 production. This response was induced not only by endotoxin but also by bacillus Calmette-Guerin (BCG) and CD40 ligand and was associated with (and likely caused by) the enhanced and prolonged expression of p40 mRNA. Moreover, NOD Mø IL-12 expression appeared to be near maximally induced by lipopolysaccharide (LPS) alone, because it was only slightly enhanced by the addition of gamma-interferon, a stimulus that substantially elevated LPS-induced IL-12 production in Mø from normal strains. Accompanied by a unique profile of TNF-alpha and IL-10, the dramatic elevation of IL-12 expression by NOD Mø reflects intrinsic defects of the innate immune system with the potential to initiate and propagate the pathogenic autoreactive T-helper type 1 response characteristic of type 1 diabetes.

Animals↗
PubMed1999

A compartmental analysis of the pharmacokinetics of propofol in sheep.

Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid i.v. administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after i.v. administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.

Anesthetics, Intravenous↗
PubMed1999

Prolonged dysequilibrium between blood and brain concentrations of propofol during infusions in sheep.

BACKGROUND: Previous work had shown dysequilibrium between the arterial blood and brain concentrations of the intravenous anaesthetic agent propofol following its rapid administration over 2 min to sheep. The extent of dysequilibrium was examined following slower administration as a constant rate 45-min infusion (10 mg/min). METHODS: Six sheep were prepared with arterial and sagittal sinus (effluent from the brain) blood sampling catheters and a Doppler flow probe for measuring an index of cerebral blood flow. Propofol concentrations in arterial and sagittal sinus blood during and after the infusions were measured using high-performance liquid chromatography with fluorescence detection. Brain concentrations were calculated from these concentrations and cerebral blood flow using direct mass balance methods. RESULTS: There was dysequilibrium between the arterial blood and brain concentrations until approximately 30 min after the start of the infusion, with marked hysteresis between the arterial blood and brain concentrations for the duration of the study. The equilibrium half-life between the blood and the brain was 3.5 min, which is comparable to the value of 4.3 min derived from the earlier rapid administration data, suggesting there was no time dependency in the kinetics of cerebral uptake. The mass of propofol entering the brain via arterial blood was the same as the mass leaving the brain via sagittal sinus blood, suggesting minimal metabolism of propofol in the brain of sheep. CONCLUSION: It is clear that pharmacokinetic analysis based on arterial blood concentrations alone cannot accurately account for the concentrations of propofol at its site of action in the brain.

Anesthetics, Intravenous↗
PubMed1999

The impact of personal problems on accessing prenatal care in low-income urban African American women.

OBJECTIVE: The purpose of this study was to investigate the nature and contribution of personal factors related to the use of prenatal care in a sample of high-risk women residing in an urban environment where care was accessible and free. STUDY DESIGN: The sample consisted of 297 African American women with low socioeconomic status and a high school education or less who were newly delivered of neonates. The level of prenatal care was classified according to the Kessner 3 Parameter Index (adequate, intermediate, inadequate). Women who received no prenatal care made up a fourth group. Subjects responded to the "Ten-Item Checklist" of Richwald. Rhodes, and Kersey and an in-person interview that queried their reasons for obtaining different levels of prenatal care. RESULTS: Both personal and structural reasons were described by women for not obtaining care earlier in pregnancy or at all. The mean number of personal and structural problems reported per subject was inversely correlated to the level of prenatal care obtained. However, personal problems were the single most important reason cited by these women. Personal problems that were statistically significant different among the groups were drug use and desire for an abortion. The structural barriers that exhibited statistically significant differences among the groups were trouble scheduling an appointment, access totransportation, dislike of health care professionals and institutions, access to child care, and not knowing where to go. CONCLUSION: Both personal and structural problems were cited as reasons for not obtaining adequate prenatal care. Structural barriers to prenatal care have been identified and extensively studied. These barriers to care continue to persist, despite innovations in program delivery and access. This study demonstrates that the significance of personal problems has not been adequately considered as a major factor associated with insufficient prenatal care.

Adult↗
PubMed1999

Agreement between ultrasonic Doppler venous outflow and Kety and Schmidt estimates of cerebral blood flow.

1. The present study compares the indirect Fick nitrous oxide equilibration method of Kety and Schmidt for cerebral blood flow (CBF) estimation with a direct ultrasonic Doppler index of venous outflow. 2. Cerebral blood flow was determined simultaneously by the direct measurement of sagittal sinus blood velocity and the indirect Kety and Schmidt method in five anaesthetized sheep during high and low steady states of CBF. High- and low-flow states were achieved by altering ventilation to produce hypercarbia and hypocarbia, respectively. 3. Four different sets of calculations were used to make the Kety and Schmidt estimations: arterial-venous nitrous oxide concentration differences during uptake or elution of the indicator and with or without extrapolation of arterial-venous differences to infinity. 4. During 15 min nitrous oxide administration, apparent blood:tissue equilibration of nitrous oxide was rapid in some data sets and slow in others. 5. There were no significant differences in CBF estimates between any of the four Kety and Schmidt calculations or the direct ultrasonic Doppler venous outflow method; however, CBF estimates based on nitrous oxide uptake correlated more strongly with the direct method than estimates based on nitrous oxide elution. 6. In the high-flow state, CBF estimates based on nitrous oxide uptake, but not those based on elution, distinguished between rapid and slow blood:tissue equilibration of nitrous oxide. 7. This provides validation of the Doppler sheep brain venous outflow method against the widely used Kety and Schmidt method.

Animals↗
PubMed1999

Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration.

UNLABELLED: Indicator dilution theory predicts that the first-pass pulmonary and systemic arterial concentrations of a drug will be inversely related to the cardiac output. For high-clearance drugs, these first-pass concentrations may contribute significantly to the measured arterial concentrations, which would therefore also be inversely related to cardiac output. We examined the cardiac output dependence of the initial kinetics of propofol in two separate studies using chronically instrumented sheep in which propofol (100 mg) was infused IV over 2 min. In the first study, steady-state periods of low, medium, and high cardiac output were achieved by altering carbon dioxide tension in six halothane-anesthetized sheep. The initial area under the curve and peak value of the pulmonary artery propofol concentrations were inversely related to cardiac output (R2 = 0.57 and 0.66, respectively). For the systemic arterial concentrations, these R2 values were 0.68 and 0.71, respectively. In our second study, transient reductions in cardiac output were achieved in five conscious sheep by administering a short infusion of metaraminol concurrently with propofol. Cardiac output was lowered by 2.2 L/min, and the area under the curve to 10 min of the arterial concentrations increased to 143% of control. IMPLICATIONS: The initial arterial concentrations of propofol after IV administration were shown to be inversely related to cardiac output. This implies that cardiac output may be a determinant of the induction of anesthesia with propofol.

Adrenergic alpha-Agonists↗
PubMed1998

A comparison of the effects of norepinephrine, epinephrine, and dopamine on cerebral blood flow and oxygen utilisation.

The concomitant effects of infusions of catecholamines on cerebral blood flow (CBF), intracranial pressure (ICP), arterio-venous oxygen content difference (AVDO2), and cerebral oxygen utilization (COU) were prospectively studied in an intact cerebral autoregulatory model. Epinephrine, norepinephrine and dopamine were infused at doses used in clinical practice in awake, chronically catheterized sheep (n = 5). Mean arterial pressure (MAP), CBF and ICP were measured continuously, COU was expressed as delta CBF x AVDO2. All 3 drugs significantly increased MAP in a dose dependent manner. Norepinephrine and epinephrine had no significant effects on ICP, CBF, AVDO2 or COU at infusions of 0-60 micrograms/min. Infusions of dopamine from 0-60 micrograms/kg/min resulted in statistically significant increases in ICP (+34.5 +/- 3.7 to +97.2 +/- 6.8) and CBF (+13.3 +/- 3.2 to +52.6 +/- 24.3) (% change baseline +/- SEM, 95% CI, ANOVA), reduction in AVDO2 (3.54 +/- 0.2. to 2.69 +/- 0.2 mg%) and a biphasic response in COU. In the intact physiological model, induced hypertension by epinephrine and norepinephrine is not associated with global changes in CBF, ICP or COU which remain constant. At equivalent doses, dopamine causes cerebral hyperaemia, increased ICP and increased global cerebral oxygen utilization.

Animals↗
PubMed1998

Tachycardia alone fails to change the myocardial pharmacokinetics and dynamics of lidocaine, thiopental, and verapamil after intravenous bolus administration in sheep.

Previous reports have suggested that tachycardia alone can increase the rate of myocardial uptake of some drugs. As part of a systematic study of the determinants of the myocardial uptake and effects of drugs in critical illness, the effect of tachycardia induced by intracardiac pacing on the myocardial disposition and effects of lidocaine, verapamil, and thiopental were studied in chronically instrumented sheep. For each drug, seven sheep received either 100 mg of lidocaine, 10 mg of verapamil, or 750 mg of thiopental over 2 min in unpaced and paced (140 beats/min) states on separate occasions and in random order. Arterial and coronary sinus (effluent from the heart) blood samples were taken at regular intervals for 30 min, and the maximum rate of change of left ventricular pressure (LV dP/dtmax) was measured as an index of myocardial contractility. There were no differences between unpaced and paced studies in the time courses of arterial and coronary sinus concentrations, or the time-courses of myocardial contractility and blood flow, after bolus iv injections of these drugs. Tachycardia alone does not appear to influence the myocardial kinetics or dynamics of lipophilic drugs that can rapidly diffuse into the heart.

Animals↗
PubMed1998

Diffusion-limited, but not perfusion-limited, compartmental models describe cerebral nitrous oxide kinetics at high and low cerebral blood flows.

This study aimed to evaluate the relative importance of diffusion-limited vs. perfusion-limited mechanisms in compartmental models of blood-tissue inert gas exchange in the brain. Nitrous oxide concentrations in arterial and brain efferent blood were determined using gas chromatographic analysis during and after 15 min of nitrous oxide inhalation, at separate low and high steady states of cerebral blood flow (CBF) in five sheep under halothane anesthesia. Parameters and model selection criteria of various perfusion- or diffusion-limited structural models of the brain were estimated by simultaneous fitting of the models to the mean observed brain effluent nitrous oxide concentration for both blood flow states. Perfusion-limited models returned precise, credible estimates of apparent brain volume but fit the low CBF data poorly. Diffusion-limited models provided better overall fit of the data, which was best described by exchange of nitrous oxide between a perfusion-limited brain compartment and an unperfused compartment. In individual animals, during the low CBF state, nitrous oxide kinetics displayed either fast, perfusion-limited behavior or slow, diffusion-limited behavior. This variability was exemplified in the different parameter estimates of the diffusion limited models fitted to the individual animal data sets. Results suggest that a diffusion limitation contributes to cerebral nitrous oxide kinetics.

Anesthetics, Inhalation↗
PubMed1998

Quality of life of adult coeliac patients treated for 10 years.

BACKGROUND: For patients with coeliac disease, adherence to a gluten-free diet (GFD) is essential to restore the intestinal mucosa. It is less clear whether this ensures well-being of the patient. We have therefore assessed aspects of the quality of life of adult coeliac patients who had been on a GFD for 10 years. METHODS: By means of the Short Form 36 Health Survey (SF-36), the subjective health status was measured in 89 adult coeliac patients (61% women) aged 35-74 years. Patients shown to be in histologic remission (n=60) were evaluated by means of the Gastrointestinal Symptom Rating Scale (GSRS). RESULTS: The coeliac patients scored significantly lower in the SF-36 than general population, notably within the General Health and Vitality domains. The low scoring was confined to the female patients, who also reported significantly more gastrointestinal symptoms in the GSRS than the male coeliacs. The functional status and perceived health of the coeliac patients appeared unrelated to their biopsy findings. CONCLUSIONS: After 10 years on a GFD adult coeliac patients fail to attain the same degree of subjective health as the general population. This is particularly true for female patients and suggests that factors beyond normalization of the intestinal mucosa are of importance for the perceived health status of coeliacs diagnosed in adult life.

Adult↗
PubMed1998

The influence of the bolus injection rate of propofol on its cardiovascular effects and peak blood concentrations in sheep.

UNLABELLED: The influence of the bolus injection rate of propofol on its cardiovascular effects has not been extensively studied. We therefore examined the influence of the injection rate of i.v. bolus doses of propofol on its acute cardiovascular effects and peak blood concentrations in seven chronically instrumented sheep. Each received i.v. propofol (200 mg) over 2 min (slow injection) and 0.5 min (rapid injection) on separate occasions in random order. The rapid injection was associated with more profound decreases in mean arterial blood pressure than slow injection (35.7% vs 23.7% maximal reductions from baseline, respectively; P = 0.02). There were no significant differences between the injection rates for peak reductions in myocardial contractility, increases in heart rate, or degree of respiratory depression. Concurrently, the rapid injections were associated with significantly higher arterial (26.9 vs 11.9 mg/L) propofol concentrations in a manner consistent with indicator dilution principles. There were no differences in the peak coronary sinus concentrations between the injection rates. We conclude that the rapid injection of propofol in the context of the induction of anesthesia produced significantly higher peak arterial propofol concentrations and suggest that it is these higher concentrations that produced relatively greater reductions in arterial blood pressure from rapid injections. IMPLICATIONS: Propofol is injected into a vein to initiate anesthesia. It can cause a rapid decrease in blood pressure, which may be dangerous to the patient. We examined the effect of rapid and slow injection rates of propofol in sheep and found that rapid injection caused a greater decrease in blood pressure. This was because rapid injection caused higher concentrations of propofol in the blood immediately after the injection. We believe that if the same processes occur in humans, there may be little advantage in injecting propofol rapidly.

Anesthetics, Intravenous↗
PubMed1998

The effect of rate of administration on brain concentrations of propofol in sheep.

UNLABELLED: A marked reduction in the dose of propofol required to achieve the onset of anesthesia with slower administration rates has previously been reported, but the mechanism of this phenomenon is unclear. We used a chronically instrumented sheep preparation to examine the effects of different administration rates of propofol on its distribution in the brain using mass balance principles to calculate brain concentrations. The administration of 100 mg of propofol i.v. at rates of 200, 50, and 20 mg/min had minimal effect on both the peak brain concentrations of propofol and the total amount of drug entering the brain. The more rapid administration rates increased the rate of uptake into the brain but resulted in large increases in peak arterial blood propofol concentrations. These faster administration rates have previously been associated with high arterial propofol concentrations and an increased risk of hypotension. Simulation of titration to an end point revealed that the dose sparing previously reported at induction with slow administration rates relates only to improved titration to effect, and does not result in more anesthesia for a given dose. Therefore, we conclude that the administration of propofol over 2 min provides a reasonable rate of induction and improved titration to effect, yet avoids excessively high arterial concentrations. IMPLICATIONS: Alterations in the rate of administration of propofol in sheep have been shown to have little effect on the quantity of propofol delivered to the brain. At induction of anesthesia, administration rates of approximately 50 mg/min seem likely to provide improved titration to effect without excessively prolonging induction.

Anesthesia, Intravenous↗
PubMed1998

The enantiomer-specific kinetics and dynamics of verapamil after rapid intravenous administration to sheep: physiological analysis and modeling.

The lung, myocardial and systemic kinetics of the enantiomers of verapamil, and their myocardial effects, were measured after administration of 10 mg of racemic verapamil during 2 min to chronically instrumented sheep; the data were used to develop a physiological model of the process. Verapamil was characterized by relatively slow transit through the lungs and heart. The lung kinetic values were membrane limited, whereas the tissue/blood equilibrium half-life for the heart was approximately 8 min. There was little difference between the kinetic values of the enantiomers, with the exception of their extent of deep distribution into the lung. The time course of the increase in myocardial blood flow caused by verapamil was best related to the time course of the arterial verapamil concentrations, whereas the time course of increases in the interval between P and R waves of the electrocardiogram and decreases in the maximum rate of rise of left ventricular pressure were best related to the time course of its myocardial concentrations. Thus, the observed hysteresis for these effects compared with arterial blood was largely caused by the time required for the myocardial equilibration. The model predicted that the myocardial concentrations of verapamil were relatively insensitive to the duration of injection of a given bolus dose, but that rapid injection caused transient, high arterial concentrations. It also predicted that the bolus dose of verapamil should be modified over a 2-fold range to account for physiologically plausible variations in base-line cardiac output and myocardial blood flow.

Animals↗
PubMed1997

Induction of IL-4-producing CD4+ T cells by antigenic peptides altered for TCR binding.

The adaptive immune responses to foreign Ags are primarily regulated by the cytokines produced by CD4 T cells. The generation of distinct cytokine-producing T cell subsets has been shown to be influenced by a number of factors, including cytokines, different types of APCs, and the amounts of priming Ag. We have previously reported that the affinity of an antigenic peptide for its presenting MHC class II molecules and that different doses of Ag peptide affect the outcome of the functional CD4 T cell response. In the current study, we further examined the impact of the affinity of an antigenic peptide for its TCR on CD4 T cell priming. We generated a panel of Ag peptide variants mutated at positions known to be critical for binding to a well-characterized TCR (known as altered peptide ligands, or APLs). Compared with the WT peptide, these APLs are defective in stimulating the proliferative responses of T cells. However, they can effectively prime in vitro naive CD4 T cells for differentiation into both Th1-like and Th2-like cells. In contrast, the WT peptide primes only for IFN-gamma-producing Th1-like cells. Using highly purified dendritic cells as APCs to present the APL or WT peptide leads to the same pattern of priming as using total splenic APCs. These results indicate that priming by APLs for both IL-4 production and IFN-gamma production does not require two different types of APCs. In summary, our data indicate that APL can directly stimulate naive CD4 T cells to become Th2 effector cells.

Amino Acid Sequence↗