Biomedical subjects

R Wootton

Publications and source records attributed to R Wootton.

At least 145 records · Page 8Linked to original sources

PubMed1985

Calculation of turnover rates in stable-isotope studies.

Tserng and Kalhan have raised the question of the appropriate equation to use for the measurement of turnover rate in a stable-isotope study. In a comparison of glucose turnover measured with 2H-glucose and with 13C-glucose they used five apparently different equations and obtained conflicting answers. There is, however, no difference in principle between the use of a stable isotope as a tracer and the use of a radioactive isotope, and the rate of appearance of tracee in a steady-state system (the turnover) can therefore be shown to be proportional to the equilibrium dilution of the infused tracer. Because the sensitivity of measurement of this dilution made using a gas chromatograph-mass spectrometer is lower than that made by radioactivity measurement, the contribution to the measured turnover rate due to the infusate cannot be neglected, as it usually is in radioisotope work. A convenient calibration curve to establish this dilution is the mole ratio of the pure infusate against the area ratio for the relevant ions. Tserng and Kalhan's apparently conflicting results for glucose turnover using 13C-glucose as the tracer can all be shown to amount to approximately 11.6 mumol min-1 kg-1. This value is only slightly lower (0.05 less than P less than 0.1) than that obtained using 2H-glucose as the tracer and supports the use of 13C-glucose as an alternative.

Blood Glucose↗

PubMed1985

A new method for measuring unidirectional transplacental flux.

A new method for measuring unidirectional transplacental flux has been developed. Unlike indicator-dilution techniques, it does not depend on the use of a second reference tracer to study the substance of interest, nor on assumptions that the placenta can be modelled as a series of long, parallel, tubular capillaries. The only assumptions required are that the placenta behaves as a linear, time-invariant system and does not distinguish between tracer and tracee. The method was validated by measuring unidirectional flux rates of Evans Blue dye in an hydraulic model in which the true flux rates were controlled by peristaltic pumps. There was excellent agreement between the calculated and true flux rates. A preliminary experiment was carried out in vitro using a dually perfused human placenta to measure the unidirectional flux rates of L-lactate. At a steady state lactate concentration of 25.5 mM, maternal to foetal flux rate was 30.1 mumol min-1 and foetal to maternal flux rate was 34.0 mumol min-1, in agreement with measurements reported by other workers.

Female↗

PubMed1985

The effects in volunteers of BW12C, a compound designed to left-shift the blood-oxygen saturation curve.

BW12C, a potent left-shifting anti-sickling compound in vitro, was administered to normal healthy male Caucasian volunteers. Doses of 2-20 mg kg-1 given by intravenous infusion over 1 h caused a dose-dependent left-shift of the blood-oxygen saturation curve and at the highest dose some 16% of the haemoglobin existed in a high affinity form. Peak left-shift was observed at the end of infusion and decayed thereafter with a mean half-life of approximately 3 h. There were no adverse systemic effects, either clinical, biochemical or haematological, but there was some local irritation at the intravenous infusion site if the infusion was too concentrated. Pharmacokinetic measurements indicated uptake into erythrocytes, low levels in plasma and a volume of distribution not appreciably greater than the blood volume. A pilot radiolabel study indicated extensive metabolism with elimination into the urine.

Adult↗

PubMed1985

Plasma apolipoprotein B metabolism in familial type III dysbetalipoproteinaemia.

Lipoprotein metabolism was studied in eleven patients with Type III hyperlipoproteinaemia, one with normolipidaemic dysbetalipoproteinaemia and eight controls. Apolipoprotein B kinetics in very low density, intermediate density and low density lipoproteins (VLDL, IDL and LDL) was investigated. Fractional catabolic rates (FCRs) of VLDL-apo B and IDL-apo B were lower (P less than 0.005 and P less than 0.001) in the patients: 0.064 +/- 0.018 and 0.059 +/- 0.006 h-1 respectively, (mean +/- SEM), compared with 0.219 +/- 0.035 and 0.243 +/- 0.028 h-1. Synthetic rates (SRs) of IDL-apo B varied widely from 1.5 mg kg-1 day-1 in the subject with normolipidaemic dysbetalipoproteinaemia to 2.8-25.2 mg kg-1 day-1 in Type III. The mean time for conversion of IDL-apo B to LDL-apo B was prolonged, 18.7 h compared with 3.8 h in the controls (P less than 0.001). LDL-apo B pool size and SR were lower in the patients (P less than 0.05 for both). Two patients treated with gemfibrozil showed reduced hyperlipidaemia and decreased SR of VLDL-apo B and IDL-apo B. Dysbetalipoproteinaemia is associated with pronounced impairment of IDL and VLDL-remnant catabolism, lipoprotein levels reflecting an interaction between this defect and SR of these lipoproteins.

Adult↗

PubMed1985

Animal house stock control based on bar-coded cage labels.

In an animal house serving the needs of a large research institute, a regular inventory of the animals in stock is a considerable help towards effective management of the facility. In particular, advising the licence-holders of what animals are being held in their name and reminding them of the costs involved is a valuable exercise. The introduction of a computerized system of stock control, based on bar-coded cage labels, is described. The system has proved economical to operate, accurate, and can be run by persons without computer expertise.

Animals↗

PubMed1984

Analysis of the effect of bezafibrate on the oxygen dissociation curve of human hemoglobin.

Analysis of the effects of a range of concentrations of the antihyperlipoproteinemia drug, bezafibrate, on the oxygen dissociation curve of dilute hemoglobin solutions indicates a 4:1 binding stoichiometry with a site binding constant of 434 mol-1 for deoxyhemoglobin. Analysis of the combined effects of a range of bezafibrate and 2,3-diphosphoglycerate (DPG) concentrations indicates that 2 of the 4 bezafibrate sites are in the vicinity of the DPG binding site, and competitive with DPG binding, and 2 of the sites are remote from the DPG binding site.

2,3-Diphosphoglycerate↗

PubMed1984

Substituted benzaldehydes designed to increase the oxygen affinity of human haemoglobin and inhibit the sickling of sickle erythrocytes.

Substituted benzaldehydes have been designed to bind preferentially to the oxy conformation of human haemoglobin at a site between the amino terminal residues of the alpha-subunits. Such compounds should stabilize the oxygenated form of haemoglobin and thereby increase its oxygen affinity. The compounds produce the expected effect, left-shifting the oxygen saturation curve of dilute haemoglobin solutions and of whole blood, although the binding pattern to haemoglobin is more complex than envisaged by the design hypothesis. The predicted best compound is also a potent inhibitor, at low oxygen pressure, of the sickling of erythrocytes from patients homozygous for sickle cell disease, and may prove to be a clinically useful anti-sickling agent.

2,3-Diphosphoglycerate↗

PubMed1983

Skeletal blood flow measured with 18F in patients with osteomalacia and hyperparathyroidism.

Blood flow to bone was measured using the 18F clearance method described by Wootton et al. (1976) in osteomalacia (nine cases) and primary hyperparathyroidism (eight cases). Bone blood flow was elevated above normal in the osteomalacia group and was normal in the hyperparathyroid group (range 3.6%-6.8% blood volume/min). It is suggested that bone blood flow is linked with the osteoblastic response of bone, and remains normal in cases of hyperparathyroidism when no clinical signs of bone involvement are present.

Adult↗

PubMed1983

Selection of test series by a modified multidimensional mapping method.

Maintaining a realistic minimum distance between compounds in a defined multidimensional parameter space ensures well-spread sets of parameter values. It has been suggested, however, that the use of this multidimensional mapping method may lead to series of compounds with high multicollinearities of parameter values. An alternative method, multidimensional mapping by distance and determinant, is discussed here. This method maximizes the determinant of the interparameter correlation matrix as well as maintaining the minimum distance criterion. Its performance is compared with other methods, and it is shown that collinearities may be overcome or maintained at low levels when this method is used.

Molecular Conformation↗

PubMed1983

Cerebral blood flow and cerebral metabolism in normal and intrauterine growth retarded neonatal piglets.

1. Cerebral blood flow and cerebral metabolism were measured in conscious, normally grown neonatal piglets and in littermates which had undergone intrauterine growth retardation. 2. Cerebral blood flow was measured by the Kety-Schmidt technique using [125I]iodoantipyrine as the tracer. The tissue: blood partition coefficient of this tracer was measured in separate groups of growth retarded and normal animals. Cerebral utilization rates of glucose and oxygen were calculated from the arteriovenous concentration differences on the Fick principle. 3. The mean body weight of the growth retarded animals was about half that of their normally grown littermates, and liver weight was reduced in proportion. Brain weight was slightly but significantly lower in the growth retarded animals. 4. Cerebral blood flow was lower in the growth retarded piglets but the rates of cerebral utilization of oxygen and glucose were not significantly different in the two groups. The fractional extraction of arterial oxygen by the brain was significantly higher in the growth retarded animals. 5. The partition coefficient of iodoantipyrine was significantly lower in the growth retarded animals, being about 75% of the normal value. It is clear that had the partition coefficients been assumed to have been the same in both groups the calculated cerebral blood flows would have been identical. 6. It is concluded that growth retarded neonatal piglets have relatively normal sized brains, with a rate of glucose and oxygen consumption that is not significantly different from normal, despite a reduction in cerebral blood flow of about 35%. Consequently the fractional extraction rate of arterial oxygen by the brain is increased from 50% to 70%.

Animals↗

PubMed1983

The accuracy of measurement required for acceptable estimation of non-steady rates of appearance and disappearance by the tracer method using a two-compartment model.

The two-compartment method for measuring non-steady-state glucose turnover rates was examined by computer simulation and by in vivo experiment. Given perfectly accurate input data, the simulations showed that the calculated turnover rates agreed closely with the true answer (agreement was not perfect however, because of the necessity for interpolation between the observed points). Contaminating the input data with a single erroneous observation of either tracee or tracer concentration produced large, spurious oscillations in the calculated turnover rates, the duration of which was inversely proportional to the frequency with which the infused compartment was sampled. Contaminating the perfect input data with observational noise of a magnitude approximately equal to the known measurement uncertainties showed that the calculations were very sensitive to noise and this was verified by in vivo experiment. It is concluded that non-steady-state glucose kinetics can be successfully measured by the two-compartment technique, but that measurements to an accuracy of at least 1% (coefficient of variation) are required.

Animals↗

PubMed1983

The measurement accuracy required for acceptable estimation of steady and non-steady rates of appearance and disappearance from the inaccessible compartment of an open, two-compartment system.

A two-compartment system for measuring non-steady state turnover rates was examined by computer simulation. Tracee appears de novo in a compartment to which the experimenter has no access, and from which material is irreversibly lost. In the steady state, Monte Carlo analysis showed that the compartment sizes and fluxes could be determined by tracer experiments with reasonable accuracy. In contrast, under non-steady state conditions, the results proved extremely sensitive to observational uncertainties. Given perfectly accurate input data, simulation showed that the calculated turnover rates agreed closely with the true answer, although not perfectly because of the necessity for interpolation. Contaminating the input data with a single erroneous observation of either tracee or tracer concentration produced large, spurious oscillations in the calculated turnover rates, the duration of which was inversely proportional to the frequency with which the infused compartment was sampled. Contaminating the input data with observational noise of a magnitude likely in practice so degraded the results that they became almost unusable. It is concluded that non-steady state measurements are feasible using this model, but that rapid sampling and random uncertainties smaller than 1% (coefficient of variation) are desirable in the measurement of tracer and tracee concentration.

Computers↗

PubMed1983

Comparative intranasal pharmacokinetics of interferon using two spray systems.

Physician-administered and self-administered interferon (IFN) nasal sprays were compared by measuring residual IFN recovered from the nose at intervals following single doses. Amounts of IFN recovered five minutes after administration and the decay curves of recoverable antiviral and immunoreactive IFN with time were variable between volunteers but similar for both methods. It follows that a self-administered IFN spray would be suitable for future trials of IFN in upper respiratory infections. It was also confirmed that IFN persists in the nose for at least 24 h and is not all recovered by nasal washing, suggesting that it may be bound to, then slowly released from, nasal mucosal cells.

Administration, Intranasal↗

PubMed1983

The tissue-blood partition coefficient of iodoantipyrine in pig brain and its change with age.

The tissue-blood partition coefficient of 125I-labelled iodoantipyrine was measured in pig brain. The mean coefficient for 11 neonatal piglets (aged 0.5 to 4 days) was 0.718 mL/g (SD 0.083). Measurements in a further 11 animals up to 144 days old (at which time pigs are sexually mature), showed that the partition coefficient increased significantly with age, possibly as a result of the accumulation of brain lipid during growth. The change in partition coefficient with age was curvilinear, rising to unity as the animals reached maturity. There were significant differences between the partition coefficients in grey and in white matter, but these were so small relative to the differences between pigs that they could be neglected for all practical purposes. Since the accuracy of measurement of cerebral blood flow (CBF) by the Kety-Schmidt technique depends directly on the partition coefficient of the tracer, it is important to confirm that apparent changes of CBF do not simply reflect alterations in the partition coefficient rather than real changes in blood flow.

Age Factors↗

PubMed1983

Intrauterine growth retardation detected in several species by non-normal birthweight distributions.

The statistical distribution of birthweights in 64 litters of pigs, 48 litters of dogs, 59 litters of rabbits, 130 litters of rats and 46 litters of mice was examined. Birthweight followed a Gaussian or normal distribution in about two-thirds of the litters inspected, as judged visually using a normal probability plot, and by the W-test statistic. In the remainder, a single outlying observation in an otherwise normal sample was detected by Dixon's test, and/or a separate sub-population of low birthweight animals could be identified by fitting two normal populations to the observed samples. In the non-Gaussian litters, the average proportion of affected members was 40% of the litter. These results suggest that growth-retarded neonates should not be regarded simply as the tail-end of a normal distribution.

Animals↗

PubMed1982

Myelomatosis with type III hyperlipoproteinemia: clinical and metabolic studies.

We investigated the metabolism of intermediate-density lipoproteins (IDL [1.006 to 1.019 g per milliliter]) and low-density lipoproteins (LDL [1.019 to 1.063 g per milliliter]) in two men with Type III hyperlipoproteinemia associated with myelomatosis. In vivo kinetic studies using radiolabeled autologous lipoproteins demonstrated a greatly reduced fractional catabolic rate of IDL, relative to control values (patients vs. normal, 0.006 and 0.025 per hour vs. 0.20 +/- 0.08 per hour [mean +/- S.E.M]) and a greatly prolonged IDL-to-LDL conversion time (45 and 17 hours vs. 5.4 +/- 1.6 hours). In studies in vitro, LDL from both patients failed to bind to the LDL receptor of normal blood lymphocytes, whereas LDL from subjects with familial Type III hyperlipoproteinemia bound normally to the receptor. In one patient immunoglobulin was shown to be associated with IDL and LDL. Thus, hyperlipoproteinemia reflected an impaired metabolism of IDL, probably secondary to the binding of immunoglobulin to the lipoproteins. A similar impairment of receptor-mediated LDL catabolism did not elevate the plasma LDL concentration because of the low IDL-to-LDL conversion rate.

Apoproteins↗

PubMed1982

Risk factors for fractured neck of femur in the elderly.

During a 15-month period, 47 elderly female patients admitted to hospital with a fractured neck of femur were studied immediately prior to discharge, in comparison with 34 elderly female control patients undergoing elective surgery who had been admitted over the same period to the same orthopaedic wards. The principal differences between the two populations were that the fracture patients had a lower forearm trabecular bone density, with lower bodyweight (both lower muscle mass and lower fat content), increased body sway, worse eyesight and reduced mental acuity. The serum biochemistry of the two groups was almost indistinguishable except that the fracture patients tended to have slightly lower concentrations of proteins. There was no evidence to implicate dietary vitamin D deficiency, osteomalacia, oestrogen deficiency or alcoholism in the aetiology of the fracture, nor was there evidence to suggest alterations in endocrine function with respect to cacitonin or parathyroid hormone.

Aged↗

PubMed1982

Accurate measurement of cerebral metabolism in the conscious, unrestrained neonatal piglet. I. Blood flow.

A technique has been developed for the accurate and precise measurement of cerebral blood flow in the conscious, unrestrained neonatal piglet. Repeat determinations under conditions in which the animals could observe the experimenters showed that there was a significant fall in cerebral perfusion rate between first and second measurement, amounting to about 15 ml/min/100g. This systematic error was subsequently avoided by use of screens and the reproducibility of the technique was then estimated to be 5.9 ml/min/100 g (SD). When 5 animals were subjected to moderate stress by handling, there was a significant (p less than 0.001) increase in cerebral perfusion rate to a mean value of 172.6 +/- 35.0 ml/min/100g (+/- SEM). Mean resting cerebral perfusion rate in 18 normal animals was 65.6 +/- 4.6 ml/min/100 g (+/- SEM), which is similar to that reported in the conscious neonates of other species including man.

Animals↗