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Biomedical subjects

D Halliday

Publications and source records attributed to D Halliday.

At least 73 records · Page 4Linked to original sources
PubMed1992

Protein turnover in pregnancy.

Whole-body protein metabolism was studied at 13, 24 and 35 weeks gestation in six healthy women using a continuous infusion [13C]leucine technique. Values were expressed in terms of fat-free body weight (FFM) calculated using literature standards for changes in total body potassium during pregnancy. Mean protein synthesis increased from 5.3 (+/- 0.6 SD) g/kg FFM/24h at 13 weeks to 5.9 +/- 0.5 (P less than 0.1) at 24 weeks and 6.1 +/- 0.6 at 35 weeks (P less than 0.05 vs 3 weeks). Similar increases were noted in catabolism so that net loss changed little. Protein synthesis at 24 and 35 weeks gestations was significantly greater than that in 17 healthy, non-pregnant women (4.9 +/- 0.6, P less than 0.001). These data indicate that there are substantial increases in protein turnover during pregnancy.

Adipose Tissue↗
PubMed1991

Acute illness in maple syrup urine disease: dynamics of protein metabolism and implications for management.

Acute metabolic decompensation in maple syrup urine disease (MSUD) during otherwise minor illnesses has generally been presumed to result from massive release of leucine from protein catabolism. A stable isotope method based on the continuous infusion of (2H5)phenylalanine was used to measure protein metabolism in vivo in two children with MSUD during acute illness and when well. Net protein catabolism was greater in the unwell state (0.51 and 0.40 gm/kg per 24 hours in each child, respectively) than in the basal state (0.34 and 0.32). This rate of release of leucine from protein is compatible only with a slow (several days) rather than a dramatic rise in plasma leucine levels during acute illness in MSUD. Poor oral intake leading to a relative increase in time spent in the fasting state appears to be a more important determinant of increasing leucine levels than the catabolic effect of infection in itself. These factors suggested that branched-chain amino acid restriction should be commenced at the start of minor illness in children with MSUD, and that intake of other nutrients should be maintained or increased throughout the illness. A regimen based on these concepts was used during nine episodes of minor illness in two children with MSUD. Plasma branched-chain amino acid levels remained acceptable (less than 700 mumol/L) throughout each of these episodes. Dietary supplementation of this type may reduce the risk of metabolic decompensation during acute illnesses in children with MSUD.

Acute Disease↗
PubMed1991

Measurement of whole-body protein turnover in insulin-dependent (type 1) diabetic patients during insulin withdrawal and infusion: comparison of [13C]leucine and [2H5]phenylalanine methodologies.

1. The aims of this study were twofold: (i) to investigate the ability of a recently described [2H5]phenylalanine method for quantifying whole-body protein turnover during acute physiological perturbation; (ii) to determine specifically whether the previously observed increase in protein synthesis on insulin withdrawal in insulin-dependent (type 1) diabetic patients seen when employing the [13C]leucine technique could be corroborated by using [2H5]phenylalanine. 2. Whole-body protein turnover was measured by both the [2H5]phenylalanine and [13C]leucine primed continuous infusion methods applied simultaneously to six type I post-absorptive diabetic patients during insulin withdrawal and infusion. 3. Values were determined by the [13C]leucine method by measuring either [13C]leucine (primary pool) or alpha-[13C] ketoisocaproic acid (reciprocal pool) enrichment in plasma. 4. Values of whole-body protein breakdown during insulin withdrawal derived from the [2H5]phenylalanine and primary and reciprocal pool [13C]leucine models respectively were 3.54 +/- 0.43, 3.85 +/- 0.41 and 4.62 +/- 0.44 g day-1 kg-1 (means +/- SD). Insulin infusion resulted in a significant reduction (P less than 0.02) to 3.07 +/- 0.34, 3.05 +/- 0.26 and 3.82 +/- 0.4 g day-1 kg-1, respectively. Synthesis values fell significantly but by a smaller amount than breakdown, resulting in increased (P less than 0.05) net protein deposition, regardless of the model used. 5. These data demonstrate that the [2H5]phenylalanine and [13C]leucine methods generate similar results both in absolute and relative terms in response to short-term insulin infusion. 6. The confirmation of increased whole-body protein synthesis during insulin withdrawal by two independent methods supports the validity of this observation.

Adult↗
PubMed1991

Albumin metabolism in fasted subjects during late pregnancy.

1. Albumin fractional synthetic rate was determined in five non-pregnant subjects and five normal pregnant subjects in late gestation after an overnight fast by simultaneous prime and intravenous infusion of two precursor amino acids, [15N]glycine and L-[1-13C]leucine, with additional priming of the large but, slowly turning over, urea pool with [15N2]urea. 2. The two tracers yielded similar values of albumin fractional synthetic rate: 6.1 and 6.0%/day in non-pregnant subjects and 7.3 and 7.6%/day in pregnant subjects, for glycine and leucine, respectively. While plasma volume was greater and serum albumin concentration was significantly reduced during pregnancy, the calculated intravascular albumin mass was significantly increased in pregnant subjects. 3. The amount of albumin synthesized in the intravascular compartment was significantly greater at 8.8 and 9.5 g/day in pregnant subjects compared with 6.4 and 6.3 g/day in non-pregnant control subjects (glycine and leucine methods, respectively). Calculated whole-body protein turnover using glycine was not different between the two subject groups, but leucine flux was higher in pregnant subjects. Partitioning of nitrogenous products in urine revealed that pregnant subjects excreted less urea, less ammonia and less creatinine than the non-pregnant control subjects. 4. These findings suggest that whereas the serum albumin concentration decreases during pregnancy secondary to the large increase in plasma volume, there is an increase in albumin synthesis such that total intravascular albumin mass is increased in late pregnancy.

Adult↗
PubMed1991

Nitrogen balance and protein turnover during the growth failure in newly born low-birth-weight infants.

Weight gain, nitrogen balance, protein turnover, and energy and protein intakes were measured during the first week of life of 14 low-birth-weight (LBW) infants, 5 small-for-gestational-age (SGA) infants and 9 appropriate-for-gestational-age (AGA) infants enterally fed at rates determined by the infants ability to assimilate feed. Mean gross intakes were 334 KJ and 1.75 g/kg protein; 4 infants were increasing and 10 were losing weight at rates proportional to gross energy and protein intakes and to nitrogen balance (0.031 g protein balance/g wt gain). Rates of protein synthesis and degradation measured by an intragastric infusion of [1-13C]leucine, averaged 14.5 and 15.9 g protein.kg-1.d-1, some 50% higher than previously reported in older preterm infants and not correlated with nitrogen balance. The growth failure of these infants was not associated with inadequate overall rates of protein turnover, but appeared to reflect an influence of the insufficient energy and protein intakes on the high rates of protein turnover, inducing changes in protein balance in either direction through relatively small changes in protein synthesis and/or degradation.

Dietary Proteins↗
PubMed1991

Postoperative protein metabolism: effect of nursing elderly patients for 24 h after abdominal surgery in a thermoneutral environment.

We have studied the effect of intraoperative body heat conservation and 24-h thermoneutrality on postoperative whole body protein turnover using stable isotope methodology in a group of elderly patients undergoing colorectal surgery for rectosigmoid adenocarcinoma. Two groups of eight patients were studied. One group (control, or cold) received routine intraoperative and postoperative care. All patients in the second group (warmed) were maintained at normothermia during anaesthesia and surgery; these patients were nursed after surgery in a warm room (ambient temperature 28-30 degrees C) for a period of 24 h. General anaesthesia, surgical care and nutritional support were similar in both groups. A constant nutritional intake, based on nitrogen 0.1 g kg-1 day-1 and energy 20 kcal kg-1 day-1, was provided orally for 7 days before surgery and i.v. after operation for 4 consecutive days. Whole body protein breakdown and synthesis, as assessed by stable isotope methodology, increased significantly 2 and 4 days after surgery in both groups (P less than 0.01), but the increase in protein breakdown in the warmed group on day 2 was significantly less than that in the cold group (P less than 0.05). The increase in leucine oxidation in the warmed group on the 2nd day after surgery was not significant, and was less than the increase observed in the cold group (P less than 0.05). However, by the 4th day, leucine oxidation was enhanced significantly in both groups (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMed1991

Protein metabolism after abdominal surgery: effect of 24-h extradural block with local anaesthetic.

We have studied the effect of intraoperative and postoperative (24 h) extradural block with local anaesthetic on whole body protein turnover (stable isotope methodology) and urinary excretion of urea nitrogen, adrenaline, noradrenaline and cortisol in a group of well nourished elderly patients undergoing colorectal surgery who received a constant nutritional intake before (7 days) and after (4 days) surgery. One group (control, n = 8) received routine anaesthetic and surgical care. Patients in the test group (extradural, n = 9) received extradural bupivacaine, and sensory block (T4-S5) was maintained during and after surgery for a period of 24 h. Whole body protein breakdown and amino acid oxidation increased significantly after surgery in both groups (P less than 0.05), but the increase in protein breakdown in the extradural group was significantly less than that in the control group. Urinary excretion of urea nitrogen, adrenaline and noradrenaline increased in the control group after surgery, whilst the increase in the extradural group was very small. In contrast, urinary excretion of cortisol increased significantly in both groups after surgery. We conclude that extradural block maintained for 24 h after surgery significantly minimized postoperative protein breakdown without compromising whole body protein synthesis.

Abdomen↗
PubMed1991

The effect of chronic alcohol ingestion on whole body and muscle protein synthesis--a stable isotope study.

The cause of the proximal myopathy associated with chronic alcohol ingestion has yet to be established. The clinical feature of muscle wasting implies either inhibited skeletal muscle protein synthesis, stimulated breakdown or a combination of both. Previous data suggest that breakdown is reduced, rather than promoted. This provides evidence, albeit indirect, that the myopathy is the result of inhibited muscle protein synthesis, which has been demonstrated recently in the rat model. We have examined the influence of chronic alcohol intake on post-absorptive fractional skeletal muscle protein synthesis in man using a primed continuous (1 mg/kg/hr) infusion of L-[1-13C]leucine for 8 hr. Percutaneous quadriceps muscle biopsies (200 mg) were taken after 2 and 8 hr of the infusion for measurement of the incorporation of 13C leucine into muscle protein. Plasma 13C enrichment of alpha-ketoisocaproic acid, the deaminated product of leucine, was used to represent that of the precursor pool. We studied 6 fully ambulant alcoholics, who exhibited no overt evidence of skeletal muscle disease and who had consumed at least 100 g alcohol daily for a minimum of 10 years. Mean (+/- S.D.) fractional muscle protein synthesis was 0.0274 +/- 0.0087 (95% confidence intervals 0.0204-0.0344%/hr). This value is significantly lower than recently published control values obtained using identical protocols which range from 0.046 to 0.055%/hr. In addition, whole body leucine oxidation was lower (P less than 0.05) in the chronic alcoholics than in healthy controls, whereas neither whole body protein synthesis nor breakdown was significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Influence of insulin on leucine kinetics in the whole body and across the forearm in post-absorptive insulin dependent diabetic (type 1) patients.

Acute effects of insulin on protein metabolism (whole body and forearm muscle) were simultaneously assessed using doubly labelled (13C15N) leucine in post-absorptive Type I diabetic patients. Whole body protein kinetics were calculated using either plasma 13C leucine or alpha-ketoisocaproic acid (alpha-KIC) enrichment to represent labelling of the precursor pool. Forearm muscle protein metabolism was measured using a previously described arterio-venous model. Acute insulin infusion (2-3 units per hour) for 2-3 hours reduced whole body protein breakdown (p < 0.01), synthesis (p < 0.05) and oxidation (p < 0.05) irrespective of the basis of calculation. Across forearm muscle, insulin reduced overall net negative protein balance (p < 0.05) by inhibiting protein breakdown, 80% and synthesis, 71%. Insulin reduced the deamination of leucine to alpha-KIC (p < 0.05) and its reamination (p < 0.05). This study demonstrates that whole body protein metabolism is broadly paralleled by events in skeletal muscle though the forearm approach is considerably more sensitive to noise than whole body protein kinetic measurements. This results from the less damped nature of the forearm model and the necessity to measure a greater number of variables required to solve the appropriate balance equations. Failure of insulin per se to promote protein synthesis in man is not model dependent and suggests that the observed differences relating to insulin mediated control of protein kinetics found in man compared with small mammals are both real and species related.

Adult↗
PubMed1990

Intermediate filaments in smooth muscle from pregnant and non-pregnant human uterus.

The intermediate filament proteins desmin and vimentin from pregnant and non-pregnant uterine muscle and smooth-muscle cells in culture were analysed using SDS/PAGE. The desmin content in uterine muscle increases dramatically during pregnancy, whereas vimentin remains unchanged or changes very little. When muscle cells are kept in culture, a considerable increase in vimentin content is observed as compared with vimentin in freshly isolated non-pregnant uterine tissue. Our results strengthen the view that vimentin and desmin filaments have independent function and turnover, and point to a predominantly structural role for desmin filaments.

Blotting, Western↗
PubMed1990

Mechanism of muscle wasting in myotonic dystrophy.

Myotonic dystrophy is associated with progressive muscular atrophy. In order to determine the mechanism of muscle wasting in this condition, we measured fractional mixed skeletal muscle protein synthesis in the postabsorptive state in 8 patients with myotonic dystrophy, and compared the results with those of 10 normal subjects. Fractional muscle protein synthesis was determined by measuring the increment of 13C leucine in mixed skeletal muscle protein obtained by needle biopsy from the quadriceps muscle during a primed-continuous infusion of L-(1-13C) leucine. We used plasma 13C alpha-ketoisocaproate (representing intracellular leucine labeling) as the precursor pool for the calculation of fractional muscle protein synthesis and leucine kinetics. Fractional muscle protein synthesis was depressed in the patients with myotonic dystrophy (28% decrease, p less than 0.02). Leucine flux, leucine oxidation, and the nonoxidative portion of leucine flux were not different between the patients with myotonic dystrophy and the normal control subjects. Muscle atrophy in myotonic dystrophy reflects a selective decrease in muscle protein synthesis without any similar decrease in nonmuscle protein synthesis. This decrease may result from an impaired end-organ response to anabolic hormones or substrates.

Adult↗
PubMed1990

Influence of glucagon on protein and leucine metabolism: a study in fasting man with induced insulin resistance.

The counter-regulatory hormones, including glucagon, may be involved in the generation of postoperative negative nitrogen balance. We examined the influence of glucagon on whole body and forearm muscle protein kinetics, determined by L-[1-13C, 15N]leucine, in two matched groups of healthy fasting subjects. In one study somatostatin alone was infused continuously (0.12 mg h-1) and in another with glucagon (0.04 mg h-1) to generate insulin resistance. Somatostatin infusion increased leucine oxidation (P less than 0.05) and reduced the negative protein balance (P less than 0.01) across the forearm; the 15 per cent decrease in protein breakdown was not significant. Whole body leucine kinetics showed increased flux (P less than 0.05) and synthesis (P less than 0.01) but reduced oxidation (P less than 0.05). Hyperglucagonaemia caused a threefold enhancement of leucine oxidation (P less than 0.02), while the negative protein balance further increased (P less than 0.05) across the forearm. Whole body leucine flux was unchanged; oxidation increased (P less than 0.01) and synthesis decreased (P less than 0.01). These studies confirm that physiological hyperglucagonaemia during insulin resistance is catabolic in the short-term and indicates, for the first time, that glucagon may influence muscle protein metabolism acutely in man. We suggest that therapeutic manoeuvres designed to reduce glucagon levels after surgery may ameliorate protein kinetic abnormalities.

Adult↗
PubMed1990

The use of metronidazole in management of methylmalonic and propionic acidaemias.

Gut bacteria have been implicated as an important source of propionate in children with inborn errors of propionate metabolism. We have investigated the value of oral metronidazole (10-20 mg/kg per day) in five children with methylmalonic acidaemia (MMA) and four with propionic acidaemia (PA). Urinary excretion of propionate metabolites fell significantly during the treatment in all subjects, the mean decrease being 41% (range 12-76, P less than 0.01), while mean plasma propionate was reduced from 45.0 mumol/l to 25.1 mumol/l (P less than 0.05). Substantial reduction of the gut bacterial population was confirmed by lactulose breath hydrogen tests and by stool culture, and stool propionate concentration was reduced in most subjects. Clinical improvement was noted in three children. These results suggest that long-term antimicrobial therapy may offer significant clinical benefit to children with inborn errors of propionate metabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

In vivo propionate oxidation as a prognostic indicator in disorders of propionate metabolism.

Biochemical markers such as plasma and urinary metabolite concentrations and in vitro enzyme activity are of limited prognostic value in the most common disorders of propionate metabolism, methylmalonic acidaemia (MMA) and propionic acidaemia (PA). In vivo propionate oxidation was compared with conventional prognostic measures as predictors of clinical severity in seven children with MMA and six with PA. Propionate oxidation was measured using a continuous infusion of [1-13C]propionate and was expressed as the rate of appearance of 13CO2 as a percentage of the propionate infusion rate. Children with MMA (mean oxidation 51.2%, range 17.5-91.6, P less than 0.05) and with PA (mean oxidation 36.3%, range 3.0-91.1, P = NS) oxidised substantially less propionate than controls (mean oxidation 81.9%, range 69.4-101.0, n = 5). Percentage oxidation was a better predictor of the clinical severity score (r = 0.75, P less than 0.01) than was in vitro enzyme activity, plasma propionate or methylmalonate concentration or urinary metabolite excretion. Studies were repeated after an interval of 1-3 weeks in six of the subjects; the percentage oxidation in each subject was virtually unchanged between studies (coefficient of variation 8.6%). These results suggest that in vivo oxidation measurements using [13C]propionate are both reproducible and prognostically useful in disorders of propionate metabolism.

Adolescent↗
PubMed1990

The contribution of protein catabolism to metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria.

Leucine and protein metabolism were studied using stable isotope techniques in 6-year-old twins with 3-hydroxy-3-methylglutaric aciduria during acute metabolic decompensation. The decompensation was preceded by prolonged fasting in twin 1 and by an upper respiratory infection in twin 2. Twin 2 was also studied when well (control study). During infection, leucine oxidation (36 mumol/kg per hour), protein catabolism (6.0 g/kg per day) and urinary excretion of major leucine metabolites (104 mumol/kg per hour) were all increased compared with the control study (16 mumol/kg per hour, 4.7 g/kg per day and 28 mumol/kg per hour respectively). During fasting, leucine oxidation (18 mumol/kg per hour) was unchanged and protein catabolism (4.1 g/kg per day) was decreased despite substantially increased urinary metabolite excretion (87 mumol/kg per hour) compared with the control study. These results indicate that protein mobilisation and leucine oxidation played important roles in metabolic decompensation during infection but not during fasting. It is likely that the increased metabolite excretion during fasting arose primarily from fatty acid catabolism, indicating the importance of this substrate in metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Sources of propionate in inborn errors of propionate metabolism.

Amino acids are widely regarded as the most important sources of propionate in disorders of propionate metabolism. Propionate production was measured in the fasting state by continuous infusion of sodium [1-13C]propionate in three children with methylmalonic acidemia (MMA) and three with propionic acidemia (PA). The contribution of isoleucine, valine, threonine, and methionine catabolism to total propionate production was estimated by extrapolation from the hydroxylation of phenylalanine determined by a continuous-infusion [2H5]phenylalanine technique. The contribution of gut bacterial propionate production was determined by measuring total propionate production before and after treatment with oral metronidazole (10 to 20 mg/kg/d for 1 week). Amino acid catabolism accounted for a mean of 51.7% (range, 24.5% to 66.4%) of total propionate production. The mean decrease in propionate production after metronidazole was 22.2% +/- 8.5 (P less than .02); this percentage is likely to represent the minimum propionate production attributable to gut bacteria. Approximately 30% of total propionate production was unaccounted for, and is likely to arise primarily from odd-chain fatty acid catabolism in the fasting state. These results indicate that sources of propionate other than from protein catabolism are important in disorders of propionate metabolism, and explain the generally disappointing response to dietary protein restriction.

Amino Acids↗