Fetal proteins in uremia: a metabolic encore?
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Animals↗
Biomedical subjects
J A Little
Publications and source records attributed to J A Little.
Leptin levels do not change acutely with food administration in normal or obese subjects, but are negatively correlated with pituitary-adrenal activity.
BACKGROUND: Leptin is a peptide secreted by white adipose tissue which has been shown to have a major influence on body weight regulation, while animal studies have revealed widespread interconnections between leptin and other endocrine systems, especially with insulin. However, its acute regulation has been little studied in the human. We have therefore investigated the effect of a 1000 kcal meal and fasting on the levels of leptin, insulin and cortisol, in both normal and obese subjects. SUBJECTS AND DESIGN: We have studied the effect of food and fasting on circulating leptin levels in 20 subjects of normal body mass index (BMI range 18-25) and in a group of 12 moderately-severely obese subjects (BMI range 34-61). We also studied the effect of food and fasting in a patient both before and after the successful removal of a pancreatic insulinoma as a model of excess insulin secretion. RESULTS: Mean leptin levels were significantly higher in the obese than in the lean group (42.7 +/- 3.41 vs 5.35 +/- 1.55 micrograms/l, mean +/- SEM; P < 0.001), and showed a positive correlation with body mass index (r = +0.71; P < 0.001). Frequent (every 20 minutes) sampling for 3 hours after food did not show any acute changes in circulating leptin levels. On the fasting day we observed a small but significant fall in circulating leptin levels in the last 4 hours of a 20-hour fast in our subjects as a group (92 +/- 0.03% of basal, P = 0.03); however, in the lean subjects the fall was greater (86 +/- 0.04% of basal, P = 0.02) than in the obese, where it did not reach statistical significance (96 +/- 0.05% of basal). Pre-meal and peak insulin levels showed a positive correlation with circulating mean leptin levels (r = +0.65; P < 0.001 and r = +0.78; P < 0.001, respectively) in all subjects, while pre-meal and peak serum cortisol levels showed an inverse relation with leptin levels (r = -0.53; P = 0.002 and r = -0.41; P = 0.02, respectively); this effect was independent of BMI in the obese subjects. In the patient with the insulinoma the markedly elevated insulin and leptin levels measured before the operation returned to normal after removal of the tumour, in accord with reports of experimental animal data that long-term insulin excess per se is associated with increased circulating leptin concentrations. CONCLUSION: Leptin is a robust indicator of BMI and insulin levels, both basal and stimulated, but does not change acutely following food. Fasting causes a proportionately greater decline in leptin levels in lean subjects than in obese subjects. Circulating leptin is inversely correlated with the activity of the hypothalamo-pituitary-adrenal axis: whether this is a direct influence of leptin on hypothalamo-pituitary-adrenal activity, or whether both are indirect indicators of body fat stores, requires further investigation.
Adult↗
The registration of multiple medical images acquired from a single subject: why, how, what next?
This paper reviews some of the recent techniques which have been used to register multiple images of the same patient. Image registration is a problem which has been receiving significant attention from the medical image processing community in recent years. A successful image registration can aid in patient diagnosis, treatment assessment, image guided interventions, surgery planning and surgery. At present the majority of work has focused on rigid body transformations of images. We shall discuss some of the approaches used and outline a key automatic method in detail. In order to allow image registration of parts of the body which do not remain rigid, either due to patient movement or a change in pathology, nonlinear deformation techniques are being developed. We shall talk of the history of these methods before explaining deformations using landmarks and a recent extension to allow the definition of rigid structures in such warps in more detail. Validation of these methods is of great importance and we shall discuss work which has already been carried out on this topic for rigid body registrations as well as ideas for the validation of deformation algorithms.
Algorithms↗
Development of enzyme immunoassay for endogenous ouabain-like compound in human plasma.
Widespread evidence supports the existence of an endogenous digitalis-like compound in mammals. We report here the development of a novel enzyme immunoassay for ouabain that, in conjunction with a detailed HPLC study, identifies a ouabain-like compound (OLC) in extracted human plasma. The assay is sensitive-minimum detection limit for OLC 37 pmol/L (11 pmol/L in plasma)-and has a working range (between-assay CV < 10%) of 180-10000 pmol/L (54-3000 pmol/L in plasma). Mean recoveries of ouabain added to plasma ranged from 90% to 100%, and plasma extracts diluted in parallel to the standard curve. Plasma OLC concentrations in 10 healthy volunteers averaged 92 pmol/L (range 55-168), assuming 100% cross-reactivity of OLC in the ouabain assay. HPLC analysis with two distinct chromatographic conditions demonstrated that endogenous human plasma OLC co-eluted with authentic ouabain. The enzyme immunoassay is rapid and easy to perform and will support further investigation of the nature of this controversial endogenous steroid.
Chromatography, High Pressure Liquid↗
Misleading results from immunoassays of serum free thyroxine in the presence of rheumatoid factor.
A novel interference with measurements of serum free thyroxine (FT4) caused by rheumatoid factor (RhF) is described. We found misleading, sometimes gross, increases of FT4 results in 5 clinically euthyroid elderly female patients with high RhF concentrations. All 5 patients had high FT4 on Abbott AxSYM or IMx analyzers. "NETRIA" immunoassays gave misleading results in 4 of the 5 patients; Amerlex-MAB in 2 of 4 patients; AutoDELFIA in 2 of the 5; and Corning ACS-180 and Bayer Diagnostics Immuno 1 in 1 of the 5. BM-ES700 system results for FT4 in these women remained within the reference range. Results for serum T4, thyroid-stimulating hormone, free triiodothyronine, thyroid-hormone-binding globulin, and FT4 measured by equilibrium dialysis were normal in all 5 patients. Drugs, albumin-binding variants, and anti-thyroid-hormone antibodies were excluded as interferences. Addition to normal serum of the RhF isolated from each of the 5 patients increased the apparent FT4 (Abbott AxSYM). Screening of 83 unselected patients demonstrated a highly significant positive correlation between FT4 (Abbott AxSYM) and RhF concentrations. Discrepant, apparently increased FT4 with a normal result for thyroid-stimulating hormone should lead to measurement of the patient's RhF concentration.
Aged↗
Sex difference in high density lipoprotein cholesterol in six countries.
It is known that women have higher levels of high density lipoprotein (HDL) cholesterol than men. The authors examined the association between HDL cholesterol and biologic sex in 8,631 women and 10,690 men aged 45-54 years from six countries studied between 1972 and 1989. The variation in the sex difference for HDL cholesterol was significant; the smallest difference (0.06 mmol/liter) was seen in China and the largest (0.40 mmol/liter) in Canada. Adjustment for differences in body mass index, smoking, alcohol use, and heart rate reduced but did not eliminate the variability. The sex difference in HDL cholesterol levels, usually assumed to be due to biologic factors, differs across cultures and may be related to environmental factors.
Arteriosclerosis↗
An enzyme immunoassay for 6-sulphatoxy-melatonin in human urine.
We describe a newly developed enzyme immunoassay (EIA) for the determination of 6-sulphatoxy-melatonin (aMT6s) in human urine, using a aMT6s-bovine serum albumin-horseradish peroxidase (aMt6s-BSA-HRP) conjugate as the enzyme label. The assay incorporates a highly specific antibody raised in rabbits. The EIA has a sensitivity of 2 pg/well (40 pg/ml) with intraassay coefficients of variation of 2.3-6.1% in the range of the assay. The material with the highest level of cross-reactivity was N-acetyl serotonin sulphate, with a relative potency of 0.000078%. One hundred thirty-four urine samples from children and adults at different time points were assayed and the results compared with those from an established radioimmunoassay (RIA) and with a newly developed RIA using the same antibody as the EIA. The correlation coefficient, r, comparing the two RIA's was 0.9869, and the regression equation was log (kit) = 0.9340 log (new) + 0.1213. The correlation coefficient, r, comparing the EIA with the newly developed RIA, was 0.9686, and regression equation log (new) = 0.9674 log (EIA) + 0.0600. The EIA for the measurement of aMT6s in urine represents a new approach in the investigation of pineal function.
Adolescent↗
Insulin-like growth factor-I and- II in combination inhibit the release of growth hormone-releasing hormone from the rat hypothalamus in vitro.
This study was designed to investigate the feedback loop between insulin-like growth factor-I (IGF-I) and IGF-II and the hypothalamic hormones growth hormone-releasing hormone (GHRH) and somatostatin (SS) using an in vitro rat hypothalamic model. IGF-I and, to lesser extent, IGF-II, both activate type 1 IGF receptors, while type 2 receptors are activated by IGF-II alone. IGF-I, IGF-II, their various specific analogues (Des[1-3]IGF-I, [Arg54/Arg55]IGF-II and [Leu27]IGF-II), insulin and the type 2 receptor antagonist beta-galactosidase were used on their own or in combination to study their effect on GHRH and SS release. Our results suggest that the simultaneous activation of type 1 and type 2 IGF receptors is needed for the negative feedback effect of IGFs on GHRH release in this in vitro system, in agreement with earlier findings in vivo. Somatostatin was not altered by any combination of peptides.
Animals↗
Metabolic persistence of fetal hemoglobin.
Hereditary persistence of fetal hemoglobin (HPFH) has typically been ascribed to mutations in the beta-globin gene cluster. Pharmacologic agents, including the short-chain fatty acid butyrate, have been shown to upregulate fetal and embryonic globin gene expression. In this report we investigate the possibility that metabolic derangements characterized by an inability to metabolize another short-chain fatty acid, propionate, could be associated with a persistence of fetal hemoglobin unrelated to alterations in the beta-globin cluster. Embryonic globin gene upregulation in a murine adult erythroid cell culture was shown by RNase protection after induction with three short-chain fatty acids (C2-C5). Chart reviews and measurement of fetal hemoglobin in five patients with abnormalities in propionate (C3) metabolism were undertaken; SSCP/dideoxy fingerprint analysis of the gamma-globin gene promoters was done in three of these five patients. Twelve patients with other metabolic derangements served as controls. Only the four patients with clinically severe abnormalities in propionate metabolism (ages 2 to 11), but without anemia, showed a sustained elevation in fetal hemoglobin (3% to 10%). The level of elevation of fetal hemoglobin in these patients, who lack erythropoietic stress, suggests that propionic acid and/or its metabolites are potent stimulators of fetal hemoglobin expression. Study of this group of patients should allow unique insights into the long-term effects of sustained exposure to elevations of short-chain fatty acid levels.
Acyl-CoA Dehydrogenase↗
An experimental comparison of equivalent terminal and rotational crossbreeding systems in swine: pig performance.
Eleven thousand forty-nine pigs produced from 934 litters using 262 rotational and F1 crossbred sows were used to study differences in pig weights, survival rates and pen average daily gain, daily feed intake, and feed conversion between pigs from equivalent three-breed rotational and three-breed terminal crossbreeding systems using Duroc, Yorkshire, and Landrace breeds. Pig weights at birth and 21 and 56 d and days to reach 100 kg did not differ (P > .10) between the terminal and rotational crossbreeding systems. However, ultrasound backfat thickness of pigs from the terminal crossbreeding system was .04 cm greater (P < .007) than that of pigs from the rotational crossbreeding system. Survival rate from 56 d to 100 kg was .8% greater (P < .01) for pigs from the terminal crossbreeding system than for those from the rotational crossbreeding system. The crossbreeding system had no effect (P > .10) on survival rate at birth, from birth to 21 d, from 21 to 56 d, or from birth to 100 kg. Differences between the two crossbreeding systems were nonsignificant (P > .20) for pen average daily gain, daily feed intake, and feed conversion. Breed composition of pigs was an important source of variation (P < .01) for pig weights at birth and at 56 d. Similarly, breed composition of the pig also affected ultrasound backfat thickness at 100 kg (P < .01), but not days required to reach 100 kg (P > .10). For survival traits, only survival rate from 56 d to 100 kg was influenced by breed composition of the pig.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
An experimental comparison of equivalent terminal and rotational crossbreeding systems in swine: sow and litter performance.
Two hundred sixty-two rotational and F1 sows were mated to Duroc, Yorkshire, or Landrace boars to study performance differences between equivalent three-breed rotational and three-breed terminal crossbreeding systems. Matings were made to maximize heterosis. The sows were fed either 1.8 or 2.7 kg/d (2.25 and 3.15 kg/d in winter months) during gestation. These matings produced 934 litters to determine the effect of crossbreeding system, breed composition within crossbreeding system, and gestation feeding level on litter sizes and weights, sow weight and backfat thickness at weaning, daily feed intake of the sow during lactation, interval from weaning to estrus, and farrowing rate. Feeding level during gestation was not an important source of variation for any of the traits except litter birth weight and daily feed intake of the sow during lactation. Litter size marketed was .37 pigs/litter greater (P < .05) for the terminal-cross sows than those sows from the rotational crossbreeding system. Litter weights at birth and 56 d were .8 and 6.5 kg heavier (P < .02, .03), respectively, for the terminal crossbreeding system than for the rotational crossbreeding system. Sow weight and backfat thickness at weaning, daily feed intake during lactation, and farrowing rate were not affected (P > .10) by crossbreeding system. Weaning-to-estrus interval was 1.3 d shorter (P < .03) for sows in the terminal crossbreeding system than for those in the rotational system.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
Hepatic lipase deficiency. Clinical, biochemical, and molecular genetic characteristics.
Hepatic lipase (HL) is an important enzyme in the metabolism of triglyceride-rich lipoproteins and high density lipoproteins. The clinical syndrome of HL deficiency is rare and difficult to identify. We studied carriers of mutant HL to ascertain whether there are distinctive clinical and/or biochemical characteristics of the heterozygous state. In an Ontario kindred, compound heterozygosity for two HL mutations, S267F and T383M, underlies the clinical syndrome of complete HL deficiency. We report that simple heterozygotes for either HL mutant do not have a discrete lipoprotein abnormality, except for relative triglyceride enrichment of lipoprotein fractions with d > 1.006 g/mL. Postheparin HL activity is depressed to a greater degree in carriers of S267F compared with carriers of T383M. Retinyl palmitate loading studies in a compound heterozygote revealed impaired clearance of chylomicron remnants. The dyslipoproteinemia in a compound heterozygote was ameliorated by lovastatin. There was no difference in the quantity and distribution of HL mRNA in the liver of a compound heterozygote when compared with that of a normal subject. Thus, HL deficiency associated with structural variation of the HL gene is characterized by premature atherosclerosis, triglyceride enrichment of lipoprotein fractions with d > 1.006 g/mL, the presence of circulating beta-very low density lipoproteins, and abnormal catabolism of postprandial triglyceride-rich lipoproteins.
Adult↗
Beta-VLDL in hepatic lipase deficiency induces apoE-mediated cholesterol ester accumulation in macrophages.
Hepatic lipase-deficient subjects in the Ontario kindred are compound heterozygotes for hepatic lipase mutations (Ser267-->Phe and Thr383-->Met). Cholesteryl ester-rich beta-very-low-density lipoprotein (beta-VLDL) accumulates in plasma and such subjects have premature atherosclerosis. To determine a possible mechanism, we hypothesized that hepatic lipase-deficient beta-VLDL, homozygous for apolipoprotein (apo) E3, would cause cholesteryl ester accumulation and foam cell formation in macrophages. beta-VLDL and pre-beta-VLDL were isolated by Pevikon electrophoresis and incubated with J774 macrophages, cells that do not secrete apoE. beta-VLDL increased cellular cholesteryl ester content 13-fold, whereas pre-beta-VLDL increased cholesteryl ester sevenfold. beta-VLDL increased acyl CoA:cholesterol acyltransferase activity fourfold (measured as [14C]oleate incorporation into cholesteryl ester). Preincubation of hepatic lipase-deficient beta-VLDL with the anti-apoE monoclonal antibody 1D7, which inhibits binding of apoE to low-density lipoprotein receptors, inhibited cellular cholesteryl ester accumulation by 75%, whereas the anti-apoB blocking monoclonal antibody 5E11 failed to inhibit cellular cholesteryl ester accumulation. In contrast to hepatic lipase deficiency, beta-VLDL from type III subjects (E2/E2) failed to increase cellular cholesteryl ester or acyl CoA:cholesterol acyltransferase more than 1.5-fold. Thus, hepatic lipase-deficient beta-VLDL readily induces cholesteryl ester accumulation in J774 macrophages, a process mediated by functional apoE3. This may explain the premature atherosclerosis observed in this kindred.
Apolipoproteins E↗
Identification of disulfide-linked apolipoprotein species in human lipoproteins.
We wished to determine whether apolipoprotein C-IIToronto, a mutant form of apolipoprotein C-II that contains a C-terminal cysteine residue, exists as a monomeric species or as multiple disulfide-linked species in plasma lipoproteins. The plasma lipoproteins from a heterozygous carrier and two homozygous carriers of apoC-IIToronto were investigated. The mutant apolipoprotein was found in homodimeric form and as heterodimers with apolipoprotein A-II, apolipoprotein B-100, and apolipoprotein E. Of particular interest was the demonstration of the existence of the disulfide-linked species apolipoprotein B-100:A-II and B-100:C-IIToronto in the very low density and low density lipoproteins in subjects who were carriers of apoC-IIToronto. We also observed that apoE3:C-IIToronto and apoE3:A-II dimers were present in the chylomicrons and very low density lipoproteins of these subjects. The observation of the existence of apolipoprotein B-100:A-II was extended to other hypercholesterolemic and hypertriglyceridemic subjects. The highest proportion of apolipoprotein B-100:A-II was observed in the very low density lipoproteins of hypertriglyceridemic subjects. The concentration of this species was significantly higher in hyperlipidemic subjects than in normolipidemic controls. These results demonstrate that the molecular species of cysteine-containing apolipoproteins are complex and should be considered in studies of human lipoprotein composition and function.
Apolipoprotein A-II↗
Gas chromatographic profiles of plasma total lipids as indicators of dietary history. Correlation with carbohydrate and alcohol intake based on 24-h dietary recall.
Quantitative gas chromatographic estimates of the major lipid classes and molecular species in fasting plasma were correlated with total carbohydrate, starch, fibre, sucrose and alcohol intake based on 24-h dietary recall. Spearman coefficients (rs) and tests of significance (P) were obtained for groups of 775 males and 471 females aged 20-59 years from a Toronto-McMaster Lipid Research Clinics Population Study. The most significant correlations varying from rs 0.1 to 0.2 and P 0.001 to 0.0005 (n = 400-773) were between increased intake of alcohol and increased ratios of C50/C54 triacylglycerols, C34/C36 phosphatidylcholines and phosphatidylcholine/free cholesterol (PC/FC) of plasma. Increase in total dietary carbohydrate, starch and fibre correlated with decreasing C50/C54 triacylglycerol, C34/C36 phosphatidylcholine and PC/FC ratios (rs = -0.1-0.2; P less than 0.002-0.04; n = 400-773). In contrast, consumption of high levels of alcohol was associated with increasing C50/C54 triacylglycerol, C34/C36 phosphatidylcholine and PC/FC ratios. A high intake of alcohol (50-150 ml per day) distinguished itself from other simple carbohydrate-induced lipid profiles by its marked effect on increased C50/C52 triacylglycerol and PC/FC ratio.
Adult↗
Plasma lipids and lipoproteins and the prevalence of risk for coronary heart disease in Canadian adults. Canadian Heart Health Surveys Research Group.
OBJECTIVE: To report population reference values for blood lipids, to determine the prevalence of lipid risk factors and to assess their association with other risk factors. DESIGN: Population-based cross-sectional surveys. Survey participants were interviewed at home and provided a blood sample at a clinic. All blood lipid analyses were done in the Lipid Research Laboratory, University of Toronto. The laboratory is standardized in the National Heart, Lung Blood Institute-Centres for Disease Control Standardization Program. SETTING: Nine Canadian provinces, from 1986 to 1990. PARTICIPANTS: A probability sample of 26,293 men and women aged 18 to 74 was selected from the health insurance registers for each province. Blood samples were obtained from 16,924 participants who had fasted 8 hours or more. OUTCOME MEASURES: Concentration of total plasma cholesterol, triglycerides and high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol in blood samples from fasting participants. MAIN RESULTS: Of the study population, 46% had total plasma cholesterol levels above 5.2 mmol/L, 15% had LDL-cholesterol levels above 4.1 mmol/L, 15% had triglyceride levels above 2.3 mmol/L and 8% had HDL-cholesterol levels below 0.9 mmol/L. Total plasma cholesterol, LDL-cholesterol and triglyceride levels rose with age in men to a maximum in the 45-54 age group; in women there was little change with age up to ages 45 to 54, at which time the level of each of these lipids increased appreciably. The age-standardized prevalence of obesity was positively associated with elevation of total plasma cholesterol. CONCLUSION: The results suggest the need for a multifactorial approach in health promotion efforts to lower blood cholesterol levels and reduce other risk factors in the population. A considerable number of adults were found to be at risk at all ages in both sexes. In the short term, men aged 34 and older and women aged 45 and older might benefit most from prevention programs.
Adult↗
Compound heterozygosity for mutant hepatic lipase in familial hepatic lipase deficiency.
In a kindred with three hyperlipidemic subjects who had premature atherosclerosis and complete deficiency of hepatic lipase activity, we had previously identified a novel structural hepatic lipase gene variant. We now report the identification of three more hepatic lipase gene mutations in this family and demonstrate that compound heterozygosity for two hepatic lipase mutations (designated S267F and T383M) underlies hepatic lipase deficiency.
Amino Acid Sequence↗
Gas chromatographic profiles of plasma total lipids as indicators of dietary history. Correlation with fat intake based on 24-h dietary recall.
Fasting plasma total lipid profiles were determined by high-temperature gas chromatography on a total of 1246 free living urban subjects, ages 20-59 years, from the Toronto-McMaster Lipid Research Clinic Population Study. Quantitative estimates of the major molecular species, lipid classes and lipid class ratios were correlated with a total of twelve dietary lipid components, including total saturated and unsaturated fats. oleic and linoleic acids, and cholesterol, to give appropriate Spearman coefficients (rS) and tests of significance (P) for groups of 775 males and 471 females. The intake of the various nutrients was derived from a 24-h dietary recall. The most significant correlations varying from rs +/- 0.1-0.4 and P less than 0.0001-0.0005 were between the intake of total fat, individual saturated and unsaturated fats, and the ratios of C50/C54 triacylglycerols and the C34/C36 phosphatidylcholines, which reflected the nature and quantity of the dietary fat consumed. Increases in dietary cholesterol and saturated fat produced small increases in plasma cholesterol and saturated triacylglycerols, while unsaturated dietary fat produced small decreases in saturated and increases in unsaturated plasma triacylglycerols. These changes in the plasma lipid parameters are consistent with those observed previously in much more limited dietary experiments with accurately known composition of ingested fats. It is, therefore, concluded that direct gas chromatographic profiling of plasma total lipids provides a simple and rapid method of verifying the overall correctness of the dietary recall.
Adult↗