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Biomedical subjects

J A Little

Publications and source records attributed to J A Little.

At least 19 recordsLinked to original sources
PubMed1995

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↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1993

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↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1991

5'-flanking sequences mediate butyrate stimulation of embryonic globin gene expression in adult erythroid cells.

A stable transfection assay was used to test the mechanism by which embryonic globin gene transcription is stimulated in adult erythroid cells exposed to butyric acid and its analogs. To test the appropriate expression and inducibility of chicken globin genes in murine erythroleukemia (MEL) cells, an adult chicken beta-globin gene construct was stably transfected. The chicken beta-globin gene was found to be coregulated with the endogenous adult mouse alpha-globin gene following induction of erythroid differentiation of the transfected MEL cells by incubation with either 2% dimethyl sulfoxide (DMSO) or 1 mM sodium butyrate (NaB). In contrast, a stably transfected embryonic chicken beta-type globin gene, rho, was downregulated during DMSO-induced MEL cell differentiation. However, incubation with NaB, which induces MEL cell differentiation, or alpha-amino butyrate, which does not induce differentiation of MEL cells, resulted in markedly increased levels of transcription from the stably transfected rho gene. Analysis of histone modification showed that induction of rho gene expression was not correlated with increased bulk histone acetylation. A region of 5'-flanking sequence extending from -569 to -725 bp upstream of the rho gene cap site was found to be required for both downregulation of rho gene expression during DMSO-induced differentiation and upregulation by treatment with NaB or alpha-amino butyrate. These data are support for a novel mechanism by which butyrate compounds can alter cellular gene expression through specific DNA sequences. The results reported here are also evidence that 5'-flanking sequences are involved in the suppression of embryonic globin gene expression in terminally differentiated adult erythroid cells.

Acetylation↗
PubMed1991

A hepatic lipase gene mutation associated with heritable lipolytic deficiency.

Absent hepatic lipase (HL) activity results in dyslipidemia and premature atherosclerosis. DNA sequencing of the HL gene from subjects with heritable HL deficiency identified a new C to T substitution within exon 8 that in the mature enzyme caused a threonine to methionine change at position 383 (T383M). With a rapid DNA detection method we observed that all 6 individuals with complete HL deficiency from 2 families had the T383M mutation. None of 50 random unrelated unaffected subjects had this mutation. We propose that T383M is specific to families with heritable HL deficiency. Furthermore, structural variation at the HL gene, possibly in combination with other factors, appears to be etiologic in HL deficiency.

Adult↗
PubMed1989

Comparisons of specific crosses from Duroc-Landrace, Yorkshire-Landrace and Hampshire-Landrace sows managed in two types of gestation systems: pig performance.

Ten thousand one hundred sixty-nine pigs were farrowed in 844 litters that were produced by mating Duroc (D), Yorkshire (Y) and Hampshire (H) boars to Duroc-Landrace (DL), Yorkshire-Landrace (YL) and Hampshire-Landrace (HL) sows to study the effect of sire breed, dam breeding and gestation environment (pasture lots vs confinement stalls) on pig weights, survival rates and feed efficiency. Pigs sired by H boars were .05 kg heavier at birth than Y-sired pigs and .2 kg heavier at 21 d than Y- and D-sired pigs, but they were .6 kg smaller at 56 d. D-sired pigs grew .028 kg/d faster from 56 d to 100 kg and reached 100 kg approximately 5 d sooner than the Y- and the H-sired pigs. At birth, pigs out of DL sows were .21 kg heavier than pigs out of YL sows. Pigs out of HL sows grew .025 and .021 kg/d slower from 56 d to 100 kg compared with pigs out of DL and YL sows, respectively. Sows in the pasture gestation system produced pigs that were .05 kg heavier at birth than pigs out of sows in gestation stalls. Three-breed-cross pigs were .9 kg heavier at 56 d, grew .039 kg/d faster and took 7.9 fewer days to reach 100 kg than backcross pigs. The H sire breed had lower survival rates of pigs at 21 d and to 100 kg of those born alive (P less than .10), compared with pigs sired by D and Y boars. Pigs out of HL dams had the highest survival rates, whereas pigs out of YL sows had the lowest survival rates at birth, 21 d and at 100 kg. Three-breed-cross pigs averaged .025, .028 and .035 greater survival rates at birth, 21 d and 56 d than backcross pigs. Feed efficiency was most desirable in pens of pigs sired by H and D boars compared with pens of pigs sired by Y boars. However, pens of pigs with YL dams were more efficient than pens of pigs with HL dams.

Animals↗
PubMed1988

The beta very low density lipoprotein present in hepatic lipase deficiency competitively inhibits low density lipoprotein binding to fibroblasts and stimulates fibroblast acyl-CoA:cholesterol acyltransferase.

Beta very low density lipoprotein (VLDL) was isolated from a patient with hepatic lipase deficiency. The particles were found to contain apolipoprotein B-100 (apoB) and apolipoprotein E (apoE) and were rich in cholesterol and cholesteryl ester relative to VLDL with pre beta electrophoretic mobility. These particles were active in displacing human low density lipoprotein (LDL) from the fibroblast apoB,E receptor and produced a marked stimulation of acyl-CoA:cholesterol acyltransferase. Treatment of intact beta-VLDL with trypsin abolished its ability to displace LDL from fibroblasts. Incubation of trypsin treated beta-VLDL with fibroblasts resulted in a significant stimulation of acyl-CoA:cholesterol acyltransferase activity. beta-VLDL isolated from a patient with Type III hyperlipoproteinemia and an apoE2/E2 phenotype had a higher cholesteryl ester/triglyceride ratio than the beta-VLDL of hepatic lipase deficiency and contained apoB48. It displaced LDL from fibroblasts to a small but significant extent. The Type III beta-VLDL stimulated acyl-CoA:cholesterol acyltransferase to a level similar to that of trypsin-treated beta-VLDL isolated from the hepatic lipase-deficient patient. These results demonstrate that the cholesterol-rich beta-VLDL particles present in patients with hepatic lipase deficiency are capable of interacting with fibroblasts via the apoB,E receptor and that this interaction is completely due to trypsin-sensitive components of the beta-VLDL. These particles were very effective in stimulating fibroblast acyl-CoA:cholesterol acyltransferase. This stimulation was due to both trypsin-sensitive and trypsin-insensitive components.

Apolipoproteins↗
PubMed1988

A alpha and A beta class II I-A determinants of antigen-specific T-helper factor and its antigen-nonbinding chain.

Antigen-specific T-helper factor (ThF) of CBA (H-2k) origin in the picryl (TNP) contact sensitivity system (Mr 60-70 kDa) was reduced with dithiothreitol under mild conditions. Affinity chromatography on antigen yielded an antigen-binding chain (Mr 20-30 kDa) and an antigen-nonbinding chain (Mr 40-50 kDa). Both chains were glycoproteins and were bound by lentil lectin. Affinity chromatography on anti-I-A monoclonal antibodies showed that I-A determinants occurred on the complete molecule and on the antigen-nonbinding, but not on the antigen-binding, chain. In contrast, five different monoclonal antibodies to I-E alpha failed to absorb ThF. Moreover, the complete molecule and the I-A+ antigen-nonbinding chains had determinants of the alpha and beta chains of I-A and conformational determinants which are based on both chains. Sequential absorption and elution showed that A alpha and A beta determinants occurred on the same molecular complex. These data suggest a minimal model of ThF as a two-chain disulfide-bonded structure with an antigen-binding chain and a separate I-A+ antigen-nonbinding chain which behaves as a single unit in phosphate-buffered saline and has elements of both A alpha and A beta.

Animals↗
PubMed1988

Coronary prevention and regression studies updated.

There have been a multitude of clinical, animal and epidemiology studies which prove that high serum cholesterol and low density lipoprotein (LDL) cholesterol concentrations are specific causes of coronary artery disease (CAD). Although the variations in experimental design make comparisons difficult, the aggregate results of many human prevention trials since 1960 lead to the definite conclusion that a 10% lowering of serum cholesterol reduces the risk of CAD by one-sixth. Recently, other factors for CAD risk have been identified that will be useful in guiding treatment, namely serum high density lipoprotein (HDL) cholesterol, apolipoproteins B and AI, HDL triglycerides and phosphatidylcholine to free cholesterol ratio. Studies have shown that aggressive drug and diet therapy slows progression and causes regression of atheromas. Primary prevention of CAD is obviously preferable to secondary prevention. Also, the evidence to date indicates that prevention of CAD through lifestyle changes should begin in childhood.

Cholesterol↗
PubMed1987

Structure of apolipoprotein C-IIToronto, a nonfunctional human apolipoprotein.

We previously reported a family with apolipoprotein C-II (apoC-II) deficiency characterized by the presence of a mutant apoC-II, apoC-IIToronto. We now report the purification and primary structure of apoC-IIToronto. The sequence of apoC-IIToronto is identical to that of normal apoC-II from residues 1-68. It differs from residue 69, where Asp69-Gln70-Val71-Leu72-Ser73-Val74- Leu75-Lys76-Gly77-Glu78-Glu79 is replaced by Thr69-Lys70-Phe71-Phe72-Leu73-Cys74. This is consistent with the deletion of a nucleotide in the codon for either Thr68 or Asp69 and a translation reading frame shift.

Amino Acid Sequence↗