Biomedical subjects
J A Little
Publications and source records attributed to J A Little.
The inheritance of sinking-pre-beta lipoprotein and its relation to the Lp(a) antigen.
We have investigated the genetics of plasma sinking-pre-beta lipoprotein (sp beta) as determined by the method of Breckenridge and Maguire, using several approaches: (i) a population study, (ii) a twin study and (iii) the use of family data. In addition, by the use of split samples, the sp beta level as determined by us was correlated with Lp(a) typing carried out in Oslo by Dr. Kåre Berg. Although the sp beta level is a continuous character, the results clearly showed it to be to a considerable extent under the control of the major autosomal gene pair constituted by the alleles Lpa and Lp, which mainly control the production of the Lp(a) antigen, Lpa being dominant. In our data the boundary between the LpLp and LpaLp genotypes appeared to fall between the sp beta 2 and 3 mg% levels, while that between LpaLp and LpaLpa was in the 15 mg% region. These boundaries, which were inferred from both typing and population statistics, received good confirmation from the family data. It appears that some 88% of the variation in sp beta level is directly ascribed to segregation of Lpa and Lp. On the basis of the twin study and other data, we conclude that the residual observed variation in sp beta is almost entirely ascribed to analytical error of determination and polygenic effects, the influence of environment being negligible. The heritability is close to 100%.
Recruitment from medical referrals and clinical laboratories.
Medical referrals represent a recruitment source with a relatively low volume of initial contacts and entries and a high ratio of entries to initial contacts, while referrals from clinical laboratories comprise a relatively moderate volume of initial contacts, a low volume of entries and a moderate ratio of entries to initial contacts. Both sources require a relatively low effort level for the recruitment team. In the CPPT, all centers used these strategies, to provide, overall, 3% of initial contacts, 8% of first protocol visits and 10% of entries. Unwillingness to participate at the first protocol visit excluded less than one-half as many medical referrals as was observed for all sources, while referrals from clinical laboratories were excluded due to unwillingness to participate much more frequently than the all-source mean. Low yields preclude reliance on these sources for any but the smallest clinical trial.
Lipid class and molecular species interrelationships among plasma lipoproteins of normolipemic subjects.
As evidence of lipoprotein interconversion and/or equilibration, a gas-liquid chromatographic (GLC) examination was made of the lipid class and molecular species interrelationships among the major fasting plasma lipoprotein fractions within each of seven male and four female normolipemic subjects subsisting on free choice diets. The lipoprotein fractions were prepared by conventional ultracentrifugation and the lipid class and molecular species composition of the corresponding lipoprotein fractions were determined by GLC of the intact cholesterol and glycerol esters and of ceramides. In general, each lipoprotein fraction possessed a well defined lipid class composition, which was characterized by a dramatically decreasing triacylglycerol and an increasing phospholipid and cholesteryl ester content when progressing from the very low (VLDL), to the low (LDL2) and high (HDL) density lipoproteins, as already established by conventional analyses. However, the LDL2 contained about a two times higher proportion of total phospholipids as sphingomyelin than VLDL and HDL. Furthermore, the sphingomyelins of the HDL fraction contained about 30% more of the higher molecular weight species than the sphingomyelins of either VLDL or LDL. Smaller differences were seen in the molecular species composition of the phosphatidylcholines, cholesteryl esters and triacylglycerols among the corresponding fractions of lipoproteins. In general, the lipid class and molecular species distribution is incompatible with the hypothesis which postulates VLDL conversion into LDL and HDL under the influence of lipoprotein lipase and lecithin:cholesterol acyltransferase. The significant differences noted in the lipid class and molecular species distribution suggest that the true transformations of the lipoproteins are much more complex and may also involve cholesteryl ester-triacylglycerol, triacylglycerol and phosphatidylcholine exchanges via appropriate carrier plasma proteins, as well as possible phase separation of lipids during the removal of the excess surface material from the VLDL remnants, as already demonstrated in in vitro experiments. It is concluded that a direct GLC analysis of the neutral and polar lipid components of plasma lipoprotein classes provides important evidence of lipoprotein interrelationships which may be utilized to test existing and new hypotheses of lipoprotein interconversion.
Differential distribution of sphingomyelins among plasma lipoprotein classes.
Individual and pooled samples of plasma from normolipemic and hyperlipemic subjects were separated into very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein fractions (HDL2 and HDL3) by conventional ultracentrifugation and total lipid extracts prepared by standard methods. The composition of the molecular species of the sphingomyelins in each lipoprotein class was determined by packed column and capillary gas-liquid chromatography of the trimethylsilyl (TMS) and t-butyldimethylsilyl (t-BDMS) ethers and by gas chromatography - mass spectrometry of t-BDMS ethers of ceramides derived by phospholipase C hydrolysis of the corresponding parent compounds. It was demonstrated that the molecular weight of the species of the sphingomyelins increases with the density of the lipoprotein fraction in normolipemic subjects, and that this increase is due to an increase in the chain length of the fatty acids in the ceramide molecules. In contrast, patients with type IV hyperlipoproteinemia possessed similar species in the LDL and HDL fractions, while maintaining normal differences between HDL and VLDL. Type III patients possessed normal HDL and VLDL differences, but had variable LDL. Type II patients had ceramide profiles for VLDL, LDL, and HDL fractions that were very similar to those of normals. The differential distribution of the molecular species of the sphingomyelins is rationalized on the basis of a lateral phase separation of the short and long chain sphingomyelins during the shedding of the excess VLDL or chylomicron surface material and a subsequent preferential transformation of the long chain species into HDL. The LDL sphingomyelins in type III hyperlipemia are variable and approximate either the VLDL or HDL composition.
Comparisons of specific crosses from Landrace, Duroc-Landrace and Yorkshire-Landrace sows.
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Comparative determination of plasma phospholipids by automated gas--liquid chromatographic and manual colorimetric phosphorus methods.
Plasma samples obtained during a prevalence study of hyperlipemia in a free-living urban population were analyzed for phosphatidylcholine, sphingomyelin and lysophosphatidylcholine content by automated high-temperature gas--liquid chromatographic (GLC) and manual colorimetric phosphorus (thin-layer chromatographic, TLC) methods. The GLC estimates were obtained from a quantitative analysis of the diacylglycerol, ceramide and monoacylglycerol moieties released from the parent phospholipids by digestion with phospholipase C, while the TLC estimates were derived by manual colorimetric phosphorus analyses of the individual phospholipid classes resolved by TLC. On samples analyzed over a two-year period the methods gave excellent correlation for the total phospholipids (r = 0.98), phosphatidylcholine (r = 0.98) and sphingomyelin (r = 0.90), but resulted in a poor agreement for lysophosphatidylcholine (r = 0.69). Comparable results were obtained for estimates of these phospholipids in plasma very low density, low density and high density lipoproteins. The between-method coefficient of variation ranged from 3 to 5% for phosphatidylcholine and from 5 to 10% for sphingomyelin. The relative error for the estimates of lysophosphatidylcholine ranged from 10 to 25%, and was due to the inclusion in the GLC estimates of a variable proportion of plasma free monoacylglycerols. Other differences between the two methods are due to various analytical errors and biases inherent in the two techniques. The within-day, within GLC, relative error averaged 1% for phosphatidylcholine, 3% for sphingomyelin and 5% for lysophosphatidylcholine. The apparent high precision and accuracy of the GLC method recommend it as an alternative to conventional direct methods of phospholipid analyses based on TLC isolation of lipid classes and colorimetric measurements of their phosphorus content. The GLC analyses of the plasma phospholipids are particularly convenient in conjunction with GLC measurements of plasma cholesterol and triacylglycerols, where a smaller throughput of samples is not a limitation and where both total amount and relative proportion of the lipids are of interest.
Plasma lipoprotein levels and the prevalence of hyperlipoproteinemia in a Canadian working population.
The lipids and lipoproteins - cholesterol (C), triglyceride (TG) and high-density, low-density, very-low-density and sinking pre-beta-lipoprotein cholesterol (HDL-C, LDL-C, VLDL-C and SPB-C) - in plasma samples from 1620 fasting white adults and children from the Toronto-Hamilton area were analysed. The mean concentration of HDL-C was about 45 mg/dl in men and about 60 mg/dl in women, and the levels were constant throughout adult life in both sexes. Boys had higher mean HDL-C levels than men, but girls had lower mean HDL-C levels than women. Mean LDL-C levels, like total C levels, increased with age, from about 87 mg/dl in boys to 136 mg/dl in men, and from about 91 mg/dl in girls to 145 mg/dl in women. The mean levels of VLDL-C followed the TG patterns for age and sex, rising from about 7 mg/dl in boys to 26 mg/dl in men, and from about 11 mg/dl in girls to 19 mg/dl in women. SPB-C was detectable visually in 39% of the population and with the aid of densitometry in 54%; the levels were not related to age, sex or oral contraceptive use, and the median level was 3 mg/dl.Prevalence estimates of hyperlipoproteinemia showed that type IV was the most common, and it was found more than three times as often in men as in women. This was in part due to the customary use of plasma TG cut-off points that do not reflect the large difference in TG levels between males and females. Type IIA hyperlipoproteinemia was found in about 2% of the adults and type IIb in a further 1%. Types I, III and V were all rare. The prevalence of types II and IV hyperlipoproteinemia was four times greater in women using oral contraceptives than in nonusers in the same age range.
Associations of plasma high-density lipoprotein cholesterol with clinical chemistry data.
We examined data from the participants in the Lipid Research Clinics Program Prevalence Study for associations between high-density lipoprotein (HDL) cholesterol and clinical chemistry tests. There is a negative relationship between serum thyroxine and HDL cholesterol: men 20-69 years and women 20-44 years with low thyroxine levels have significantly higher HDL cholesterol than those with high thyroxine levels. Women 45-69 years with hyperglobulinemia (> 3.2 g/dl) have significantly lower HDL cholesterol levels than those with lower globulin levels. There is a weak negative association between HDL cholesterol and serum uric acid in men 20-44 years and a stronger association in women. A weak negative association between HDL cholesterol and plasma glucose is present only in men 20-44 years and women 45-69 years. Subjects with high serum bilirubin or serum aspartate aminotransferase (AST, SGOT) values have higher HDL cholesterol levels that are statistically significant in men 20-69 years and women 20-44 years (bilirubin) and men 45-69 years and women 45-69 years (AST). There is a negative association between alkaline phosphatase and HDL cholesterol in women and young men. These results suggest that thyroid hormones may be involved in the regulation of HDL cholesterol, and that there are associations between HDL cholesterol and the clinical chemistry tests that are not necessarily explained by disease. However, in the whole population, the plasma constituents measured as clinical chemistry tests, or the mechanisms that regulate their levels, are not important determinants of plasma HDL cholesterol levels.
The association of plasma high-density lipoprotein cholesterol with dietary intake and alcohol consumption. The Lipid Research Clinics Prevalence Study.
We examined the associations of diet and alcohol consumption with levels of high-density lipoprotein (HDL) cholesterol using cross-sectional data from 4855 white participants, ages 20 years and older, seen at visit 2 of the Lipid Research Clinics Prevalence Study. There was a strong positive gradient of HDL cholesterol levels with reported amount of alcohol intake in both men and women, regardless of type of alcoholic beverage consumed. We found a difference in HDL cholesterol levels between the two groups of participants who reported no alcohol consumption during the past week. Those who said that they never drank had lower mean HDL cholesterol levels than those who reported that they did drink but had not consumed any alcohol during the past week. Weaker inverse relations (p < 0.05) were found between HDL cholesterol levels and intakes of total carbohydrate sucrose and starch (percent calories and grams). Dietary saturated, monounsaturated and polyunsaturated fat intakes were unrelated to HDL cholesterol levels; similarly, no association was seen for HDL cholesterol and total calories and total fat. Cholesterol intake (mg and mg/1000 calories) was generally unrelated to HDL cholesterol levels, except in women not taking exogenous gonadal hormones.
Lipolysis of ApoC-II deficient very low density lipoproteins: enhancement of lipoprotein lipase action by synthetic fragments of apoC-II.
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Nature of the familial influence on plasma lipid levels.
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Pathogenesis of acidosis in hereditary fructose intolerance.
An 18-yr-old man with a classical history of hereditary fructose intolerance (HFI) developed typical biochemical changes following an oral fructose load: fructosemia, hypoglycemia, hypophosphatemia, hyperuricemia, and metabolic acidosis. Hypokalemia (3.1 meq/liter) was also noted. Three aspects of this case expand the published literature on this syndrome: (1) Metabolic acidosis was found to be due to both lactic acidosis and proximal renal tubular acidosis (RTA). We could quantitate the relative contribution of each, and found that urinary bicarbonate loss due to proximal RTA accounted for less than 10% of the fall in serum bicarbonate. The major cause of the metabolic acidosis was lactic acidosis. (2) Hypokalemia was found to be due to movement of potassium out of the extracellular space rather than to urinary loss. Potassium may have entered cells with phosphate or may have been sequestered in the gastrointestinal tract. (3) The coexistence of proximal RTA and acidemia made it possible to study the effect of acidemia on the urine-blood partial pressure of carbon dioxide (PCO2) gradient in alkaline urine (U-B PCO2). The U-B PCO2 measured during acidemia was much higher at the same urine bicarbonate concentration than in normal controls during alkalemia, providing evidence in humans that acidemia stimulates distal nephron hydrogen-ion secretion.
Sources of variance in 24-hour dietary recall data: implications for nutrition study design and interpretation.
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Inheritance of apolipoprotein C-II deficiency with hypertriglyceridemia and pancreatitis.
A study of the relatives of a patient with apolipoprotein C-II deficiency showed that the defect is inherited as an autosomal recessive trait. The kindred studied originated from an isolated population in which considerable inbreeding has occurred for 140 years. Seven homozygotes had marked fasting chylomicronemia and triglyceridemia, and lacked detectable apolipoprotein C-II by several assay methods. Five homozygotes had experienced one to many attacks of pancreatitis from as early as six years of age. Obligate heterozygotes had apolipoprotein C-II concentrations about 30 to 50 per cent of normal values and had normal plasma triglyceride concentrations. This metabolic defect should be considered in patients with markedly elevated plasma triglycerides who have apparent lipoprotein lipase deficiency, and usually also have pancreatitis.
Comparative determination of plasma cholesterol and triacylglycerol levels by automated gas--liquid chromatographic and autoanalyzer methods.
Plasma samples obtained during a prevalence study of hyperlipemia in a free living urban population were analyzed for total cholesterol and triacylglycerol content by automated high-temperature gas--liquid chromatographic (GLC) and automated colorimetric (Auto-Analyzer, AA11) methods. The analyses were done over a three-year period. The methods gave excellent overall correlation for both total cholesterol (r = 0.9811) and total triacylglycerols (r = 0.9739). Detailed comparisons of the results obtained by the two methods with natural samples over the entire concentration range, indicated that the GLC method gave cholesterol values 5--10 mg% lower and triacylglycerol values 10--20 mg% lower than the corresponding AA11 determinations. The differences between the two methods are attributed to an overestimation of the cholesterol and triacylglycerol levels by the AA11 method due to presence of variable amounts of interfering chromogens in the plasma extracts. The between-method relative error ranged from 3 to 5% for cholesterol and from 5 to 10% for triacylglycerols. The within-day standard deviation of GLC averaged 2.3 mg% for cholesterol and 3.5 mg% for triacylglycerols. The between-day standard deviation of the GLC method averaged about 6 mg% for both cholesterol and triacylglycerols. The within-day, within GLC, relative error averaged 1.12% for cholesterol and 2.66% for triacylglycerols. The apparent high precision and high accuracy of the GLC method recommend it as an alternative to the indirect methods of plasma cholesterol and triacylglycerol analysis, especially where a smaller throughput of samples is not a limitation and where both total amount and composition of the lipids is of interest.
Hypertriglyceridemia associated with deficiency of apolipoprotein C-II.
A 59-year-old man with severe hypertriglyceridemia and no post-heparin lipolytic activity was studied because of a marked fall in plasma triglyceride concentrations after a blood transfusion. An apolipoprotein activator (apolipoprotein C-II) for lipoprotein lipase could not be detected by polyacrylamide-gel electrophoresis of apoproteins, immunodiffusion of the plasma against anti-apolipoprotein CII or activation assays for lipoprotein lipase. Furthermore, the patient's triglyceride-rich lipoproteins would not serve as substrate for lipoprotein lipase. The patient had latent post-heparin lipolytic activity, which appeared after the addition of apolipoprotein CII to the post-heparin plasma. After a transfusion of 1 unit of plasma from a normal subject the patient's plasma triglycerides fell, within one day, from 1000 to 250 mg per deciliter and remained below preinfusion concentrations for six days. We conclude that this patient's hyperlipoproteinemia resulted from a deficiency of apolipoprotein C-II.