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Biomedical subjects

A C Nestruck

Publications and source records attributed to A C Nestruck.

At least 19 recordsLinked to original sources
PubMed1998

Safety and immunogenicity of a new influenza vaccine grown in mammalian cell culture.

In a phase I safety and immunogenicity study, 112 healthy adult volunteers were randomly allocated to receive a new bivalent (A/Texas/36/91[H1N1-like], B/Harbin/7/94) split virion influenza vaccine propagated in Madin-Darby Canine Kidney cell culture or an identical vaccine manufactured using currently licensed egg propagated virus technology. Soreness at the injection site was common but generally mild (75% of the cell culture-derived vaccine group and 62.5% of the egg-derived vaccine group; p = not significant). General reactions were less common; headache was the most frequently reported adverse effect (26.8 and 30.4%, respectively; p = not significant). Geometric mean haemagglutination inhibition titres post-immunization against the A/Texas strain were 1012 reciprocal dilution in the cell culture-derived vaccine group and 790 in the egg-derived vaccine group; against the B/Harbin strain titres were 420 and 447, respectively (all comparisons, p = not significant). It is concluded that the cell culture-derived split virion influenza vaccine is safe and immunogenic in healthy adult volunteers.

Adolescent↗
PubMed1991

Characterization of a new apolipoprotein E5 variant detected in two French-Canadian subjects.

We have found a novel apoE5 mutation, using isoelectric focusing (IEF), in two apparently unrelated French-Canadian subjects. Co-dominant inheritance was demonstrated in the family of the first proband, a healthy male subject. The presence of the apoE5 form was not associated with lipid abnormalities or cardiovascular disease in this family. The second proband was a hyperlipidemic female patient suffering from angina, with no informative relatives available for study. In both individuals, monoclonal antibody studies demonstrated that the mutation was associated with the loss of two overlapping epitopes at the amino terminus of the protein. Cysteamine treatment of the very low density lipoproteins indicated that the mutant apoE contained only one cysteine residue, suggesting that apoE3 was the parental form. Two-dimensional electrophoresis suggested that the mutated protein had a slightly lower molecular weight (by 1-2 kDa). However, DNA sequencing of the third exon of the apoE gene in both probands revealed a single G to A substitution at the 48th nucleotide, changing the amino acid at position 13 from glutamic acid to lysine. These results were confirmed by oligo melting experiments with allele-specific probes in relatives of the probands. The study of this apoE variant should provide additional insight into the structure-function relationship of apoE.

Adult↗
PubMed1990

Influence of a triphasic oral contraceptive preparation on plasma lipids and lipoproteins.

The influence of a triphasic oral contraceptive preparation on plasma lipid, lipoprotein, and apolipoprotein levels was studied in 20 women during 12 treatment cycles. Multiple blood samples representing all phases of the therapeutic cycle as well as posttherapy were obtained. Total and low-density lipoprotein (LDL) cholesterol fluctuated transiently in the earlier part of the study but after 9 and 12 cycles of therapy did not differ from baseline. Cyclic elevations in total cholesterol corresponding to changes in LDL cholesterol were noted twice. Total high-density lipoprotein (HDL) cholesterol remained remarkably stable over the entire study while HDL2 cholesterol decreased and HDL3 cholesterol increased. Triglycerides (total and lipoprotein fractions) increased during treatment and fell to baseline levels within one posttreatment cycle. Very low-density lipoprotein (VLDL) cholesterol was also elevated during the study. Apolipoprotein (apo) AI, apo AII, and apo B rose under therapy, the latter increase producing a lowered LDL cholesterol/apo B ratio. Apolipoprotein E showed a temporary decrease early in the study but otherwise remained unchanged.

Adolescent↗
PubMed1990

Analytical isoelectric focusing with immobilized pH gradients of human apolipoprotein E from very low density lipoproteins and total plasma.

A method for analytical isoelectric focusing (IEF) of apolipoprotein E (apoE) in immobilized pH gradients (IPG) and immunodetection of the separated isoforms has been developed for use with either very low density lipoproteins (VLDL) or whole plasma. Both VLDL and plasma were sequentially delipidated with 1,4-dioxane, acetone-ethanol, and ether. Neuraminidase treatment preceded the delipidation when required. Using preformed plates, pH 5.0-6.0 (LKB, Bromma) after rehydration with 6 M urea and dextran T-10, the IPG focusing pattern of the common isoforms (E2, E3, E4) was found to be equivalent to conventional IEF with the added resolution of the E4 disialo form. The use of self-poured narrower gradients permitted the further resolution of the E4 monosialo form, a previously unrecognized heterogeneity of the E2, E3, and E4 monosialo isoforms and differentiation of the apoE2** mutant; all of these forms comigrate with the common isoproteins in conventional IEF. Finally, the conditions for IPG of whole plasma using apoE monoclonal antibodies and enzyme-conjugated anti-mouse IgG for detection were established. Thus, IPG focusing is shown to be a powerful method for resolution of the apoE sialoforms and apoE mutant forms. The method has important implications in accurate and diagnostic phenotyping. Moreover, it is a convenient method for phenotyping which requires only very small volumes of plasma.

Apolipoproteins E↗
PubMed1989

Lipoprotein composition changes induced by fenofibrate in dysbetalipoproteinemia type III.

Fenofibrate (300 mg daily) was given to 9 subjects (7 men, 2 women) with dysbetalipoproteinemia type III. The treatment brought about important plasma level reductions in cholesterol (-35%), triglycerides (-56%), VLDL-cholesterol (-63%) and VLDL-triglycerides (-59%). The VLDL-C/TG ratio, which was 0.40 before treatment, was 0.30 after 4 weeks of fenofibrate, still suggestive of type III. LDL-C, when measured by conventional methods, was unchanged but isolation of the IDL (1.006-1.019 g/ml) fraction from the 1.006 g/ml infranatant revealed that true LDL-C levels actually increased in 6 individuals while IDL-C decreased considerably. The total HDL-C increase was mostly due to a 33% HDL3-C change. Apolipoprotein levels were considerably modified, notably apo B, C-III and E which were decreased, as well as the lipoprotein particles containing combinations of these apolipoproteins, namely LpE:B and LpC-III:B. Apo A-I was slightly modified as LpA-I: A-II particle levels increased and LpA-I decreased. There were marked compositional modifications of apo B-containing lipoproteins which corresponded to changes of the whole lipoprotein profile. Some abnormal classes of lipoproteins (e.g., beta-VLDL, dense LDL), characteristic of this disease, tended to disappear and were in some cases replaced by material of different size and density.

Adult↗
PubMed1987

Apolipoprotein E polymorphism and plasma cholesterol response to probucol.

Probucol has been shown to be an effective and well-tolerated cholesterol-lowering drug. However, response in terms of cholesterol reduction has been shown to vary significantly among individuals. The purpose of this study was to assess the role of apolipoprotein E polymorphism in determining this variation. A retrospective study of 89 hypercholesterolemic type II patients who had been treated with probucol (1 g/d) and for whom the apolipoprotein E phenotype was known was carried out. The patients were first grouped into those with heterozygous familial hypercholesterolemia (FH) and those considered to have other forms of hypercholesterolemia (non-FH). Further subclassification of the individuals in both groups as IIa or IIb, allowed the definition of four diagnostic classes, FH IIa or IIb and non-FH IIa or IIb. Among these classes there was no significant heterogeneity for the relationship between response and age or sex. After correction for between-class heterogeneity in duration of probucol treatment, comparison of individuals with the apo E3/3 phenotype with those carrying the epsilon 4 allele showed significant differences in cholesterol reduction both absolute change and percent change. Further contrasts between diagnostic and apo E genotype stratifications of these data showed that the FH patients carrying the epsilon 4 allele had the greatest reduction in cholesterol level.

Adult↗
PubMed1987

Standardization of an enzymometric assay for apolipoprotein A-I by using mixtures of monoclonal antibodies).

For the standardization of human plasma apolipoprotein A-I assay two well characterized monoclonal antibody mixtures were used to develop a sandwich immunoenzymometric assay. The monoclonal antibody mixture 1 (A05-A17-A30) in solid phase technique was selected on the basis of its higher binding capacity of [125I]HDL (41 ng per well) compared to polyclonal antibody (23 ng per well). The epitopes recognized by monoclonal antibody mixture 1 are surface antigenic sites of apolipoprotein A-I expressed on native HDL as determined by competitive inhibition of labeled HDL. The peroxidase conjugated monoclonal antibody mixture 2 (A03-A05-A17-A51) was selected on the basis of its ability to bind to apolipoprotein A-I captured by monoclonal antibody mixture 1. For this, we used the 125I-labeled monoclonal antibodies. Under optimized assay conditions, the immunoenzymometric assay is precise (intra- and inter-assay coefficients of variations 5.4% and 9.2% respectively). It yields plasma apolipoprotein A-I values that correlate highly with those obtained with polyclonal antibody (r = 0.96). So the use of well characterized monoclonal antibody mixtures reacting only to surface antigenic sites of apolipoprotein A-I present on native lipoprotein may provide the possibility of standardization of apolipoprotein A-I measurement.

Antibodies, Monoclonal↗
PubMed1986

Severe hypoalphalipoproteinemia induced by a combination of probucol and clofibrate.

Observation of a markedly depressed HDL-cholesterol (5 mg/dL) in a patient with familial hypercholesterolemia (FH) receiving probucol (1 g/day) and clofibrate (2 g/day) prompted a review of all cases treated by this combination at our lipid clinic. Hypoalphalipoproteinemia (HDL-C less than 15 mg/dL) developed in 19 of 28 (70%) hyperlipidemic subjects who received this combination for an average of 1.5 years. This effect was sustained and reversible; it did not occur on either drug alone and was manifested on average 17 weeks after the combination was started. Plasma triglycerides increased significantly in most of those patients susceptible to this reduction in HDL-C. Plasma apolipoprotein A-I was decreased 82%, in proportion to the HDL-C fall, whereas apo A-II was lowered 65%. Since apo C-III concentrations tended to be high, the apo A-I/C-III ratio was markedly depressed. Apo E levels were unchanged and apo B levels reflected the high LDL concentrations of the underlying disease. An intermediate response was observed in subjects whose HDL-C remained well above 15 mg/dL on the combination. No deleterious side-effects could be attributed directly to the administration of the combined drugs in this high-risk group. One patient actually showed complete regression of xanthelasma and extensor tendon xanthomas of the finger on the combination. A parallel is drawn with Fish-Eye disease and the presence of the apolipoprotein A-I Milano variant, where similar HDL-C levels are observed in the absence of an increased atherogenic risk. It is mandatory to monitor plasma HDL-C in hypercholesterolemic patients treated with this combination, otherwise the pronounced HDL-deficiency could go unnoticed.

Apolipoproteins↗
PubMed1986

Effect of indomethacin treatment on prostaglandin excretion and tissue phospholipid fatty acid composition in rats bearing mammotropic pituitary tumor, MtT-F4.

The hypothesis that hormonal changes induced by the mammotropic pituitary tumor, MtT-F4, might accelerate the conversion of n-6 fatty acids to prostaglandins, resulting in a partial depletion of n-6 fatty acids was examined. In tumor-bearing rats, the administration of indomethacin induced a 50% reduction of the urinary prostaglandin levels, but exerted no significant effect on the fatty acid composition of the tissue phospholipids. It is concluded that the observed depletion of n-6 fatty acids in tumor-bearing rats is not caused by an increased production of prostaglandins.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Risks for hyperlipidemia.

The predisposition for the development of hyperlipidemia rests almost equally on genetic and environmental factors and their interplay. Because one of the least understood factors is the duration of exposure to risk, the authors have chosen to review here some of the genetic factors and some of the relatively long-term environmental factors, such as diet and drug therapies, that are known to increase the risk of hyperlipidemia and likely the predisposition to cardiovascular disease.

Adrenergic beta-Antagonists↗
PubMed1986

Tendon xanthomas associated with cholestanolosis and hyperapobetalipoproteinemia.

Large Achilles tendon xanthomas of the type found in severe familial hypercholesterolemia were the first manifestation of cholestanolosis (cerebrotendinous xanthomatosis) in our patient, an otherwise asymptomatic normolipidemic 21-year-old woman. Extensive laboratory investigation disclosed the presence of hyperapobetalipoproteinemia which did not resolve with the administration of probucol. Immunofluorescent studies revealed marked accumulation of apolipoprotein B in a xanthoma excised from the tricipital area. This was in contrast to the spotty and weak fluorescence observed in a tuberous xanthoma, from the same anatomical area and histologically otherwise identical, obtained from a patient with heterozygous familial hypercholesterolemia. Hyperapobetalipoproteinemia has been reported before in association with sitosterolemia but not with cholestanolosis. We suggest that cholestanol, like sitosterol, may interfere with the normal uptake and degradation of low-density lipoproteins by peripheral cells.

Adult↗
PubMed1985

Plasma carnitine and lipid-lowering drugs.

Oral carnitine has been reported to have a lipid-lowering effect with concomitant elevation of high density lipoprotein cholesterol (HDL-C) levels in normo- and hyperlipidemic individuals. Unexpectedly, basal carnitine concentrations were found to be abnormally high in subjects receiving a combination of probucol (1 g/day) and clofibrate (2 g/day), and who also had reduced HDL-C levels. Changes in plasma carnitine levels were found to correlate with clofibrate therapy and to be readily reversible with cessation of this drug. These increases of circulating carnitine were not accompanied by a rise in HDL-C.

Carnitine↗
PubMed1984

Distribution of apolipoprotein E phenotypes in Friedreich's ataxia.

Allelic polymorphism at the apolipoprotein E (apo E) gene locus (alleles epsilon 2, epsilon 3, and epsilon 4) is responsible for the existence of 6 discrete electrophoretic phenotypes of plasma apo E. Since the presence of the epsilon 2 allele in the genotype tends to be associated with higher triglyceride levels, a study was undertaken to determine if a higher frequency of this allele could account for the presence of higher plasma triglycerides in subsets of patients with Friedreich's Ataxia. The frequency of the apo E phenotypes was determined in 37 subjects with Friedreich's Ataxia and compared with that of 102 normolipidemic and 102 hyperlipidemic individuals. There was no increased prevalence of the E3/2 phenotype and the epsilon 2 allele in the Friedreich's sample as is found in a hyperlipidemic sample. Furthermore, the epsilon 2 subset did not have significantly higher plasma triglycerides than the non-epsilon 2 subset and the hypothesis was rejected. On the other hand, there was a trend for a decreased frequency of the E4/3 phenotype in the Friedreich's sample relative to the hyperlipidemic group but the difference did not reach statistical significance. The apo E phenotype distribution was also measured in a smaller sample of Charlevoix-Saguenay disease; this led to the discovery of two siblings with the relatively rare E2/2 phenotype and unexpectedly low levels of plasma lipid and lipoprotein concentrations. Plasma apolipoprotein E concentrations in both diseases were within the normal range except for subjects bearing the E2/2 phenotype.

Adolescent↗
PubMed1984

Plasma cholesteryl sulfate in Friedreich's ataxia.

Alteration of membrane fluidity and anomalies of membrane structural proteins have been suspected in Friedreich's ataxia. Plasma lecithin:cholesterol acyltransferase (LCAT) activity is also lowered in this disease, presumably because of a substrate effect. The membrane-stabilizing effect of cholesteryl sulfate (CS) and its inhibitory effect on LCAT activity prompted us to measure this substance in the plasma of Friedreich's ataxia patients as well as in normal subjects and in patients with Charlevoix-Saguenay disease. Plasma cholesteryl sulfate concentrations were significantly higher in Friedreich's ataxia, with levels above the upper limit of normal in nearly half of the cases. This increase was unrelated to age, sex or plasma cholesterol levels, but closely associated with the severity of the disease and thus considered to be secondary. A similar phenomenon (except the association with severity) was observed in Charlevoix-Saguenay ataxia. Levels also tended to be higher in first-degree relatives of Friedreich cases. The significance of these findings is discussed in the light of recent knowledge and experimental data obtained in this laboratory on rats made deficient in essential fatty acids. The highest concentrations of CS observed in Friedreich's ataxia (1097 micrograms/dL, 6 times the normal mean) was only 25% as high as the concentrations reported to inhibit LCAT activity.

Adolescent↗
PubMed1983

Chromatofocusing of human high density lipoproteins and isolation of lipoproteins A and A-I.

Using chromatofocusing, a column chromatography method with an internally generated pH gradient and focusing effects, human plasma high density lipoproteins (HDL) were fractionated into six subclasses within an interval of less than 1 pH unit (pH 5.1-4.2). All fractions floated in the ultracentrifuge at density = 1.21 g X ml-1, retained a typical HDL electron micrographic morphology and as a single band, alpha-migration on agarose electrophoresis. Compositional analysis of the subclasses revealed an inverse relationship between cholesterol ester and cholesterol on a molar basis. Distinct differences in the distribution of the apolipoproteins between the fractions were found. Two of the subclasses contained only apolipoprotein A-I and were therefore considered to be two forms of the lipid-combined form of apolipoprotein A-I, i.e., lipoprotein A-I. One subclass contained only apolipoproteins A-I + A-II and was, therefore, lipoprotein A. One subclass contained apolipoproteins A-I + A-II + D, and the two remaining contained additionally apolipoproteins C and E. Lipoprotein A-I was also demonstrated after immunoabsorption of apolipoprotein A-II-containing lipoproteins from whole serum. It is suggested that this method, which allows the fractionation of HDL into subclasses with distinct differences in apolipoprotein composition, offers new avenues for the study of the structural and metabolic heterogeneity of HDL.

Apolipoprotein A-I↗
PubMed1980

Studies on the polymorphism of human apolipoprotein A-I.

Upon preparative isoelectric focussing of human apo-HDL, four major forms of apolipoprotein A-I have been isolated. As identified by the following nomenclature and pI, they comprise: apolipoprotein A-I1, pI 5.62; apolipoprotein A-I2, pI 5.53; apolipoprotein A-I3, pI 5.45; apolipoprotein A-I4 pI 5.36. These forms of apolipoprotein A-I were shown to have identical migration on polyacrylamide gel electrophoresis, molecular weights of 26 000 on sodium dodecyl sulfate gel electrophoresis and a common antigenicity with antisera against apolipoprotein A-I or A-I1. Each form had very similar amino acid compositions with the exception of form apolipoprotein A-I4 which contained one isoleucine residue per mol. All forms but apolipoprotein A-I4 were activators of lecithin:cholesterol acyltransferase, the latter was inhibitory to the reaction. From these results, it was concluded that apolipoprotein A-I1, A-I2 and A-I3 are equivalent forms of apolipoprotein A-I whereas apolipoprotein A-I4 is different or heterogeneous. Upon refocussing, the polymorphs were shown to be stable at their pI and not affected by changes in concentration and by the presence of urea or ampholytes. Exposure of a form of apolipoprotein A-I to alkaline pH partially regenerated the original heterogeneity; however, apolipoprotein A-I4 regenerated from apolipoprotein A-I1 did not contain isoleucine, which further demonstrates form apolipoprotein A-I4 heterogeneity.

Amino Acids↗