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Biomedical subjects

D S Fredrickson

Publications and source records attributed to D S Fredrickson.

At least 55 records · Page 3Linked to original sources
PubMed1975

The pathology of Tangier disease. A light and electron microscopic study.

Tangier disease (deficiency of high density plasma lipoproteins) is characterized clinically by: low levels of plasma cholesterol; enlarged, orange-yellow to yellow-gray tonsils and, frequently, peripheral neuropathy. Histologic and ultrastructural studies were made of various tissues from 5 patients with Tangier disease, and comparisons were made of these findings with those in the 12 other patients thus far known to have this disease. Deposits of cholesteryl esters were found in: reticuloendothelial cells (foam cells) in tonsils, bone marrow, skin and jejunal submucosa; Schwann cells in peripheral nerves and myenteric plexus; and in nonvascular smooth muscle cells. These deposits appeared electron lucent and intensely birefringent, varied from spherical to crystalline in shape, often were extensively confluent throughout large areas of cytoplasm, and were not limited by membranes. Certain foam cells in bone marrow also contained membrane-limited clusters of lipid particles resembling chylomicrons. The foam cells in Tangier disease differ morphologically from those in numerous lysosomal enzyme deficiency states, particularly Wolman's disease and cholesteryl ester stroage disease, and in proliferative diseases of the reticuloendothelial system in which cholesteryl esters also accumulate in abnormal histiocytes. Morphologic and biochemical data suggest several hypotheses to explain the accumulation of cholesteryl esters in tissues of patients with Tangier disease. Among these hypotheses, the most likely are considered to be the presence in plasma of abnormal lipoprotein particles that are subject to phagocytic removal by reticuloendothelial cells, and the failure of a process that normally removes locally synthesized cholesterol from cells to plasma. (Am J Pathol 78:101-158, 1975)

Adolescent↗
PubMed1975

Accumulation of oxygenated steryl esters in Wolman's disease.

7alpha- and 7beta-hydroxycholesteryl esters, 7-ketocholesteryl esters, and 5,6alpha- and 5,6beta-epoxycholesteryl esters have been identified in tissues of patients affected by Wolman's disease. Their structural identities were determined by mass spectroscopy and nuclear magnetic resonance spectroscopy and confirmed by chemical synthesis. It is postulated that cholesteryl ester hydrolase deficiency in Wolman's disease might lead to accumulation of oxygenated steryl esters in vivo and impairment of bile acid formation.

Adrenal Glands↗
PubMed1974

Familial hypercholesterolemia (one form of familial type II hyperlipoproteinemia). A study of its biochemical, genetic and clinical presentation in childhood.

Primary hyperbetalipoproteinemia (type II hyperlipoproteinemia) is a common disorder associated with premature vascular disease. It is frequently due to genetic abnormalities, some of which are expressed in childhood. We have examined the manner in which that form of hyperbetalipoproteinemia known as familial hypercholesterolemia may be expressed in 236 children aged 1-19 born of 90 matings in which one parent had hyperbetalipoproteinemia of this variety and one parent did not.Two Gaussian populations were fitted to the distribution of both low density lipoprotein cholesterol (C(LDL)) and plasma cholesterol (C) in these children and a likelihood ratio test strongly favored a two over a one population model for both C(LDL) (X(2) = 18.41, P < 0.0005) and C (X(2) = 7.81, P < 0.025). 45% of the children were in the population identified as affected; their mean C(LDL) was 229. The remaining 55% were in the normal population with a mean C(LDL) of 110 which was indistinguishable from that of an unrelated control population, aged 1-19. On the basis of an assumed frequency of hyperbetalipoproteinemia in the general population of 5%, the Edwards' test indicated that a polygenic model of inheritance was highly unlikely (expected, 22%; observed, 45%). The segregation ratio obtained from the derived intersection between the two population curves (C(LDL), 164 mg/100 ml; C, 235 mg/100 ml) was 45/55 (abnormal/normal). The percentage of abnormal children in the first decade (52%) significantly exceeded that in the second (39%) (P < 0.01). The ratios (II/N) were 50/47 and 55/84 in the offspring of affected female and male parents, respectively (X(2) = 3.819, 0.05 < P < 0.10). Only 10% of hyperbetalipoproteinemic children were considered to have hyperglyceridemia. These children, frequently, but not invariably, had a parent with hyperglyceridemia in addition to hyperbetalipoproteinemia (P < 0.05). None of the affected children who were examined had ischemic heart disease (IHD) and 7% had tendon xanthomas. Half of the parents (mean age, 37.4 yr) who were examined had IHD and three-quarters had xanthomas. The data agree well with the hypothesis that hyperbetalipoproteinemia is inherited as a monogenic trait with early expression in these children. More than one genetic defect within the group is not excluded, but retrospective analyses of the 345 first-degree adult relatives of the affected parents indicated that most of the abnormal parents probably represented familial hypercholesterolemia, rather than combined hyperlipidemia, the other most generally recognized form of familial hyperbetalipoproteinemia.

Adult↗
PubMed1974

Selective measurement of two lipase activities in postheparin plasma from normal subjects and patients with hyperlipoproteinemia.

An assay has been developed for specific measurement of two different lipase activities in postheparin plasma. Lipoprotein lipase, derived from extrahepatic sources, is measured as protamine-inactivated lipase activity; hepatic lipase activity is protamine-resistant under the conditions of this assay. In 100 normal subjects, both enzyme activities were noted to be related to age and sex. Protamine-resistant lipase, which comprised 46-95% of the total activity, was highest in men over 18. Protamine-inactivated lipase activity was greatest in younger males and was age-correlated in women, doubling between the second and sixth decades. In 12 patients with hyperchylomicronemia, including five previously shown to have familial type I hyperlipoproteinemia, protamine-inactivated lipase activity was markedly reduced, whereas protamine-resistant lipase was below normal in only 1. The results were not due to lack of plasma activator, presence of plasma inhibitor, or diet, and the deficiency was not overcome by increasing the provoking dose of heparin from 10 U to 75 U/kg. Mean values for both lipase activities were not reduced in 32 other patients with hyperchylomicronemia, nine with "floating beta" lipoproteins (type III hyperlipoproteinemia), and 23 with hyperprebetalipoproteinemia (type IV). Mean protamine-resistant lipase activity was below normal in a group of four women with hypothyroidism, in whom protamine-inactivated lipase was not reduced. Both of the lipase activities were capable of hydrolyzing lipid in very low-density lipoproteins, but the relative rate of hydrolysis of chylomicrons by protamine-resistant lipase was markedly limited. These results indicate the importance of distinguishing between lipases of hepatic and extra-hepatic origin in the measurement of postheparin lipolytic activity.

Adipose Tissue↗
PubMed1973

A comparaive study of the effects of chemical modification on the immunochemical and optical properties of human plasma low-density lipoprotein(s) and apoproteins.

1. The structure of human plasma low-density lipoprotein(s) [LD lipoprotein(s)] was investigated by several immunological and optical techniques. The effects of delipidation and of chemical modification by 3-carboxypropionylation, acetylation, diazotization and amidination were examined. A sensitive double-antibody radioimmunoassay for human LD lipoproteins is presented and is used to assess the extent of immunochemical modification. A computer best-fit analysis is used to analyse circular-dichorism (c.d.) spectra. These methods permit comparisons of the relative effects of chemical modification and delipidation of LD lipoprotein under similar experimental conditions. 2. 3-Carboxypropionylation, acetylation or diazotization produces qualitative and quantitative changes in the immunochemical properties of LD lipoprotein. Amidination causes minor changes detected by radioimmunoassay but not by double-diffusion experiments. In general, the order of effectiveness in displacing (125)I-labelled LD lipoprotein is amidinated>diazo or acetyl>3-carboxypropionyl derivatives. 3. The order of the extent of conformational alteration induced in apoLD lipoprotein and LD lipoprotein, as judged by c.d. analyses, was 3-carboxypropionylation>diazotization>acetylation or amidination. 4. Delipidation of LD lipoprotein results in immunological alterations that are qualitatively detected by antisera to LD lipoprotein. Four of five antisera to apoLD lipoprotein form precipitin lines of identity between native LD lipoprotein and apoLD lipoprotein in double-diffusion experiments. An anti-(apoLD lipoprotein) serum that forms precipitin lines of complete identity between LD lipoprotein and apoLD lipoprotein reacts differently with these two antigens in radioimmunoassay. ApoLD lipoprotein is only one-fourth to one-half as effective as LD lipoprotein, on a protein basis, in the displacement of (125)I-labelled LD lipoprotein from this anti-(apoLD lipoprotein). 5. Conformational analysis indicates that apoLD lipoprotein retains a high proportion of the structural integrity of the native lipoprotein. Delipidation induces a small decrease in the content of beta-structure and a small increase in disordered structure, without greatly affecting the alpha-helical content. Chemical modification produces more severe conformational changes of apoLD lipoprotein than of LD lipoprotein. Computer analysis of the c.d. spectra of apoLD lipoprotein indicates that addition of high concentrations of sodium decyl sulphate abolishes most of the beta-conformation concomitant with increases in alpha-helical and disordered structure. 6. There is parallelism between the alteration of the charge of LD lipoprotein and apoLD lipoprotein and the extent of immunochemical and conformational changes.

Acylation↗