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Several letters to the editor are presented in response to articles in previous issues including an article on U.S. Secretary John Foster Dulles' moral order in politics in the September 28, 1953 issue, "Bombs for Everybody," and a report on the decision of John L. Lewis to stop buying coal in the September 28, 1953 issue.

The Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/mental retardation syndrome caused by a deficiency of the enzyme 7-dehydrocholesterol Delta(7)-reductase. This enzyme converts 7-dehydrocholesterol (7-DHC) to cholesterol in the last step in cholesterol biosynthesis. The pathology of this condition may result from two different factors: the deficiency of cholesterol itself and/or the accumulation of precursor sterols such as 7-DHC. Although cholesterol synthesis is defective in cultured SLOS cells, to date there has been no evidence of decreased whole body cholesterol synthesis in SLOS and only incomplete information on the synthesis of 7-DHC and bile acids. In this first report of the sterol balance in SLOS, we measured the synthesis of cholesterol, other sterols, and bile acids in eight SLOS subjects and six normal children. The diets were very low in cholesterol content and precisely controlled. Cholesterol synthesis in SLOS subjects was significantly reduced when compared with control subjects (8.6 vs. 19.6 mg/kg per day, respectively, P < 0.002). Cholesterol precursors 7-DHC, 8-DHC, and 19-nor-cholestatrienol were synthesized in SLOS subjects (7-DHC synthesis was 1.66 +/- 1.15 mg/kg per day), but not in control subjects. Total sterol synthesis was also reduced in SLOS subjects (12 vs. 20 mg/kg per day, P < 0.022). Bile acid synthesis in SLOS subjects (3.5 mg/kg per day) did not differ significantly from control subjects (4.6 mg/kg per day) and was within the range reported previously in normals. Normal primary and secondary bile acids were identified.This study provides direct evidence that whole body cholesterol synthesis is reduced in patients with SLOS and that the synthesis of 7-DHC and other cholesterol precursors is profoundly increased. It is also the first reported measure of daily bile acid synthesis in SLOS and provides evidence that bile acid supplementation is not likely to be necessary for treatment. These sterol balance studies provide basic information about the biochemical defect in SLOS and strengthen the rationale for the use of dietary cholesterol in its treatment.

In order to study the biosynthesis, composition, and origin of sterols in the Florida land crabs, Cardisoma guanhumi (Latreille), we fed 17 male crabs either a cholesterol-free or a high cholesterol diet for 2 to 7 weeks. The origin of sterols in these crabs, whether from biosynthesis or from the diet, was determined by tahree procedures: the incorporation of isotopic mevalonate into the cholesterol when the diet was cholesterol-free; the absorption of isotopic cholesterol and sitosterol from the diet; the cholesterol and plant sterol concentrations of hepatopancreas, plasma, and muscle under conditions of cholesterol-free and high cholesterol diets. In addition, the interconversion of cholesterol and sitosterol was investigated. Dietary sterols of plant and animal sources were readily absorbed and provided the major source of sterols for this species of crab. The biosynthesis of cholesterol from mevalonate in this crab was minimal. However, cholesterol was synthesized from dietary sitosterol by dealkylation. Cholesterol and the three plant sterols (24 epsilon-methyl cholesterol, stigmasterol, and sitosterol) were found in the hepatopancreas, plasma, and muscle of the crab. Plant sterols contributed from 9 to 37% of the total sterols in the hepatopancreas, plasma, and muscle of the crabs fed a cholesterol-free diet.

Docosahexaenoic acid [22:6 omega 3; 22:6-(4,7,10,13,16,19)] is the major polyunsaturated fatty acid in the photoreceptor membranes of the retina and in cerebral gray matter. It must be obtained either from the diet or by synthesis from other omega 3 fatty acids, chiefly alpha-linolenic acid (18:3 omega 3). We tested the effect of dietary omega 3 fatty acid deprivation during gestation and postnatal development upon the fatty acid composition of the retina and cerebral cortex and upon visual function. Rhesus monkeys (Macaca mulatta) were fed semipurified diets very low in 18:3 omega 3 throughout pregnancy, and their infants received a similar diet from birth. A control group of females and their infants received a semipurified diet supplying ample 18:3 omega 3. In near-term fetuses and newborn infants of the deficient group, the 22:6 omega 3 content of phosphatidylethanolamine was one-half of control values in the retina and one-fourth in cerebral cortex. By 22 months of age, the content of 22:6 omega 3 in these tissues approximately doubled in control monkeys, but it failed to increase in the deficient group. Low levels of 22:6 omega 3 in the deficient animals' tissues were accompanied by a compensatory increase in longer-chain omega 6 fatty acids, particularly 22:5 omega 6. Functionally, the deficient animals had subnormal visual acuity at 4-12 weeks of age and prolonged recovery time of the dark-adapted electroretinogram after a saturating flash. Abnormally low levels of 22:6 omega 3 may produce alterations in the biophysical properties of photoreceptor and neural membranes that may underlie these functional impairments. The results of this study suggest that dietary omega 3 fatty acids are retina and brain.

Previously we demonstrated high concentrations of desmosterol and docosahexaenoic acid (DHA, 22:6 n-3) in monkey testes and sperm. Desmosterol, a cholesterol precursor, is not present elsewhere in the body. High concentrations of DHA are found elsewhere only in the retina and brain. To examine the distribution of these compounds in the heads and tails of sperm, we separated them and determined their sterol, fatty acid, and phospholipid molecular species composition. Desmosterol predominated in tails (134.4 vs. 1.7 microg/10(9) cells in heads). The cholesterol content was also greater in the tails (66.2 vs. 30.3 microg/10(9) cells in heads). Sperm tails had more polyunsaturated fatty acids than the heads (34.1 vs. 12.1% of total fatty acids) which resulted mainly from the higher contents of DHA (19.6 vs. 1.1%) and arachidonic acid (20:4 n-6) (6.4 vs. 1.6%) in the tails. These differences in fatty acid composition occurred mainly in phospholipids: phosphatidyl choline and phosphatidyl ethanolamine for n-3 fatty acids and phosphatidyl serine and cardiolipin for n-6 fatty acids. Fifteen phospholipid molecular species were identified. Sperm tails had more molecular species containing unsaturated fatty acids than the heads. Our results reveal the large differences in membrane lipid composition between the heads and tails of sperm. Most (99%) of the desmosterol and DHA in sperm is located in the tail. These differences may be responsible for the different functions of these two components of sperm. The large number of double bonds in DHA, six, and in desmosterol, two, may contribute to the membrane fluidity necessary for the motility of the sperm tails.

Abstract. The influence of fish oils rich in n‐3 fatty acids on plasma lipid and lipoprotein concentrations in patients with primary hyperlipoproteinaemia is reviewed. When used as a dietary supplement, n‐3 fatty acids exert their greatest effect on the concentrations of triglyceride‐rich lipoproteins and these effects are dose dependent. Low doses of n‐3 fatty acids reduce plasma triglyceride concentrations in patients with phenotypic type IV, type V and type IIB hyperlipoproteinaemia, but concurrently result in modest increases in the plasma concentrations of low density lipoprotein (LDL). With very high doses plasma concentrations of LDL cholesterol decrease in patients with the type IIB phenotype. At low doses n‐3 fatty acids do not significantly lower concentrations of LDL cholesterol in patients with primary hypercholesterolaemia whereas at higher doses a modest LDL lowering effect is achieved. The results indicate that the therapeutic potential of n‐3 fatty acids as hypolipidaemic agents is greatest in patients with hypertriglyceridaemia.

Docosahexaenoic acid [22:6(n-3); 22:6(4,-7,10,13,16,19) (DHA)] is required in quantity by the developing nervous system of the fetus. This need could be met through synthesis of DHA from linolenic acid in the fetus or through placental transfer of DHA directly. To study the placental transfer of n-3 fatty acids, we obtained umbilical and maternal blood samples from 26 healthy women and infants at parturition and measured the fatty acid composition and content of both plasma and erythrocytes. A striking finding was a considerable venous-arterial difference for DHA in the umbilical erythrocytes as a proportion of total fatty acids and in absolute concentration. This difference of 2.2 micrograms per billion erythrocytes was 6 times larger than the difference in fetal plasma, when the plasma and erythrocyte concentrations were normalized to whole blood. Most other erythrocyte fatty acids showed a similar trend. In umbilical plasma, significant venous-arterial differences were found for 16:0, 16:1, 18:2, and total saturated fatty acids. There was a similar trend for most other plasma fatty acids. Compared with maternal blood, fetal plasma and erythrocytes had higher levels of 20:4 and DHA and lower levels of 18:2 and 18:3(n - 3) fatty acids as a proportion of total fatty acids. These results suggest that erythrocytes play a major role in the necessary transport of the essential fatty acid DHA into the fetus.

To explore the mechanisms of the profound plasma cholesterol elevations in familial homozygous hypercholesterolemia (type IIa), cholesterol turnover, sterol balance, cholesterol absorption, and low density lipoprotein studies were carried out under controlled dietary conditions in two sisters (aged 13 and 16). Cholesterol turnover was prolonged. The half-life of the first exponential of the plasma cholesterol specific activity decay curve was double that of normal adults. The rate constants for the removal of cholesterol from pool A (KAA = 0.0652) and for the excretion of cholesterol from the system (Kaa = 0.0197) were less than half of normal. The production rates of cholesterol were low, only 6.30 and 6.86 mg/kg per day as measured by cholesterol turnover and sterol balance techniques, respectively. Fecal neutral steroid and bile acid excretion were 5.22 and 1.64 mg/kg per day, which is remarkably low in comparison to those of normal and heterozygous children. Cholesterol absorption was within the upper limit of the values reported for normal adults. THE HDL cholesterol values were extremely low (27 mg/dl) in contrast to profoundly elevated LDL levels. The fractional catabolic rate of LDL (0.127 per day) and the rate of synthesis and catabolism of apo-LDL (15 mg/kg per day) were low in comparison to previously reported values in homozygotes. These composite data indicated that the definable metabolic defects of these two sisters with homozygous familial hypercholesterolemia were the sluggish clearance of cholesterol from the body coupled with low total body synthesis of cholesterol.

Rhesus monkeys were fed high cholesterol and cholesterol-free diets for 21-24 months. The animals were then given isotopic cholesterol intravenously and autopsied from 1 to 51 weeks later. The plasma and aortic cholesterol contents were 633 +/- 130 mg/dl and 35.6 +/- 11.4 mg/g dried tissue (45.5% in ester form) for atherosclerotic monkeys and 135 +/- 25 mg/dl and 9.9 +/- 3.6 mg/g (15.0% in ester form) for control monkeys, respectively. The minimal influx rate of cholesterol from plasma into the aorta was much greater for atherosclerotic animals, 0.470 +/- 0.20 mg/g per day versus 0.088 +/- 0.031 for control monkeys. There was a rapid turnover of both free and esterified cholesterol in the atherosclerotic aortas, greater than for normal aortas. These studies of cholesteryl ester metabolism indicated a likely origin of aortic cholesteryl ester from the plasma cholesteryl esters. Our data indicated a dynamic cholesterol metabolism and turnover in the aorta during atherogenesis.

Six samples of human coprolites, some more than 2,000 years old, were analyzed for fecal steroid composition. Despite this very lengthy period of storage, the fecal steroids of coprolites were remarkably similar to those of stool samples collected today. The sterol nucleus was clearly rather stable under the dry environmental conditions of the Nevada Caves. The steroid content (µg/g dried weight) of coprolite was low in comparison to that of modern man. The bile acid/cholesterol and plant sterol/cholesterol ratios of the coprolite, however, were similar to these ratios of the stools of modern man. In the six coprolites, an average 73% of the neutral steroids was digitonin-precipitable. This precipitate was composed of cholesterol and three plant sterols (campesterol, stigmasterol, and β-sitosterol) and their bacteria-modified products. A portion of the neutral steroids had been converted to products tentatively identified as epimers of these steroids. Individual bile acids were identified in the coprolite. The bile acid composition of the coprolite was similar to that of the stool of modern man.

THE CLINICAL syndrome of idiopathic hyperlipemia has been described fully in several recent surveys.* In essence it embodies a triad of signs and symptoms which include abdominal pain, hepatosplenomegaly, and cutaneous xanthomata with an elevated fasting level of serum neutral fat. Increase of serum neutral fat may also be seen in diabetes mellitus, nephrosis, alcoholic cirrhosis, hypothyroidism, and glycogen-storage disease. In the absence of other causative disease, hyperlipemia may be termed idiopathic.5 Although it has been suspected that this disorder of lipid metabolism might predispose to coronary atherosclerosis, as yet no pathological reports of such association have been found. That hyperlipemia may be associated with coronary artery disease has been demonstrated clinically.† The single report in the literature of the postmortem findings in a case of idiopathic hyperlipemia revealed no evidence of coronary atherosclerosis, with death being due to an intercurrent infection.7 The following case history records the

The effect of hypophysectomy upon the serum lipids was studied in rats in which nephrosis was produced by the amino-nucleoside of puromycin. Hypophysectomy prevented the usual rise of the serum cholesterol and triglyceride in the nephrotic rats. It is postulated that the hyperlipemia of nephrosis may result from enhanced lipoprotein synthesis in the liver from an effect of pituitary hormones. The hypophysectomized rats with nephrosis had higher blood urea nitrogen values and less proteinuria than did the nonhypophysectomized rats with nephrosis.

By its use in a variety of blood clotting systems, soybean phosphatide has been shown to act as a partial thromboplastin in blood coagulation. In vitro, this substance displayed anti-heparin activity in human and dog blood and anti-protamine activity in human plasma. A simplified thromboplastin generation test is described for the study of hemorrhagic disorders. Soybean phosphatide serves as a complete substitute for platelets in this test.

Smith–Lemli–Opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthetic pathway, 7‐dehydrocholesterol Δ7‐reductase (DHCR7). We diagnosed SLOS in a fetus following intrauterine demise at 32 weeks' gestation. Chorionic villus (CV) sampling had been performed at 30 weeks because oligohydramnios and atrioventricular septal defect were noted on fetal ultrasound. On fetal post‐mortem examination, a midline U‐shaped soft palate cleft, micrognathia, postaxial polydactyly of the fingers with single transverse palmar creases bilaterally, and cutaneous syndactyly of toes two–three bilaterally suggested SLOS. We hypothesized that SLOS could be confirmed by analysis of tissue sterols despite extensive autolysis, and by measurement of enzyme activity in CV cells. Measurement of DHCR7 activity in CV cells was undertaken using ergosterol as a substrate. CV cells were unable to convert any ergosterol to brassicasterol after a 72 h incubation period while control CV cells reduced 12.6–71.8% of ergosterol to brassciasterol in a 72 h period. SLOS was confirmed by measurement of elevated 7‐dehydrocholesterol (7‐DHC) in the CV cells. Measurements of sterols were made in multiple fetal tissues. All tissues analysed showed elevated 7‐DHC with markedly increased 7‐DHC/cholesterol ratios. Copyright © 2000 John Wiley & Sons, Ltd.

Smith–Lemli–Opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol Δ⁷-reductase (DHCR7). We diagnosed SLOS in a fetus following intrauterine demise at 32 weeks' gestation. Chorionic villus (CV) sampling had been performed at 30 weeks because oligohydramnios and atrioventricular septal defect were noted on fetal ultrasound. On fetal post-mortem examination, a midline U-shaped soft palate cleft, micrognathia, postaxial polydactyly of the fingers with single transverse palmar creases bilaterally, and cutaneous syndactyly of toes two–three bilaterally suggested SLOS. We hypothesized that SLOS could be confirmed by analysis of tissue sterols despite extensive autolysis, and by measurement of enzyme activity in CV cells. Measurement of DHCR7 activity in CV cells was undertaken using ergosterol as a substrate. CV cells were unable to convert any ergosterol to brassicasterol after a 72 h incubation period while control CV cells reduced 12.6–71.8% of ergosterol to brassciasterol in a 72 h period. SLOS was confirmed by measurement of elevated 7-dehydrocholesterol (7-DHC) in the CV cells. Measurements of sterols were made in multiple fetal tissues. All tissues analysed showed elevated 7-DHC with markedly increased 7-DHC/cholesterol ratios. Copyright © 2000 John Wiley & Sons, Ltd.

The coagulation of the blood has excited the curiosity of men from Hippocrates and Aristotle to the present. Yet not until the 19th century were the theoretical conceptions of blood clotting founded upon sound experimental facts. This progress came about, as Paul Morawitz suggests in his title, because of a recognition that the blood coagulated as a result of the "fermentative" interaction of "chemical" constituents. In 1832 Johannes Mueller first proved the existence of fibrin in solution in plasma. In 1905 Morawitz assembled the scientific work of others and himself and formulated a theory of blood coagulation which is still the basis of today's thinking. Thrombin was the catalyst of the fibrinogen-fibrin reaction. Morawitz considered that calcium and thromboplastic substances from platelets, leukocytes, and tissue juice converted the inactive form of thrombin (prothrombin) into the enzymatically active thrombin. A wetable surface was important in this transformation. Once thrombin had formed