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A pyridoxine (B6) dietary deficiency was studied in female adult Sprague-Dawley rats by hind-limb walking-track analysis. Serum levels of pyridoxine and three metabolites were quantified by high-pressure liquid chromatography with fluorescence measurement. Morphometric analysis of the sciatic and posterior tibial nerves (from within the tarsal tunnel) was performed after 1 year on a diet deficient in vitamin B6. The B6-deficient rats developed abnormal walking-track patterns by 8 months, and these track parameters were different from age- and sex-matched normal diet control rats at the p < 0.05 level. Adding B6 at 10 parts per million to the diet then partially corrected these parameters, whereas the addition of 30 parts per million B6 corrected the abnormal pattern completely. Serum pyridoxal concentration correlated with the functional parameters, dropping from a mean of 115 mg per liter to 39.5 mg per liter (p < 0.05), and correcting with the B6 additive. Morphometric analysis demonstrated that the B6-deficient nerve from the tarsal tunnel had a decreased nerve fiber density (p < 0.001), with a normal total myelinated nerve fiber number, and an increased axon-to-myelin ratio (p < 0.003). It is concluded that a diet totally deficient in vitamin B6 results in a peripheral neuropathy.

Objective: The primary purpose was to investigate whether serum vitamin A concentration is associated with idiopathic intracranial hypertension (IIH). The secondary aim was to obtain pilot data regarding the amount of vitamin A ingested by patients and controls., Background: Vitamin A is an attractive candidate mediator of IIH as many of the symptoms and signs of hypervitaminosis A mimic those of IIH., Methods: We prospectively determined serum retinol and retinyl ester concentration in 16 women with IIH and 70 healthy young women. Using a survey instrument, we also determined the average daily vitamin A ingestion in a convenience sample of patients and controls., Results: Serum retinol concentration was significantly higher in the patient group (median 752 ug/L) compared with the control group (median 530 ug/L), even after adjusting for age and body mass index (p < 0.001). Retinyl ester concentration, however, was similar in the patient (median 48 ug/L) and control (median 41 ug/L) groups (p = 0.32). There was no significant correlation between serum retinol concentration and body mass index in the patients (r = 0.16) or controls (r = -0.02). Finally, there was no significant difference in the amounts of vitamin A ingested by the patients or controls, although the small number of subjects in both groups reduced the power of this conclusion., Conclusions: Elevated serum retinol concentration is associated with IIH. Obesity, by itself, does not explain these higher levels. Patients may ingest an abnormally large amount of vitamin A, metabolize it abnormally, or be unusually sensitive to its effects. Alternatively, elevated level of serum retinol may reflect an epiphenomenon of another variable we did not measure or a nonspecific effect of elevated retinol binding capacity.

Background: Elevated lipoprotein(a) [Lp(a)] levels have been associated with the presence of atherosclerotic disease. However, the results of prospective studies of Lp(a) and cardiovascular disease have been contradictory., Methods and Results: From 1968 through 1982, lipoprotein analysis was performed in 11,335 Olmsted County residents. Quantitative cholesterol and triglycerides were obtained along with semiquantitative Lp(a) levels based on electrophoretic pattern. Lp(a) bands were scored from 0 (absent) to 3 (increased). A cohort of 4967 men and 4968 women with no prior history of atherosclerotic disease who had baseline Lp(a) determinations were followed up for 14 years for development of coronary artery disease (CAD) and cerebrovascular disease (CVD). During 131,330 person-years of follow-up, there were 1848 CAD events and 841 CVD events. Age, diabetes, hypertension, cholesterol, and triglycerides were significantly and independently associated with an increased risk of CAD and CVD in men and women. There was a significant increase in the adjusted hazards ratio for CAD with increasing Lp(a) levels for men and women. For Lp(a) level 3, the hazard ratio was 1.9 (range, 1.3 to 2.9) in women and 1.6 (range, 1.0 to 2.5) in men. The adjusted hazard ratio for CVD showed an irregular association with Lp(a) levels in men and no association in women., Conclusions: In this cohort of 9936 men and women initially free of cardiovascular disease who were followed up for 14 years, Lp(a) was a significant predictor of risk of future CAD. Lp(a) was a weak risk factor for CVD in men and was not a significant predictor of CVD risk in women.

Porphyrias are relatively uncommon inherited or acquired disorders in which clinical manifestations are attributable to a disturbance of heme synthesis (porphyrin metabolism), usually in association with endogenous or exogenous stressors. Porphyrias are characterized by elevations of heme precursors in blood, urine, and/or stool. A number of chemicals, particularly metals and halogenated hydrocarbons, induce disturbances of heme synthesis in experimental animals. Certain chemicals have also been linked to porphyria or porphyrinuria in humans, generally involving chronic industrial exposures or environmental exposures much higher than those usually encountered. A noteworthy example is the Turkish epidemic of porphyria cutanea tarda produced by accidental ingestion of wheat treated with the fungicide hexachlorobenzene. Measurements of excreted heme precursors have the potential to serve as biological markers for harmful but preclinical effects of certain chemical exposures; this potential warrants further research and applied field studies. It has been hypothesized that several otherwise unexplained chemical-associated illnesses, such as multiple chemical sensitivity syndrome, may represent mild chronic cases of porphyria or other acquired abnormalities in heme synthesis. This review concludes that, although it is reasonable to consider such hypotheses, there is currently no convincing evidence that these illnesses are mediated by a disturbance of heme synthesis; it is premature or unfounded to base clinical management on such explanations unless laboratory data are diagnostic for porphyria. This review discusses the limitations of laboratory measures of heme synthesis, and diagnostic guidelines are provided to assist in evaluating the symptomatic individual suspected of having a porphyria.

Background: Blood products like hemoglobin are problematic as markers for colorectal neoplasia because bleeding is intermittent. Levels of calprotectin, a leukocyte-derived protein, are increased in stools from colorectal cancer patients. However, this blood constituent may gain luminal access via interstitial leukocyte migration, which could be a less variable mechanism of entry than bleeding., Methods: To correlate the levels of and to compare the variability of fecal calprotectin and hemoglobin, quantitative assays were performed independently on multiple serially collected stools from 14 patients with colorectal cancer. Marker level association was estimated with Pearson's correlation coefficient, and variation estimated with an analysis of variance model., Results: Fecal calprotectin and hemoglobin levels were discordant in 55 (50%) of 110 matched aliquots, and marker levels failed to correlate. The estimated between-subject correlation was -0.10 (95% CI, -0.60 to 0.46), and mean within-subject correlation -0.27 (95% CI, -0.73 to 0.34). The between-stool coefficient of variation was less for calprotectin (22%) than for hemoglobin (80%)., Conclusions: In patients with colorectal cancer, the mechanism of luminal calprotectin entry appears to be both different from and less erratic than bleeding.

The term porphyria represents seven neuropathic and/or dermopathic diseases caused by disturbances of the heme-forming system. Accumulation of the heme precursor, delta-aminolevulinic acid (delta ALA), is associated with the neurologic manifestations, and accumulation of photoreactive by-products, the porphyrins, causes cutaneous photosensitivity and dermopathic manifestations. The degrees of expression range from mild to severe, and acute episodes of neuropathic porphyrias can progress to paralysis and life-threatening respiratory failure. Diagnostic laboratory tests include quantitation of delta ALA, porphobilinogen, and porphyrins in blood, urine, and feces and analysis of activities of enzymes of the heme-forming system. Both inheritable and noninheritable forms of porphyria can be induced by toxic chemicals, and, therefore, tests for porphyria are becoming included increasingly in examinations of persons who have experienced problematic chemical exposures.

Objectives: To define the validity of fecal blood as a marker for colorectal neoplasia in the screening setting and to compare yields by Hemoccult and HemoQuant fecal occult blood screening tests., Design: A multicenter masked comparison of fecal blood test results against structural colorectal evaluations and longitudinal follow-up, serving as criterion standards, in nonreferred subjects at risk for colorectal neoplasia., Setting: Communities, primary care centers, referral centers., Participants: Two groups: (1) 1217 patients aged at least 18 years undergoing routine structural surveillance evaluations following curative resection of a colorectal tumor and (2) 12312 relatives of colorectal cancer patients aged at least 50 years., Interventions: Blinded Hemoccult II and HemoQuant testing on three mailed-in stool samples per subject., Main Outcome Measure: Sensitivity of fecal blood tests for colorectal neoplasia., Results: In the postresection group, surveillance evaluations revealed 46 malignant colorectal neoplasms and 402 polyps. At matched specificity, sensitivity of either test for cancer was 26% (95% confidence interval, 13% to 39%). Hemoccult was positive in 21% of intraluminal recurrences, 33% of all new primary tumors, and 29% of Dukes A or B cancers; HemoQuant was elevated in 24%, 28%, and 29%, respectively. Sensitivity for polyps 1.0 cm or larger was 13% by Hemoccult and 11% by HemoQuant. In the group of relatives, estimated sensitivity for cancer at 1 to 3 years of follow-up was 25% to 33% by Hemoccult, not significantly different from the 29% to 43% by HemoQuant., Conclusions: Based on our observations in the screening setting, fecal blood appears to be a poor marker for colorectal neoplasia. Most cancers and the vast majority of polyps will be missed. Hemoccult and HemoQuant are similarly insensitive.

In 36 normolipemic pigs randomized to a 4-week feeding with regular pig chow (n = 18, control group) or chow supplemented with cod liver oil (1 ml/kg per day) (n = 18, treated group), treatment with cod liver oil produced a significant decrease in serum cholesterol, low density lipoprotein cholesterol, and triglycerides. Deep carotid arterial wall injury (media exposed) by balloon angioplasty was associated with less 111In-labeled platelet deposition (24.6 +/- 4.8 x 10(6)/cm2 versus 62.5 +/- 17.0 x 10(6)/cm2, p less than 0.05; difference, -33.8 x 10(6)/cm2; 95% confidence interval [CI], -1.9 x 10(6)/cm2 to -73.9 x 10(6)/cm2) and injury-related vasoconstriction (21.3 +/- 2.2% versus 30.9 +/- 2.9%, p less than 0.05; difference, -9.6%; 95% CI, -2.2% to -17.0%) in the cod liver oil-treated group than in the control group; with mild injury (media not exposed), platelet deposition was low and unchanged (6.2 +/- 0.5 x 10(6)/cm2 versus 7.8 +/- 0.7 x 10(6)/cm2; difference, -1.6 x 10(6)/cm2; 95% CI, -1.1 x 10(6)/cm2 to +4.3 x 10(6)/cm2), but associated vasoconstriction was reduced respectively (16.3 +/- 2.0% versus 23.0 +/- 2.2%, p less than 0.05; difference, -6.7%; 95% CI, -0.6% to -12.8%). When arterial blood from cod liver oil-treated pigs superfused normal aortic media ex vivo, platelet deposition onto the normal aortic media was lower than when arterial blood from control pigs superfused the normal aortic media (43.7 +/- 8.8 x 10(6)/cm2 versus 66.8 +/- 13.0 x 10(6)/cm2, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

We administered lovastatin to two sisters, aged 4 and 17 years, who had cholesterol ester storage disease, an autosomal recessive disorder manifested by hypercholesterolemia and hypertriglyceridemia. The drug, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was taken orally for 6 months. Serum lipid concentrations were determined monthly. Computed tomography of the liver was performed before and during therapy to evaluate liver fat content. The younger sister had liver biopsies before and after 6 months of lovastatin therapy to assess hepatic cholesterol stores. Both patients had marked decreases in serum levels of cholesterol, triglycerides, and low-density lipoprotein-cholesterol; high-density lipoprotein-cholesterol levels increased. Computed tomography during treatment demonstrated a significant increase in linear attenuation, suggesting a decreased liver fat content. Liver tissue obtained 6 months after lovastatin therapy was initiated had 13% less esterified cholesterol than the liver sample obtained before treatment. We conclude that lovastatin may be effective in treating children with cholesterol ester storage disease.

Lipid and lipoprotein findings are described in a group of 707 persons consisting of normal control subjects, patients with clinical peripheral occlusive arterial disease, patients with diabetes and no occlusive arterial disease, and diabetic patients with occlusive arterial disease. The mean serum triglycerides were elevated in all groups compared with the normal controls and varied, depending on the type and treatment of the diabetes and fasting plasma glucose concentration. Mean total serum cholesterol did not change among the groups. Unexpectedly, the mean level of low-density lipoprotein cholesterol was significantly lower in patients with diabetes who had no occlusive arterial disease than in normal subjects. The mean high-density lipoprotein cholesterol level was higher in normal-weight, insulin-treated diabetic patients than in obese diabetics regardless of their treatment. Disturbances in triglyceride metabolism and the related lipoproteins appear to characterize both diabetes and occlusive arterial disease, with the highest mean levels of serum triglycerides being found in subjects with both diabetes and occlusive arterial disease.

The lipoprotein electrophoregrams and the cholesterol and triglyceride levels of the pleural fluid were evaluated for patients with chylous pleural effusions, as defined by the presence of a distinctive band of chylomicrons on the lipoprotein electrophoregram, and in patients with nonchylous effusions of various causes. One hundred forty-one patients were studied during a 3-year period. The chylous effusions had strikingly higher triglyceride levels (median 249, range 49 to 2,270 mg/dl) than the nonchylous group (median 33, range 13 to 107 mg/dl); there were no significant differences in cholesterol or protein between the two groups. The gross description of the fluid was a poor indicator of its origin, being described as consistent with chyle in less than 50% of cases of chylous effusions. The triglyceride values distinguished chylous effusion from nonchylous effusion; values greater than 110 mg/dl are highly suggestive of a chylous effusion. Equivocal cases--triglyceride values between 50 and 110 mg/dl--required lipoprotein analysis. Pleural effusions of undetermined cause, regardless of gross appearance of the fluid, require that a screening triglyceride value be obtained to rule out a chylous effusion.

An adult woman with hypoglycemia, hyperlactatemia, hyperuricemia, hypertriglyceridemia, hyperketonemia and inability to make new glucose from galactose, fructose, glycerol and alanine was found to have no hepatic glucose-6-phosphatase and deficient fructose-1,6-diphosphatase. Nonautonomous hyperglucagonemia was demonstrated and shown to contribute to the hyperlactatemia and hyperketonemia. A paradoxic hyperlactatemic response to glucose and galactose was observed. Studies of substrate utilization showed prompt adaptation to changes in dietary supply of energy which probably accounted for her never having experienced symptoms of hypoglycemia.

Lipoproteins and lipoprotein profiles were determined in 96 adult nephrotic patients. The serum cholesterol-serum albumin, serum triglycerides-serum albumin and 24-hour urine protein loss-serum albumin values were all significantly inversely correlated. The serum triglycerides and serum cholesterol levels were not significantly lower in the group of lupus nephrotic patients compared to the nonlupus nephrotics. All lipoprotein types except type I were observed. The lipoprotein types fell into three nearly equal groups--IIa, IIb, and V. Type IV, the most common lipoprotein abnormality in uremic patients, was distinctly uncommon.

Urinary porphyrins are separated, according to number of carboxyl groups, in a system consisting of a mu-Bondapak C18 stationary phase and a mobile phase of methanol and aqueous sodium phosphate (pH 3.5) in a linear gradient. The specimen is prepared simply by adjusting the pH of a 5-mL sample to 2.0 and removing solids by centrifugation. The eluted porphyrins are measured fluorometrically. Naturally occurring non-porphyrin fluorescent substances are eluted ahead of the porphyrins. Chromatography requires about 20 min, and a re-establishment of initial conditions requires an additional 15 min.

The effect of diuretics, mainly chlorthalidone, on serum cholesterol was studied in 7,006 of the Hypertension Detection and Follow-up Program (HDFP) hypertensive patients not on antihypertensive medication at baseline. Several investigators have reported that diuretic therapy increases serum cholesterol in treated subjects. However, data from two long-term studies indicated that no increase in cholesterol occurred after two years of diuretic treatment. In the present study, yearly changes in serum cholesterol in hypertensives treated with diuretics were observed. The results were in agreement with those reported from both short-term and long-term studies, in that a significant increase in cholesterol was observed in six months to one year into the study but not from the second to the fifth year of therapy. In fact, the serum cholesterol levels were the same as baseline values after two years of drug treatment and decreased slightly thereafter. In the untreated group, no change or a decrease in serum cholesterol was observed during the course of the study. The possible causes for changes in serum cholesterol concentration such as regression to the mean, change in body weight, baseline cholesterol concentration, and the action mechanism of diuretic drugs are discussed.

We separately evaluated split specimens of serum for lipoprotein cholesterol in 38 five- to 14-year-old children, by the heparin/Ca2+ precipitation method and the ultracentrifugation/dextran sulfate precipitation method. Statistical analysis of the results indicated an excellent agreement (especially in beta- and alpha-lipoprotein cholesterol values) between results by the two methods. The percentage of alpha-lipoprotein cholesterol (mean +/- SD: 38.6 +/- 5.0) in children further confirmed the earlier observations that cholesterol derived from alpha-lipoprotein in children constitutes a relatively greater part of the serum total cholesterol than is true of adults.

In a pilot study, short-term (Monday, Wednesday, and Friday of the same week) variability of cholesterol and triglycerides in serum and in very low-density, low-density, and high-density lipoproteins were studied in 10 children aged 6 to 16. All of the subjects had normal levels of cholesterol and triglycerides. Analytic error was determined by blinded triplicate analyses of a fourth specimen from five of the same subjects. In the triglycerides, except for the smallest fraction (high-density), the differences from day to day in the same child were larger than the differences between children. The results indicate that single determinations of whole serum triglyceride carry limited significance since, within the week, the level may well change by a factor of two.

Ascorbic acid is known to exist in high concentration in the aqueous humor of the eye in many species. It has been observed that diurnal mammals have a very high concentration in aqueous humor whereas nocturnal mammals do not. It has been hypothesized that ascorbic acid protects the eye from the harmful effects of sunlight. We have discovered that of two closely related species of spiny mice, the diurnal species (Acomys russatus) has a concentration in aqueous humor that is 35 times higher than that of the nocturnal species (Acomys cahirinus). Studies of these two species may be fruitful to extend what is known about adaptation of the eye to protect itself from intense solar radiation.

A newly developed radioimmunoassay specific for conjugates of cholic acid (CCA) was used to measure the fasting serum levels of these bile acids in 233 patients with primary hyperlipoproteinemia classified as type IIa, IIb, III, IV, or V hyperlipoproteinemia as well as in 80 healthy control subjects. Subjects with type IIa hyperlipoproteinemia had significantly lower levels of CCA (0.9 plus or minus 0.06 muM, mean plus or minus SE) than did healthy controls (0.50 plus or minus 0.08 muM). Patients with type IIb, III, IV, and V hyperlipoproteinemia had values similar to those of the control group. The abnormally low fasting value of CCA in type IIa patients is considered to reflect decreased secretion of bile acid into the intestine in such patients, who are known to have defective bile acid synthesis rates and decreased bile acid pool sizes.

We sought to determine the short-term effects of use of aspirin and ethanol on fecal occult blood levels measured with the HemoQuant assay. A factorial design was used to study 68 healthy volunteers randomized to receive various doses of aspirin, ethanol, or a combination of both for either 1 or 3 days. Fecal hemoglobin concentrations were measured before and after drug ingestions. Moderate quantities of ethanol (300 ml of 5% or 30 ml of 50% three times nightly) did not cause significant fecal blood elevation unless aspirin was administered concomitantly (P = 0.05). High-dose aspirin alone, 975 mg three times daily, induced abnormal blood loss (P less than 0.01). The highest HemoQuant levels were usually noted after concomitant administration of aspirin and ethanol at maximal doses for 3 days (P less than 0.005), some HemoQuant levels approaching 5 times the normal value. We conclude that, in a short-term analysis, social consumption of ethanol is unlikely to interfere with fecal blood testing but therapeutic doses of aspirin will.

A study of 103 healthy, white schoolchildren who were between 6 and 16 years of age revealed no positive correlation between the level of serum cholesterol and the mean daily amount of total calories, cholesterol, fat, saturated fat, or sugar in the diet.

A method is described for the removal of cholesterol fractions by means of intermittent extracorporeal plasma circulation through a column containing heparin-treated agarose in the presence of calcium. The system allows plasma perfusion in one column while simultaneously recharging another. In vitro testing demonstrated its efficiency, and in vivo testing of a normal dog proved its feasibility. In vitro testing revealed a mean removal of 22% of low-density and very low-density lipoproteins combined. Animal testing did not produce any abnormalities in clinically significant parameters.

Cholesterol and triglyceride levels in whole sera and in the major lipoprotein fractions are presented for 2,421 children and youths in Rochester, Minnesota, ranging in age from 6 to 18 years. This cross-sectional study revealed subtle changes associated with puberty and the occurrence of certain additional sex-specific changes related to age. Hyperlipoproteinemia was detected in 101 youngsters; those cases exemplified types IIa (61 cases), IIb (5 cases), III (5 cases), and IV (30 cases). One case of type V hyperlipoproteinemia was observed in a second and comparable population sample of 1,245 young persons.

We have purified Lp(a) lipoproteins from sera of four subjects by ultracentrifugation, selective precipitation, and chromatofocusing. Each subject had two forms of serum Lp(a) that were separable by chromatofocusing. We purified apolipoprotein (a) [apo(a)] from the eight isolated Lp(a)s and obtained only one form of apo(a) from each subject. The four apo(a)s seen on sodium dodecyl sulfate-polyacrylamide gel electrophoresis had different apparent molecular masses, ranging from 275 to 440 kDa. Chemical deglycosylation of the smallest apo(a) yielded a 235 kDa protein, which may be a core protein structure common to all apo(a)s. We conclude that there are many forms of serum Lp(a) and apo(a). The heterogeneity of serum Lp(a) particles can be ascribed in part to differences in size of apo(a), but other factors must account for the existence within a single patient of different Lp(a)s that contain apparently identical apo(a). One must consider the heterogeneity of Lp(a) when designing assays for this lipoprotein.

Eight of 92 consecutive silastic central venous catheters used for home parenteral nutrition occluded. Six of the eight had patency restored by the instillation of urokinase or streptokinase into the catheter. The thrombus in one of the two catheters that was not reopened with thrombolytic agents was studied in detail by electron microscopy, x-ray dispersive analysis, solubility in isopropyl alcohol-diethyl ether (1:1, v:v), and thin-layer chromatography of extracted lipids. Electron microscopy found the clot to be an amorphous mass without features to suggest crystalline properties. The x-ray dispersive analysis showed that the only elements which were significantly increased were chloride and silicon and the silicon detected was likely from the underlying catheter. Treatment with isopropyl alcohol-diethyl ether left an insoluble, flaky residue that resembled protein from a thrombus. Thin-layer chromatography detected a lipid profile suggestive of circulating endogenous fat instead of the fat that was infused through the catheter.

The non-polar lipids from sera of 54 patients, with various types of hereditary motor and sensory neuropathies, and from 72 healthy subjects were evaluated. A small but highly significant decrease in the percentage of linoleate to total fatty acids in both cholesteryl ester and triglyceride fractions was found in the sera of the neuropathy patients, except in those who had dominantly inherited sensory neuropathy (HSN-I) and who had spinocerebellar degeneration with retinitis pigmentosa and other features (SpC+). A significant decrease of serum lecithin-cholesterol acyltransferase activity was also found in those patients with hereditary motor and sensory neuropathies, Type I and Type II (two types of peroneal muscular atrophy). The biochemical basis of these abnormalities is not apparent. The biochemical abnormalities reported here have been found in several neurologic disorders and hence are unlikely to be disease-specific.

Data reported here establish that treatment regimens of 4 mg dextrothyroxine and 0.15 mg levothyroxine in hypothyroid subjects produce similar degrees of lowering of serum TSH, cholesterol, triglycerides, and phospholipid levels and equal stimulation of metabolic rate. The Murphy-Pattee total T4 determination applied to blood samples drawn 24 h after the last dose of dextrothyroxine can be used to assess adequacy of treatment. Correction of hypothyroidism requires high serum levels of dextrothyroxine than of levothyroxine. Serum T3 levels increase in patients treated with dextrothyroxine. In the treatment of hypothyroidism, the cholesterol-lowering and metabolic rate-stimulating effects of dextrothyroxine do not appear to be dissociated. Further studies are needed to determine whether such an effect can be demonstrated in euthyroid hypercholesterolemic subjects with doses established herein as equivalent in terms of the stimulating effect on metabolic rate.

The chemical composition of the major classes of lipids were evaluated in the plasma and in various other tissues of a 68-year-old woman with a syringomyelia-like syndrome affecting cranial, cervical and brachial regions. No tonsillar abnormalities were apparent on visual examination of the oropharynx but the absence of alpha-lipoproteins on serum lipoprotein electrophoresis prompted the tentative diagnosis of Tangier disease. The diagnosis was confirmed by lipid, lipoprotein and apolipoprotein analyses of the plasma. The plasma cholesterol was low (93-113 mg/dl) and the triglyceride concentration normal (133-160 mg/dl). The very low density lipoproteins had normal chemical composition and morphology, but migrated with beta rather than pre-beta mobility on paper electrophoresis. Low density lipoproteins were deficient in cholesteryl esters and enriched in triglycerides; their electrophoretic mobility and morphology were normal. A small amount of high density lipoprotein (approximately 1.4 mg/dl) was recovered from the plasma. This contained few particles of the size of normal high density lipoprotein and polyacrylamide gel electrophoresis of the lipid-free protein demonstrated a disproportionate increase in the A-II apolipoprotein. All of these abnormalities are consistent with Tangier disease. The serum concentration of glycosphingolipids was approximately 40% lower than normal, with the most marked reductions in the glucosylceramide (GL-1a) and trihexosylceramide (GL-3a) fractions. The relative quantity of long chain fatty acids (23 or more carbons) in serum sphingomyelin was reduced about 38% of that in control sera. Serum lecithin:cholesterol acyltransferase (EC 2.3.1.43; LCAT) activity was 25% of normal and the reduced activity was shown not to be related to a change of enzyme specificity or to a lack of appropriate substrate. These findings are likely related to the HDL deficiency which characterizes Tangier disease. A biopsy sample of apparently normal tonsil contained three to four times the normal amount of cholesterol, and the increase was due entirely to abnormal quantities of cholesteryl esters. Of great interest was the chemical documentation of increased cholesteryl esters in a nerve biopsy specimen. These findings indicate that the neurologic as well as the reticuloendothelial manifestations of Tangier disease may be related to cholesteryl ester accumulation. Lipoprotein profiles, their triglyceride and cholesterol concentration, and LCAT activity were obtained on the plasma of 7 closely related members of the kinship. None of these relatives were found to have the biochemical derangement of Tangier disease.

Seventy-two amniocenteses with concurrent placental grading by ultrasound were performed during 66 pregnancies. No relationship was observed between placental grade and the mean ratio of lecithin to sphingomyelin (L/S) or the phosphatidylglycerol concentration. Both placental grade and fetal lung maturity were interrelated by the independent variable of gestational age. The latter may explain the trend observed between a mature L/S ratio and the placental grade. Grade 3 placentas were present in only 20% of patients studied at 37 weeks of gestation or later (12 of 61 patients), and in every instance a Grade 3 placenta was associated with an absence of neonatal respiratory distress.

A 67-year-old woman, with the typical biochemical features of Tangier disease, had a syringomyelia-like syndrome which has now been observed in several patients with symptomatic onset in adult life. She developed progressive facial diplegia, bilateral wasting of hand muscles and loss of sensation over cranial, cervical and brachial dermatomes over 17 years. Nociception alone was first affected, then nociception and thermal discrimination and finally all modalities of sensation. Quantified tests of cutaneous sensation confirmed that sensation was normal in lower limbs but markedly abnormal in upper limbs. Biopsied fascicles of cutaneous nerves from clinically affected (forearm) and from clinically unaffected (leg) regions permitted a comparison of well-advanced and early pathologic lesions, respectively. The selective vulnerability of unmyelinated and small myelinated fibers in affected regions in this disorder has been confirmed. The earliest morphologic abnormalities of myelinated fibers, but seen infrequently, were mitochondrial enlargement and structural abnormality, aggregation of mitochondria and dense bodies and clusters of neurofilaments. Increased numbers of sudanophilic lipid droplets did not seem to form in Schwann cell cytoplasm prior to fiber degeneration. On the contrary, for myelinated fibers there appeared to be an altered process of axonal degeneration from that seen in Wallerian degeneration and in other axonal degenerations. Distinctive linear bands of closely-packed, minute, osmiophilic and clear lipid droplets formed and their further degradation appeared delayed. Although less clearly demonstrated, lipid droplets in Schwann cells of unmyelinated fibers also appeared to form following their degeneration. We would propose that in Tangier disease, the degradation of myelin ovoids to neutral lipid in Schwann cells does not appear to be delayed. However, further degradation of neutral lipid or its transport away from Schwann cells appears to be retarded.

We describe a convenient, economical procedure for measuring uroporphyrinogen I synthase (EC 4.3 1.8) activity in erythrocytes, the results of which can be used to diagnose acute intermittent porphyria, in either its latent or acute stage. By limiting the test reaction sequence to the conversion of porphobilinogen to porphyrins, we eliminated several disadvantages of alternative methods in which delta-aminolevulinate is used as substrate. The latter assay was inhibited by lead; our procedure was not. Our procedure also gave greater porphyrin synthesis with less substrate. Erythrocytes of healthy women presented a mean activity of 12.4 nmol of porphyrin formed per liter per second; erythrocytes of healthy men presented a mean activity of 11.0 nmol/L per second. The within-run coefficient of variation (CV) for our assay was 1.8%; the between-run CV was 3.1%.

Two neonates, one with extrahepatic biliary atresia and one with cystic fibrosis, and a 9-year-old child with atresia of the common bile duct had conjugated hyperbilirubinemia and elevated rubella HAI titers when kaolin pretreatment of serum was used. A beta-lipoprotein fraction of the serum that is frequently found in association with biliary obstruction was shown to be the probable source of the rubella HAI inhibitor. This beta-lipoprotein was not removed by standard kaolin treatment of serum, but was removed almost completely by dextran sulfate--calcium chloride treatment. In the presence of conjugated hyperbilirubinemia, routine kaolin pretreatment of serum is an inadequate measure for the removal of interfering substances, as false-positive rubella HAI results are obtained consistently.

In vitro lipogenesis was studied on the xanthoma tissue from 6 patients with normal plasma lipids and 4 patients with hyperlipidemia. Xanthoma tissue was incubated at 37 degrees C for 6 hr in Krebs-Ringer phosphate buffer containing sodium [14C]acetate. The radioactivity of each lipid class was determined after extraction and separation of lipids. The incorporation of acetate into all major lipid groups was much greater in xanthoma tissue than in control normal-appearing skin. There was no difference in the incorporation pattern of 14C between xanthomas of patients with normal plasma lipids and those of hyperlipidemic patients. The data exemplify considerable in situ lipid synthesis of xanthoma tissue. Although the lipids in xanthomas of hyperlipidemic persons may be derived from plasma, the plasma origin of xanthoma lipids in normolipidemic persons remains to be confirmed, and the contribution of local lipogenesis cannot be ignored. The lipids in cutaneous xanthomas are most likely derived from a multiple input system.

The relationship between Reye-Johnson syndrome and acute encephalopathy without fatty liver was investigated by comparing the lipid composition of liver samples obtained from five patients with Reye-Johnson syndrome, two patients with acute encephalopathy, and five controls. The mean total hepatic triglyceride concentration was increased nearly sevenfold in Reye-Johnson syndrome and slightly decreased in acute encephalopathy when compared with the mean control value. The mean total hepatic free fatty acid concentration was increased nearly threefold in acute encephalopathy when compared with the mean value in Reye-Johnson syndrome. Total phospholipid content was decreased in the liver in Reye-Johnson syndrome, and this difference was caused mainly by a diminution of the hepatic lecithin fraction. The ratio of palmitic acid to oleic acid and hepatic free fatty acids was 2.5 in Reye-Johnson syndrome, 0.7 in acute encephalopathy, and 0.8 in controls. These results suggest that, despite clinical similarities and laboratory evidence of hepatic dysfunction in both Reye-Johnson syndrome and acute encephalopathy, different pathogenic mechanisms may be responsible for the liver abnormalities found in the two syndromes.

Cholesterol, triglyceride, free fatty acid, and phospholipid concentrations were measured in 33 brain, liver, and adipose tissue samples obtained from 17 children who died of an acute encephalopathy associated with liver dysfunction and hyperammonemia (hyperammonemic encephalopathy). Eleven patients had Reye's syndrome, three had acute "toxic" encephalopathy (without fatty liver), two had glycogen storage disease type 1, and one had congenital hyperammonemia type 2. Hepatic triglyceride concentrations were markedly increased in Reye's syndrome, but varied from normal to increased concentrations in other hyperammonemic encephalopathies. In contrast, the acute encephalopathy could not be differentiated on the basis of clinical, laboratory, or pathologic features and the brain lipid profiles were remarkably similar among all patients studied.

Hemoglobin-heme is variably converted to porphyrin during enterocolic transit. This intestinal converted fraction, as measured by HemoQuant, was elevated as a predictor of the occult bleeding site in 152 patients with discrete lesions. The intestinal converted fraction, expressed as the percentage of total fecal hemoglobin, was similar with upper gastrointestinal and proximal colon lesions. Within the colon, values trended downward with more distal location: means +/- standard deviations were 18 +/- 14 proximal colon, 16 +/- 15 sigmoid, and 10 +/- 10 rectum. The amount of fecal blood also affected the intestinal converted fraction; correcting for hemoglobin concentration improved separation by site. Corrected intestinal converted fraction values were significantly lower with rectal (P less than 0.0005) and sigmoid (P less than 0.02) lesions than with proximal colon lesions. Unfortunately, large within-site variation caused considerable overlap between sites. We conclude that the intestinal converted fraction is influenced by the site and amount of bleeding. However, its clinical utility is compromised by substantial individual differences in luminal hemoglobin metabolism.

Liver specimens from 8 patients with Reye-Johnson syndrome, 2 patients with acute encephalopathy, and 10 patients without liver disease were analyzed for aflatoxins. An aflatoxin was obtained from the liver of one patient, a 15-year-old girl who had clinical, laboratory, and pathologic features of Reye-Johnson syndrome. Thin-layer chromatography, fluorescence emission, infrared spectroscopy, and derivatization studies characterized the aflatoxin as related structurally to but not identical with aflatoxin B1. This report is added to previous ones from Thailand, New Zealand, and Czechoslovakia in which the association of aflatoxins and fatty liver has been found in Reye-Johnson syndrome.