Biomedical subjects

L A Zech

Publications and source records attributed to L A Zech.

At least 73 records · Page 4Linked to original sources

PubMed1988

Effect of sodium-restricted diet and posture on norepinephrine kinetics in humans.

We used compartmental analysis to analyze the kinetics of distribution and metabolism of norepinephrine (NE) and to determine whether the increase in plasma norepinephrine concentration (PNE) during sodium restriction in humans is due to sympathetic nervous system (SNS) activation. [3H]-NE infusion and postinfusion decay were measured in young subjects in the supine position and during 60 min of standing during normal sodium (NS) diet and after 7 days of 10 meq/day sodium-restricted (SR) diet. The mean supine PNE was greater during SR diet compared with NS diet (154 +/- 9 vs. 185 +/- 12 pg/ml, P = 0.02, n = 10). During both NS and SR diets, upright PNE increased (163 +/- 4 vs. 359 +/- 38 pg/ml and 182 +/- 8 vs. 401 +/- 26 pg/ml, respectively, multivariate one-way analysis of variance, P less than 0.001, alpha = 0.05). The increases of PNE with both SR diet and upright posture were accompanied by a fall in NE metabolic clearance rate (MCR1). During SR diet this was due to a fall in the volume of distribution of NE (6.1 +/- 0.4 vs. 5.0 +/- 0.4 liters, P = 0.003, n = 10). In contrast to the effect of upright posture to increase NE release into the extra-vascular compartment (NE2), during SR diet there was no change in NE2 (1.63 +/- 0.09 vs. 1.62 +/- 0.1 micrograms.min-1.m-2, P = 0.97, n = 10). Thus the increase in PNE during SR diet in humans can be explained by a fall in the volume of distribution of NE, resulting in a decrease in MCR1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Metabolism of immunoglobulin E in patients with markedly elevated serum immunoglobulin E levels.

The metabolism of human IgE was studied in normals, severe atopics, and patients with the hyperimmunoglobulin E-recurrent infection (HIE; Job's) syndrome to determine whether IgE metabolism is altered in patients with marked elevation of serum IgE. Purified polyclonal 125I-IgE was administered intravenously and serial plasma and urine samples were obtained. After analysis, the metabolic data support previously published evidence that IgE (at concentrations found in normal individuals) is catabolized at a higher fractional rate than other immunoglobulins and is catabolized by both an intravascular and an extravascular pathway. In addition, the data show that the fractional catabolic rate for IgE is significantly less for the atopic patients (mean +/- SEM = 0.20 +/- 0.01) and for the HIE patients (0.15 +/- 0.02) than for the normal volunteers (0.52 +/- 0.06; P less than 0.01) and is inversely related (r = -0.851; P less than 0.001) to the serum IgE concentration. These findings have specific importance in showing that decreased fractional catabolic rate contributes substantially to elevation of IgE in atopic and HIE patients. In addition, the findings have general significance in that they lead to a unifying hypothesis of immunoglobulin catabolism.

Body Fluid Compartments↗

PubMed1987

Norepinephrine metabolism in humans. Kinetic analysis and model.

The present study was undertaken to quantify more precisely and to begin to address the problem of heterogeneity of the kinetics of distribution and metabolism of norepinephrine (NE) in humans, by using compartmental analysis. Steady-state NE specific activity in arterialized plasma during [3H]NE infusion and postinfusion plasma disappearance of [3H]NE were measured in eight healthy subjects in the supine and upright positions. Two exponentials were clearly identified in the plasma [3H]NE disappearance curves of each subject studied in the supine (r = 0.94-1.00, all P less than 0.01) and upright (r = 0.90-0.98, all P less than 0.01) positions. A two-compartment model was the minimal model necessary to simultaneously describe the kinetics of NE in the supine and upright positions. The NE input rate into the extravascular compartment 2, estimated with the minimal model, increased with upright posture (1.87 +/- 0.08 vs. 3.25 +/- 0.2 micrograms/min per m2, P less than 0.001). Upright posture was associated with a fall in the volume of distribution of NE in compartment 1 (7.5 +/- 0.6 vs. 4.7 +/- 0.3 liters, P less than 0.001), and as a result of that, there was a fall in the metabolic clearance rate of NE from compartment 1 (1.80 +/- 0.11 vs. 1.21 +/- 0.08 liters/min per m2, P less than 0.001). We conclude that a two-compartment model is the minimal model that can accurately describe the kinetics of distribution and metabolism of NE in humans.

Adult↗

PubMed1987

In vivo metabolism of proapolipoprotein A-I in Tangier disease.

Tangier disease is a rare familial disorder characterized by extremely low levels of apolipoprotein A-I (apoA-I) and high density lipoproteins (HDL). In normal subjects, proapoA-I is secreted into plasma and converted to mature apoA-I by the cleavage of the amino-terminal six amino acids with the major isoprotein in plasma being mature apoA-I. In contrast, in Tangier disease there is a marked relative increase of proapoA-I as compared with mature apoA-I. ProapoA-I and mature apoA-I were isolated from normal and Tangier disease subjects, radio-labeled, and autologous apoA-I isoproteins injected into normal and Tangier subjects. The in vivo catabolism and conversion of proapoA-I and mature apoA-I in normal and Tangier disease subjects were quantitated. A comparison of the rate of catabolism of apoA-I isoproteins from plasma revealed a significantly faster rate of catabolism of both isoproteins of apoA-I in Tangier subjects when compared with normal subjects. The fractional conversion rate of proapoA-I to mature apoA-I was 3.9 d-1 in normal subjects and 3.6 d-1 in Tangier subjects. The results indicate that (a) apoA-I enters plasma as the pro isoprotein in both normal and Tangier subjects, (b) Tangier disease subjects have a normal fractional rate of conversion of proapoA-I to mature apoA-I, (c) proapoA-I is catabolized at the same rate as mature apoA-I in Tangier subjects, and (d) Tangier subjects catabolize both pro and mature apoA-I at a much greater rate than do normal subjects. Therefore, the relative increase in proapoA-I in Tangier disease is due to a marked decrease in mature apoA-I resulting from rapid catabolism of both pro- and mature apoA-I and not to defective conversion of proapoA-I to mature apoA-I.

Adult↗

PubMed1987

A kinetic model of chylomicron core lipid metabolism in rats: the effect of a single meal.

A detailed quantitative description of the metabolism of the core lipids of chylomicrons was developed with data obtained from rats injected intravenously with radioactive chylomicrons. Groups of recipient rats were starved or else fed a single meal that was either fat-free or contained 5% fat. The kinetic model included chains of delipidation compartments and a remnant particle. Compartments for recirculation of portions of triglyceride, cholesteryl ester, and unesterified fatty acid radioactivities were all included and necessary to obtain good fits to the data. Making the simplifying assumption that remnants could be represented as particles retaining cholesteryl esters but depleted in triglycerides, a 'delipidation index' was calculated as the ratio of the cholesteryl ester residence time divided by the triglyceride residence time. Significant differences were found in the delipidation index between the starved group and both the normal-fed and fat-free-fed groups. Compared with rats fed a meal of the usual diet which contained 5% fat, starved rats showed more extensive delipidation and a trend toward a longer residence time of remnant particles. A longer residence time of triglycerides in rats fed a fat-free meal was explained by less delipidation, but remnant removal appeared to be accelerated. The kinetic model makes possible an interpretation of the patterns of metabolism in terms of the known underlying physiological mechanisms.

Animals↗

PubMed1986

Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinemia.

Patients with low-density lipoprotein (LDL) concentrations in the top 10th percentile of the population (type II hyperlipoproteinemia [HLP]) are at increased risk for premature cardiovascular disease; however, the incidence of myocardial infarction and death can be decreased by LDL cholesterol reduction. Mevinolin, an inhibitor of endogenous cholesterol synthesis, has been shown to reduce LDL cholesterol concentrations in a subset of type II patients with heterozygous familial hypercholesterolemia (FH). Using a double-blind, randomized, crossover, placebo-controlled trial, the safety and efficacy of mevinolin were compared in 24 patients with type II HLP with heterozygous FH (n = 6) or without FH type II HLP (n = 18). Compared with placebo treatment, both apolipoprotein B and LDL cholesterol levels were reduced (p less than 0.01) in both FH and non-FH patients by 28 to 34% with mevinolin treatment. In addition, high-density lipoprotein cholesterol levels were significantly increased (p less than 0.001) in both patients with FH (16%) and those with non-FH type II HLP (14%). Patients had no serious or clinically significant adverse effects. Thus, mevinolin is a useful drug for treatment of most patients with elevated plasma LDL cholesterol concentrations.

Adult↗

PubMed1986

The methodology of compartmental modeling as applied to the investigation of lipoprotein metabolism.

The statements to this point only give a cursory review of the beginning (20 years) of the kinetic approach to the classification of lipoproteins and subsystems which are involved in their synthesis and metabolism. At the present time the following partial list of theoretical findings expressed through model building can be made for the lipid and lipoprotein field: A cascade process of delipidation for VLDL exists and the rate of this process is decreased in subjects with hyperlipoproteinemia. ApoC recycles between VLDL and HDL in response to the dynamics of the delipidation cascade. New synthesis of apoB first appears with newly synthesized VLDL. VLDL apoB synthesis decreased in hyperlipidemic states examined. Multiple synthesis pathways exist for the triglyceride moiety of VLDL as determined by the transit time of a precursor through the conversion pathway. Thus the isotopic precursor methods now yield the same results as the more invasive techniques. Kinetic heterogeneity of VLDL, IDL, LDL, and HDL has been established. Kinetic heterogeneity for apoA-I, apoA-II, apoB, apoC-2 and apoC-3 have been established. The presence of direct pathways for IDL and LDL synthesis have been established. Irreversible loss of apoC from HDL has been predicted using models. Synthesis of apoC has been found to be invariant in hyperlipoproteinemic states studied. Hepatic cholesterol compartments associated with the formation of bile acids and biliary cholesterol derive a majority of their cholesterol from newly synthesized and lipoprotein-free cholesterol. More than 85% of the free cholesterol in the beta-lipoproteins cycles directly through the HDL. Free cholesterol recycles between HDL and tissue pools and between HDL and beta-lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Kinetic model of whole-body vanadium metabolism: studies in sheep.

A compartmental model for vanadium metabolism in sheep has been proposed. The model is consistent with data obtained from sheep fed a control diet (2.6 ppm vanadium) containing 0 or 200 ppm supplemental vanadium. Sheep were administered 48V dioxovanadium either orally or intravenously. Blood, feces, and urine radioactivity were monitored for 6 days postdosing. Several new insights regarding vanadium metabolism are suggested and tested against the data using the model. Some of these include significant absorption of 48V occurs from the upper gastrointestinal tract; an in vivo process is necessary in order for 48V dioxovanadium to be converted into a more biologically reactive species; at steady state the upper and lower gastrointestinal tracts contain at least 10- and 100-fold more mass of vanadium, respectively, than does blood. No statistically significant differences in transport rate constants were found between animals receiving 0 and 200 ppm supplemental dietary vanadium. The availability of a model will enable the refinement of future studies regarding vanadium metabolism in the ruminant.

Administration, Oral↗

PubMed1986

Abnormal in vivo metabolism of apolipoprotein E4 in humans.

Apolipoprotein E (apoE) is important in modulating the catabolism of remnants of triglyceride-rich lipoprotein particles. It is a polymorphic protein with the three common alleles coding for apoE2, apoE3, and apoE4. ApoE3 is considered the normal isoform, while apoE4 is associated both with hypercholesterolemia and type V hyperlipoproteinemia. We quantitated the kinetics of metabolism of apoE4 in 19 normolipidemic apoE3 homozygotes and 1 normolipidemic apoE4 homozygote, and compared this with the metabolism of apoE3 in 12 normolipidemic apoE3 homozygotes. In the apoE3 homozygous subjects, apoE4 was catabolized twice as fast as apoE3, with a mean plasma residence time of 0.37 +/- 0.01 d (+/- SEM) and 0.73 +/- 0.05 (P less than 0.001), respectively. When plasma was fractionated into the lipoprotein subclasses, the greatest amount of labeled apoE4 was present on very low density lipoproteins, while the largest fraction of labeled apoE3 was associated with high density lipoproteins. The plasma apoE concentration was decreased in an apoE4 homozygote compared with the apoE3 homozygotes (3.11 mg/dl vs. 4.83 +/- 0.35 mg/dl). The reduced apoE4 concentration was entirely due to a decreased apoE4 residence time in the apoE4 homozygote (0.36 d vs. 0.73 +/- 0.05 d for apoE3 in apoE3 homozygotes). These results indicate that apoE4 is kinetically different than apoE3, and suggest that the presence of apoE4 in hypercholesterolemic and type V hyperlipoproteinemic individuals may play an important pathophysiological role in the development of these dyslipoproteinemias.

Adolescent↗

PubMed1986

Familial apolipoprotein E deficiency.

A unique kindred with premature cardiovascular disease, tubo-eruptive xanthomas, and type III hyperlipoproteinemia (HLP) associated with familial apolipoprotein (apo) E deficiency was examined. Homozygotes (n = 4) had marked increases in cholesterol-rich very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), which could be effectively lowered with diet and medication (niacin, clofibrate). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 and apoA-IV in VLDL, IDL, and low density lipoproteins. Radioiodinated VLDL apoB and apoE kinetic studies revealed that the homozygous proband had markedly retarded fractional catabolism of VLDL apoB-100, apoB-48 and plasma apoE, as well as an extremely low apoE synthesis rate as compared to normals. Obligate heterozygotes (n = 10) generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The data indicate that homozygous familial apoE deficiency is a cause of type III HLP, is associated with markedly decreased apoE production, and that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.

Adolescent↗

PubMed1986

Abnormal low density lipoprotein metabolism in apolipoprotein E deficiency.

Apolipoprotein(apo) E deficiency is an inherited disease characterized by type III hyperlipoproteinemia and less than 1% normal plasma apoE concentration. The role of apoE in LDL metabolism was investigated by quantitating the metabolism of radiolabeled normal and apoE-deficient LDL in both normal and apoE-deficient subjects. ApoE deficiency resulted in an accumulation of plasma IDL, and a decreased synthesis of LDL consistent with a block in the conversion of IDL to LDL. The LDL isolated from the apoE-deficient patient was similar to normal LDL in hydrated density, size, and composition. However, the apoE-deficient LDL was kinetically abnormal with delayed catabolism in both normal subjects and the apoE-deficient patient. In addition, the catabolism of normal LDL in the apoE-deficient subject was increased. These results were interpreted as indicating that apoE is necessary for the conversion of IDL to LDL and the formation of kinetically normal LDL. The rapid catabolism of normal LDL in the apoE-deficient patient suggests an up-regulation of the hepatic LDL receptor pathway. Based on these results, apoE is proposed to play an important role in the conversion of IDL to LDL, the formation of kinetically normal LDL, and the regulation of LDL receptor function.

Adult↗

PubMed1985

Estimation of VLDL cholesterol in hyperlipidemia.

Lipoprotein data from 10947 fasting blood samples drawn between 1968 and 1982 in the Molecular Disease Branch at the National Institutes of Health were used to test the generalizability of estimating very low density lipoprotein cholesterol (VLDL-C) from plasma triglyceride (TG). Patient samples with total cholesterol levels over 500 mg/l and triglyceride values in the 0-100 000 mg/1 range were included in this study. A previously defined linear relationship VLDL-C = 0.20 (TG) was observed in the past by Friedewald and collaborators, allowing estimation of low density lipoprotein cholesterol (LDL-C) without ultracentrifugation for TG values up to 4 000 mg/1. The results from this report extend the use of the Friedewald relationship to higher TG levels, and to various dyslipidemic states. As the VLDL-C estimates become increasingly imprecise for TG values greater than 10 000 mg/l, caution should be exercised using the estimate in the higher TG ranges. Comparisons with an alternative equation VLDL-C = 0.166 (TG) showed equal or improved accuracy with this estimation procedure, particularly at high TG levels.

Adolescent↗

PubMed1985

Effects of combination cholestyramine-neomycin treatment on plasma lipoprotein concentrations in type II hyperlipoproteinemia.

Recent prospective clinical trials have established that cholesterol reduction in patients with elevated (upper 90th percentile) concentrations of low-density lipoproteins (LDL) reduces the incidence of myocardial infarction and sudden death. Because the level of protection from these cardiovascular sequelae is directly related to the degree of LDL reduction, combination therapy using different hypolipidemic agents has been used in patients with type II hyperlipoproteinemia (HLP). Neomycin is as effective as cholestyramine in reducing LDL levels and combination neomycin-niacin treatment normalizes the plasma lipoproteins in 92% of patients with type II HLP. Because neomycin could theoretically ameliorate some of the gastrointestinal side effects of cholestyramine in addition to further affecting cholesterol levels, the effects of combination cholestyramine-neomycin treatment on the plasma lipoprotein were assessed in 18 patients with type II HLP in a 9-month clinical trial. Compared with diet-only treatment, cholestyramine reduced total and LDL cholesterol levels by 77 mg/dl (22%) and 78 mg/dl (31%), respectively. In addition to relieving cholestyramine-induced constipation, neomycin further reduced the total cholesterol level by 20 mg/dl (6%). However, this further reduction in total cholesterol concentration was the result of a decrease in the concentration of high-density lipoprotein cholesterol. These findings indicate that combination therapy does not have an additive LDL cholesterol-lowering effect and that neomycin and cholestyramine is not a useful drug combination. In addition, these results illustrate the importance of determining the high-density lipoprotein cholesterol concentration to fully interpret the effects of hypolipidemic treatment.

Cholesterol, HDL↗

PubMed1985

The association of LDL receptor activity, LDL cholesterol level, and clinical course in homozygous familial hypercholesterolemia.

Patients with homozygous familial hypercholesterolemia (FH), reveal a marked heterogeneity in plasma cholesterol levels, response to diet as well as drug treatment, and clinical course. Low-density lipoprotein (LDL) receptor activities were assessed by the rate of 14C-oleate cholesteryl ester biosynthesis in fibroblasts from 13 FH homozygotes in tissue culture. The receptor activity of the individual patients was highly correlated with initial pretreatment plasma cholesterol and LDL cholesterol levels (P less than .001, r = -0.89). In addition, the LDL receptor activity was positively correlated with the age of onset of angina based on the Cox model (P less than .035, likelihood ratio = 6.71). An association was also noted between LDL receptor activity and cholesterol reduction with drugs. These data provide direct evidence for the correlation between the heterogeneity of the LDL receptor and the expression of the clinical manifestations of homozygous FH. The determination of pretreatment plasma cholesterol level and LDL receptor activity in patients with homozygous FH provide useful parameters on which to base predictions of the clinical progression of cardiovascular disease. These parameters may also influence the selection of a program for diet and drug therapy. Patients with markedly elevated plasma cholesterol levels and very low LDL receptor activity should be considered to be candidates for multiple drug therapy, and portacaval shunt, and/or periodic plasma exchanges.

Adolescent↗

PubMed1984

Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients.

Familial hypercholesterolemia (FH) is characterized by an autosomal codominant inheritance, an abnormality in low-density lipoprotein (LDL) receptor function, elevated plasma cholesterol levels and premature atherosclerosis. Sixteen patients with homozygous FH were studied to correlate the extent of their atherosclerotic disease with their lipid levels and receptor function. The age range at initial presentation was 3 to 38 years (mean 12), and at the last examination, 6 to 43 years (mean 20). The mean pretreatment total plasma cholesterol concentration for all patients was 729 +/- 58 mg/dl (+/- standard error of the mean), and the mean LDL cholesterol level was 672 +/- 58 mg/dl (normal 60 to 176). High-density lipoprotein cholesterol was 28 +/- 3 mg/dl (normal 30 to 74). In the 7 patients with FH who had symptoms of myocardial ischemia (Group I), the mean pretreatment LDL cholesterol value (817 +/- 62 mg/dl) was higher than that of the 9 asymptomatic patients (Group II) (560 +/- 74 mg/dl). In Group I, 5 of 7 patients had left or right coronary ostial narrowing and 3 had significant left ventricular outflow obstruction. Most coronary arterial narrowing occurred in the right coronary and left anterior descending arteries and the least amount in the left circumflex coronary artery. A femoral bruit was the physical finding that correlated best with the Group I population; brother:sister pairs revealed a milder clinical course for the female. Seven of the 16 patients have survived into their third decade without symptoms. Comparison of these persons with those in whom angina developed reveals a marked heterogeneity in their clinical course, which appears to be associated with receptor negative/defective status.

Adolescent↗

PubMed1984

Molecular properties of radioiodinated apolipoprotein A-I.

Radioiodinated apolipoprotein A-I was separated into two pools by gel chromatography on Sephadex G-150 superfine resin or by high performance liquid chromatography using a TSK-2000 column. The first pool, pool 1, was indistinguishable from unlabeled apo-A-I as judged by sedimentation equilibrium, circular dichroic measurements, and radial immunodiffusion. This pool self-associated according to a monomer-dimer-tetramer-octamer scheme and underwent the expected conformation changes with dissociation as reported previously for unlabeled apo-A-I. The radioiodinated material in pool 2 had less secondary structure as compared to the unlabeled material and did not self-associate. Protein in this pool was immunochemically less reactive than unlabeled apo-A-I. Kinetic studies, in vivo, demonstrated that these two pools of radioiodinated apo-A-I are also distinguished metabolically. Discussion centers around possible mechanisms of formation of the incompetent protein in pool 2 and factors that should be taken into consideration when using unfractionated radioiodinated apo-A-I for experimental studies.

Adult↗

PubMed1984

Neomycin and plasma lipoproteins in type II hyperlipoproteinemia.

Neomycin, a nonabsorbable aminoglycoside antibiotic, has been shown to exert a hypocholesterolemic effect in man. In a 9-mo, double-blind, randomized, crossover, placebo-controlled clinical trial, the effect of neomycin, 2 gm/day, on plasma lipoproteins, as well as its safety, was described in 20 subjects with type II hyperlipoproteinemia. A 15% (50 mg%) decline in plasma cholesterol concentration was observed with neomycin. Most of this effect resulted from a 41 mg% (16%) decrease in low-density lipoprotein cholesterol concentration. No significant or consistent effect on the concentration of high-density lipoprotein cholesterol was observed. Monthly audiologic and renal evaluation disclosed no oto- or nephrotoxicity. Neomycin treatment in patients with type II hyperlipoproteinemia is an inexpensive and effective means of lowering the concentration of low-density lipoproteins and is free of significant side effects over a 3-mo period.

Adult↗

PubMed1984

Normalization of plasma lipoprotein concentrations in patients with type II hyperlipoproteinemia by combined use of neomycin and niacin.

The oral administration of neomycin or niacin as single-drug therapy can significantly lower total and low-density lipoprotein cholesterol concentrations in patients with type II hyperlipoproteinemia. However, in the majority of patients treated with one of these drugs as sole therapy plasma lipid and lipoprotein concentrations do not normalize. The effect of combined neomycin (2 g/day) and niacin (3 g/day) treatment on the plasma lipoprotein concentrations was determined in 25 type II hyperlipoproteinemic patients in a double-blind, randomized, placebo-controlled, crossover clinical trial. Treatment with neomycin was well tolerated by all 25 study patients and significantly reduced total and low-density lipoprotein cholesterol concentrations by 23% and 29%, respectively (p less than .05). In contrast to the well-tolerated neomycin regimen, 11 patients (44%) were unable to continue niacin treatment because of adverse side effects. In the 14 patients treated with both neomycin and niacin, niacin further lowered the concentrations of total and low-density lipoprotein cholesterol by 18% and 25%, respectively, and increased high-density lipoprotein cholesterol by 32% (p less than .05) compared with that in the patients receiving neomycin plus niacin placebo. Compared with diet-only therapy, combined treatment with neomycin plus niacin reduced the total plasma cholesterol concentration by 36%, low-density lipoprotein cholesterol by 45%, and the low-density lipoprotein/high-density lipoprotein ratio by 46% and it increased plasma high-density lipoprotein concentrations by 24% (p less than .001). During the study, 80% of all the study patients and 92% of the patients who complied with the combined regimen normalized their total and low-density lipoprotein concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗