Search PubMed⌕ Search

Biomedical subjects

N E Miller

Publications and source records attributed to N E Miller.

At least 37 records · Page 2Linked to original sources
PubMed2000

Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1.

Apolipoprotein A-I (apoA-I) and an apoA-I peptide mimetic removed seeding molecules from human low density lipoprotein (LDL) and rendered the LDL resistant to oxidation by human artery wall cells. The apoA-I-associated seeding molecules included hydroperoxyoctadecadienoic acid (HPODE) and hydroperoxyeicosatetraenoic acid (HPETE). LDL from mice genetically susceptible to fatty streak lesion formation was highly susceptible to oxidation by artery wall cells and was rendered resistant to oxidation after incubation with apoA-I in vitro. Injection of apoA-I (but not apoA-II or murine serum albumin) into mice rendered their LDL resistant to oxidation within 3 h. Infusion of apoA-I into humans rendered their LDL resistant to oxidation within 6 h. We conclude that 1) oxidation of LDL by artery wall cells requires seeding molecules that include HPODE and HPETE; 2) LDL from mice genetically susceptible to atherogenesis is more readily oxidized by artery wall cells; and 3) normal HDL and its components can remove or inhibit the activity of lipids in freshly isolated LDL that are required for oxidation by human artery wall cells.

Animals↗
PubMed2000

Distribution of phospholipid transfer protein in human plasma: presence of two forms of phospholipid transfer protein, one catalytically active and the other inactive.

Plasma phospholipid transfer protein (PLTP) plays an important role in the maintenance of plasma high-density lipoprotein (HDL) content and remodeling of HDL in the circulation. In the present study we have used different fractionation methods to investigate the distribution of PLTP in human plasma. A novel enzyme-linked immunosorbent assay developed during the study allowed for simultaneous assessment of both PLTP mass and activity in the fractions obtained. Size-exclusion chromatography and plasma fractionation by nondenaturing polyacrylamide gel electrophoresis (PAGE) yielded similar results demonstrating that PLTP associates in native plasma with two distinct particle populations, while ultracentrifugation with high salt leads to detachment of PLTP from lipoprotein particles and loss of a majority of its phospholipid transfer activity. Interestingly, analysis of the size-exclusion chromatography fractions demonstrated that PLTP exists in the circulation as an active population that elutes in the position of HDL corresponding to an average molecular mass of 160+/-40 kDa and an inactive form with an average mass of 520+/-120 kDa. The inactive fraction containing approximately 70% of the total PLTP protein eluted between HDL and low density lipoprotein (LDL). Thus, the two PLTP pools are associated with different types of lipoprotein particles, suggesting that the PLTP activity in circulation is modulated by the plasma lipoprotein profile and lipid composition.

Antibodies, Monoclonal↗
PubMed2000

Promethazine as a motion sickness treatment: impact on human performance and mood states.

PURPOSE: Intramuscular (i.m.) injections of promethazine in 25 mg or 50 mg dosages are commonly used to treat space motion sickness in astronauts. The present study examined the effects of i.m. injections of promethazine on performance, mood states, and motion sickness in humans. METHODS: Subjects were 12 men, mean age 36 + 3.1, who participated in 1 training day and 3 treatment conditions: a 25-mg injection of promethazine, a 50-mg injection of promethazine, and a placebo injection of sterile saline. Each condition, scheduled at 7-d intervals, required an 8-10-h day in which subjects were tested on 12 performance tasks, and were given a rotating chair motion sickness test. On the training day subjects were trained on each task to establish stability and proficiency. Treatment conditions were counterbalanced and a double-blind procedure was used to administer the medication or placebo. RESULTS: Statistically significant decrements in performance were observed for both dosages of promethazine as compared with the placebo. Performance decrements were associated with mean blood alcohol dose equivalency levels of 0.085% for 25 mg and 0.137% for 50 mg doses. Mood scale results showed significant changes in individual subjective experiences with maximum deterioration in the arousal state and fatigue level. Only the 25-mg dosage significantly increased motion sickness tolerance when compared with the placebo. CONCLUSIONS: These data suggest that effective doses of promethazine currently used to counteract motion sickness in astronauts may significantly impair task components of their operational performance.

Adult↗
PubMed1999

Analysis of apolipoproteins and lipoproteins by capillary electrophoresis.

Capillary electrophoresis provides a valuable analytical tool for the analysis of apolipoproteins and lipoproteins. Sodium dodecyl sulfate (SDS) capillary gel electrophoresis can resolve human and animal apolipoprotein (apo) A-I, apo A-II, apo E and apo A-IV in isolated high density lipoproteins (HDLs) and is capable of analysing HDL apo A-I and apo A-II content with a coefficient of variation (CV) of less than 5%. Capillary zone electrophoresis (CZE) using coated capillaries with Tricine-urea buffer can also be used for the analysis of HDL apolipoproteins and is also capable of resolving apo A-I isoforms, pro-apo A-I, mature apo A-I and deamidated apo A-I. Furthermore it can separate human A-I from endogenous rabbit A-I in transgenic rabbits expressing the human apo A-I gene. Capillary isoelectric focusing can also separate apo A-I isoforms. Analysis of charge-modified low density lipoprotein (LDL) (ox-LDL) produced by in vitro lipid peroxidation can be performed by CZE and the technique can be used to monitor simultaneous changes in the electrophoretic mobility and absorption spectra of LDL.

Animals↗
PubMed1999

High-density lipoproteins differentially modulate cytokine-induced expression of E-selectin and cyclooxygenase-2.

Atherogenesis is a multifactorial chronic inflammatory disease in which low plasma levels of HDLs are a strong predictor of the condition. Although the mechanism of protection by HDLs is not precisely known, HDLs have been shown to influence many of the events involved in the development of atherosclerosis. Previously we have shown that HDLs inhibited the cytokine-induced expression of adhesion molecules (E-selectin, VCAM-1, and ICAM-1) by endothelial cells (ECs). As the complete transcriptional regulation of all 3 genes requires the NF-kappaB family of transcription factors, we examined the effect of HDLs on activation of NF-kappaB. We also investigated the effect of HDLs on 2 other cytokine-induced genes, granulocyte-macrophage colony-stimulating factor (GM-CSF) and cyclooxygenase (Cox-2; prostaglandin H2 synthase, EC 0.1.14.99.1). E-selectin expression in response to tumor necrosis factor-alpha (TNFalpha) was, as expected, inhibited in ECs that had been preincubated with HDLs. However, the level of secretion of GM-CSF in the same cultures was no different from control. In a similar manner, although HDLs had no effect on steady-state mRNA levels of GM-CSF, the levels of E-selectin were significantly inhibited by HDLs. In transient cotransfection experiments we found that HDLs inhibited the cytokine-induced expression of a reporter gene driven by the E-selectin proximal promoter (-383 to 80) but had no effect on the expression of a reporter gene driven under the control of the proximal promoter of GM-CSF (-627 to 28). As would be predicted from this differential response, HDLs did not influence the nuclear translocation or DNA binding of NF-kappaB, or alter the kinetics of degradation and resynthesis of the inhibitory protein IkappaBalpha. We found that HDLs synergized with cytokine to enhance the expression of Cox-2 and induce the synthesis of its main EC product, prostacyclin (PGI2), a potent inhibitor of platelet and leukocyte functions. In conclusion, HDL induces an antiinflammatory phenotype in cytokine-induced ECs, synergizing with cytokine to induce elevation of Cox-2 in addition to inhibiting adhesion molecule expression. Our studies show that these differential effects are mediated in a manner that is likely to be independent of NF-kappaB per se.

Adult↗
PubMed1999

Acute effects of intravenous infusion of ApoA1/phosphatidylcholine discs on plasma lipoproteins in humans.

To investigate the metabolism of nascent HDLs, apoA1/phosphatidylcholine (apoA1/PC) discs were infused IV over 4 hours into 7 healthy men. Plasma total apoA1 and phospholipid (PL) concentrations increased during the infusions. The rise in plasma apoA1 was greatest in small prebeta-migrating particles not present in the infusate. Total HDL unesterified cholesterol (UC) also increased simultaneously. After stopping the infusion, the concentrations of apoA1, PL, HDL UC, and small prebeta HDLs decreased, whereas those of HDL cholesteryl ester (CE) and large alpha-migrating apoA1 containing HDLs increased. ApoB-containing lipoproteins became enriched in CEs. Addition of apoA1/PC discs to whole blood at 37 degrees C in vitro also generated small prebeta HDLs, but did not augment the transfer of UC from erythrocytes to plasma. We conclude that the disc infusions increased the intravascular production of small prebeta HDLs in vivo, and that this was associated with an increase in the efflux and esterification of UC derived from fixed tissues. The extent to which the increase in tissue cholesterol efflux was dependent on that in prebeta HDL production could not be determined. Infusion of discs also reduced the plasma apoB and apoA2 concentrations, and increased plasma triglycerides and apoC3. Thus, nascent HDL secretion may have a significant impact on prebeta HDL production, reverse cholesterol transport and lipoprotein metabolism in humans.

Adult↗
PubMed1998

Plant monoterpenes do not raise plasma high-density-lipoprotein concentrations in humans.

BACKGROUND: Low plasma concentrations of HDLs are associated with an increased risk of coronary artery disease. Two uncontrolled studies suggested that plant monoterpenes may have substantial HDL-cholesterol-elevating activity in humans. Each study used a proprietary mixture of 6 monoterpenes in olive oil. OBJECTIVE: The present study was undertaken to test more rigorously the hypothesis that monoterpenes raise HDL concentrations in men with hypoalphalipoproteinemia. DESIGN: A double-blind, placebo-controlled crossover design was used. Twenty-four men aged 58-68 y (x: 62.3 y) with plasma HDL cholesterol <1.1 mmol/L, plasma triacylglycerols <3.5 mmol/L, and plasma total cholesterol <5.5 mmol/L at recruitment were randomly assigned to 6 capsules daily of a proprietary mixture of 6 monoterpenes in olive oil or 6 capsules daily of olive oil alone for 24 wk, followed by a washout period of 8 wk, and then the alternative capsules for 24 wk. RESULTS: Five men dropped out. In the others, compliance was excellent as judged by capsule counts and urinary menthol glucuronide concentrations. No significant effects were observed on plasma HDL-cholesterol or apolipoprotein A-I concentrations, nor on plasma triacylglycerol, LDL-cholesterol, or apolipoprotein B concentrations. CONCLUSIONS: Plant monoterpenes have no HDL-elevating activity of potential value for coronary artery disease prevention.

Aged↗
PubMed1998

Analysis of high density lipoprotein apolipoproteins by capillary zone and capillary SDS gel electrophoresis.

We describe new methods for analyzing the apolipoproteins (apo) of the high density lipoproteins (HDL) of several species by two modes of capillary electrophoresis: size separation using a molecular sieving buffer, and capillary zone electrophoresis (CZE) using neutral coated capillaries. By either mode HDL apos were resolved within 25 min. Results for apoA-I and apoA-II mass agreed with those by electroimmunoassay; intra-assay coefficients of variation were 1.8-4.2%. The migration times of human, rat, rabbit, and bovine apoA-I during CZE were proportional to their net charge/Mr ratios. This enabled human and rabbit apoA-I to be quantified simultaneously in transgenic rabbit HDLs. CZE also resolved human apoA-I isoforms, deamidated apoA-I, and pro-apoA-I.

Animals↗
PubMed1998

Capillary electrophoresis to monitor the oxidative modification of low density lipoproteins.

A procedure has been developed that uses high performance capillary electrophoresis to monitor the changes in the electrophoretic mobility of low density lipoproteins (LDL) resulting from Cu2+-catalyzed lipid peroxidation. Using uncoated fused silica capillaries, methylglucamine-Tricine, pH 9.0, as electrophoresis buffer and a field strength of 350 V/cm, separation of native LDL and oxidized LDL could be achieved in 8-10 min. The electrophoretic mobility of native LDL under these conditions was 1.32 x 10(-4) cm2 x V(-1) x s(-1), and the migration time could be measured with a coefficient of variation of 0.44%. The increase in the electronegativity of LDLs during incubation with 10 microM Cu2+ for 0.25-2.0 h resulted in a progressive increase in migration time. Monitoring the absorbance of the migrating LDL particles at a wavelength of 234 nm showed a progressive increase in peak area, which paralleled that in diene conjugation measured spectrophotometrically. Electronegative LDL particles formed by modification with malondialdehyde could also be separated from native LDL particles under these conditions. This new procedure should be useful in studies of factors influencing low density lipoprotein oxidation in vitro and in vivo.

Copper↗
PubMed1998

Very low activated factor VII and reduced factor VII antigen in familial abetalipoproteinaemia.

Abetalipoproteinaemia is a rare disorder of apolipoprotein B metabolism associated with extremely low plasma concentrations of triglyceride. To discover whether the general positive association between factor VII and triglyceride levels extends to this condition, 5 patients were compared with 18 controls. All patients had a triglyceride below 100 micromol/l. Plasma unesterified fatty acid concentration was normal. Although factor IX activity was only slightly reduced (mean 88% standard) and factor IX antigen was normal, mean activated factor VII in patients was strikingly reduced to 34% of that in controls, a level similar to that found in haemophilia B. The patients' mean factor VII activity and factor VII antigen were also significantly reduced to 54% and 63% of those in controls, respectively. Mean factor XI activity and tissue factor pathway inhibitor activity were reduced in patients to 70% and 75% of control values respectively, while factor XII, factor XI antigen, factor X, prothrombin and protein C were normal.

Abetalipoproteinemia↗
PubMed1996

Do dietary phytochemicals with cytochrome P-450 enzyme-inducing activity increase high-density-lipoprotein concentrations in humans?

Low plasma concentrations of high-density lipoprotein (HDL) are associated with increased risk of coronary heart disease. Several drugs that induce the microsomal cytochrome P-450-dependent enzyme system in liver and intestine, the sites of HDL apolipoprotein (apo) A-I and A-II synthesis, raise plasma HDL concentrations in humans. To test the hypothesis that phytochemicals with cytochrome P-450-inducing activity may also increase plasma HDL concentrations, two controlled dietary trials were undertaken in healthy nonsmoking males aged 20-28 y. One study examined the effect of replacing 300 g glucosinolate-free vegetables with 300 g Brussels sprouts/d for 3 wk. The other study examined the effects of 150 mg eugenol/d in capsule form, using a double-blind, placebo-controlled crossover design. There were no significant increases in plasma apo A-I, apo A-II, HDL cholesterol, or HDL phospholipids. These results suggest that dietary phytochemicals that induce members of the cytochrome P-450 system do not necessarily raise plasma HDL concentrations in humans, but do not exclude the possibility that some phytochemicals may have such an effect.

Adult↗
PubMed1996

Effects of intravenous infusion of lipid-free apo A-I in humans.

Apolipoprotein (apo) A-I is the principal protein component of the plasma high density lipoproteins (HDLs). Tissue culture studies have suggested that lipid-free apo A-I may, by recruiting phospholipids (PLs) and unesterified cholesterol from cell membranes, initiate reverse cholesterol transport and provide a nidus for the formation, via lipid-poor, pre-beta-migrating HDLs, of spheroidal alpha-migrating HDLs. Apo A-I has also been shown to inhibit hepatic lipase (HL) and lipoprotein lipase (LPL) in vitro. To further study its functions and fate in vivo, we gave lipid-free apo A-I intravenously on a total of 32 occasions to six men with low HDL cholesterol (30 to 38 mg/dL) by bolus injection (25 mg/kg) and/or by infusion over 5 hours (1.25, 2.5, 5.0, and 10.0 mg.kg-1.h-1). The procedure was well tolerated: there were no clinical, biochemical, or hematologic changes, and there was no evidence of allergic, immunologic, or acute-phase responses. The 5-hour infusions increased plasma total apo A-I concentration in a dose-related manner by 10 to 50 mg/dL after which it decreased, with a half-life of 15 to 54 hours. Coinfusion of Intralipid reduced the clearance rate. The apparent volume of distribution exceeded the known extracellular space in humans, suggesting extensive first-pass clearance by one or more organs. No apo A-I appeared in the urine. Increases in apo A-I mass were confined to the pre-beta region on crossed immunoelectrophoresis of plasma and to HDL-size particles on size exclusion chromatography. Increases were recorded in HDL PL, but not in HDL unesterified or esterified cholesterol. Increases also occurred in LDL PL and in very low density lipoprotein cholesterol, triglycerides, and PL but not in plasma total apo B concentration. These results can all be explained by combined inhibition of HL and LPL activities. Owing to the effects that this would have had on HDL metabolism, no conclusions can be drawn from these data about the role of lipid-free apo A-I in the removal of PL and cholesterol from peripheral tissues in humans. The kinetic data suggest that the fractional catabolic rate of lipid-free apo A-I exceeds that of spheroidal HDLs and is reduced in the presence of surplus PL.

Aged↗
PubMed1996

Sequential microenzymatic assay of cholesterol, triglycerides, and phospholipids in a single aliquot.

The assay of multiple analytes in a single aliquot can be advantageous from both measurement and economic standpoints. The objective of this study was to develop a simple and sensitive microenzymatic method for the determination of three biologically important lipids. Triglycerides (as glycerol), phospholipids (as choline), and total cholesterol (as unesterified cholesterol) were assayed, in that order, by sequential addition of sample, reagents, and microbial enzymes directly into a single microtiter plate well, accompanied by continuous monitoring of a common reporter reaction in which hydrogen peroxide is quantified either by colorimetry with 4-aminoantipyrine and 3-hydroxy-2,4,6-triiodobenzoic acid or by ultraviolet fluorometry with p-hydroxyphenylacetic acid. The detection limit of the method is in the subnanomole mass range for all three lipids. Results obtained with either fluorescence or colored endpoints were in excellent agreement with alternative individual chemical and enzymatic procedures.

Animals↗
PubMed1995

Clinical-experimental interactions in the development of neuroscience. A primer for nonspecialists and lessons for young scientists.

In the article, the author gives examples of some aspects of the development of neuroscience that may be of particular interest to the nonspecialist. In addition to the scientific discoveries involved, the examples illustrate how astute observations in the clinic can draw the attention of workers in the laboratory to significant new problems and how experiments in the laboratory can provide foundations for new clinical applications. These examples also illustrate general lessons that young investigators may find useful and point to the importance of facilitating communications among psychology's fragmenting specialties.

Behavioral Medicine↗
PubMed1994

Autogenic-feedback training: a potential treatment for orthostatic intolerance in aerospace crews.

Postflight orthostatic intolerance has been identified as a serious biomedical problem associated with long-duration exposure to microgravity in space. High priority has been given to the development of countermeasures for this disorder that are both effective and practical. A considerable body of clinical research has demonstrated that people can be taught to increase their own blood pressure voluntarily, and that this is an effective treatment for chronic orthostatic intolerance in paralyzed patients. The current pilot study was designed to examine the feasibility of adding training in control of blood pressure to an existing preflight training program designed to facilitate astronaut adaptation to microgravity. Using an operant conditioning procedure, autogenic-feedback training (AFT), three men and two women participated in four to nine training (15-30-minute) sessions. At the end of training, the average increase in systolic and diastolic pressure, as well as mean arterial pressures, that the subjects made ranged between 20 and 50 mm Hg under both supine and 45 degrees head-up tilt conditions. These findings indicate that AFT may be a useful alternative treatment or supplement to existing approaches for preventing postflight orthostatic intolerance. Furthermore, the use of operant conditioning methods for training cardiovascular responses may contribute to the general understanding of the mechanisms of orthostatic intolerance.

Adult↗
PubMed1994

Evaluation of effects of unmodified niacin on fasting and postprandial plasma lipids in normolipidemic men with hypoalphalipoproteinemia.

PURPOSE: The aim of this study was to define the effects of unmodified niacin on basal lipids and lipoproteins and on the plasma triglyceride response to a fatty meal--postprandial or alimentary lipemia--in individuals with low levels of high-density lipoprotein cholesterol (HDL-C) and normal fasting cholesterol and triglyceride concentrations (normolipidemic hypoalphalipoproteinemia, isolated low HDL-C). PATIENTS AND METHODS: Twenty-eight normolipidemic men (total plasma cholesterol concentration [TC] < 230 mg/dL [< 6 mmol/L], plasma triglyceride [Tg] < 250 mg/dL [2.75 mmol/L]) with low plasma concentrations of HDL-C were randomly assigned to increasing doses of crystalline niacin (up to 3,000 mg/d) or no drug for 12 weeks, then crossed over to the alternate regimen. Outcome measures included changes in plasma lipoproteins and alimentary lipemia. RESULTS: Fifteen participants completed the study. Mean baseline HDL-C +/- SD was 31.7 +/- 6.2 mg/dL (0.82 +/- 0.16 mmol/L). Mean baseline TC, plasma concentration of low-density lipoprotein cholesterol (LDL-C), and Tg were 192 +/- 29.4 mg/dL (4.97 +/- 0.76 mmol/L), 123 +/- 27 mg/dL (3.17 +/- 0.69 mmol/L), and 197 +/- 75 mg/dL (2.17 +/- 0.83 mmol/L), respectively. Unmodified niacin treatment resulted in significant (P < 0.001) reductions of 14% in TC (to 165 mg/dL, 4.26 mmol/L), 40% in Tg (to 119 mg/dL, 1.31 mmol/L), and 18% in LDL-C (to 101 mg/dL, 2.60 mmol/L) and significant increases of 30% in HDL-C (to 42 mg/dL, 1.07 mmol/L), 100% in HDL2 cholesterol (from 5 mg/dL to 9 mg/dL, 0.12 mmol/L to 0.24 mmol/L), and 21% in HDL3 cholesterol (from 27 mg/dL to 33 mg/dL, 0.70 mmol/L to 0.85 mmol/L). Unmodified niacin treatment reduced alimentary lipemia by 45% (P < 0.02). CONCLUSIONS: Crystalline niacin effectively raises HDL-C, lowers LDL-C, and reduces alimentary lipemia in patients with isolated low HDL-C. However, many patients have difficulty tolerating the drug, and supervision may be required to sustain patient compliance and avoid toxicity.

Dietary Fats↗
PubMed1994

Plasma low density lipoprotein cholesterol concentration in cynomolgus monkeys; differing effects of age and body weight in animals consuming low and high cholesterol diets.

It has been reported in cross-sectional studies that plasma cholesterol concentration does not increase with age in nonhuman primates who consume a cholesterol-free diet over their lifetimes. However, dietary composition and body weight may confound any change in plasma cholesterol concentration during aging, as is the case in humans in industrialized societies. To determine if the relationship between age and plasma cholesterol concentration is affected by dietary cholesterol and body weight in nonhuman primates, we compared post-pubertal male cynomolgus monkeys consuming low cholesterol (0.04 mg cholesterol/kcal; n = 10) and high cholesterol (0.39 mg cholesterol/kcal: n = 21) diets. A univariate repeated measures analysis of covariance of low density lipoprotein (LDL) cholesterol concentration was performed from a longitudinal data set (monkeys aged 5 to 20 years), containing an average of 34 observations per animal. The interaction of age and body weight on LDL cholesterol concentration differed among the two dietary groups. In monkeys consuming the low cholesterol diet, an increase in age was associated with a small increase in mean LDL cholesterol concentration. This effect of age increased with increasing body weight. Monkeys on the high cholesterol diet had higher mean LDL concentration, but showed no significant effect of aging on concentration. Instead, at all ages, LDL concentration was strongly affected (positively) by body weight in this group. A qualitatively similar (but quantitatively smaller) effect of body weight was observed only at older ages in the low dietary cholesterol group. We conclude that the associations of LDL concentration with age and body weight in cynomolgus monkeys are strongly influenced by dietary cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗