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The treatment of vascular anomalies of the head and neck typically focuses on restoration of abnormal structures of the soft tissues. However, vascular anomalies can affect the craniofacial skeleton, and osseous reconstruction may be indicated. Osseous involvement occurs as either a primary or secondary phenomenon. In primary osseous involvement, the vascular anomaly expands the bone from within. Secondary osseous involvement occurs when bony hypertrophy develops because of increased flow of the surrounding soft tissue. This article focuses on the management of the osseous deformities associated with vascular anomalies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The most common craniofacial malformation in the newborn is the orofacial cleft, consisting of cleft lip with or without cleft palate and isolated cleft palate. Given its prevalence it is important to understand the etiology of the deformity, medical management prior to surgical correction, surgical techniques and timing.

Wound healing is a complex process that often becomes problematic in complicated patients. When abnormal wound healing occurs, there are many possible ways to intervene. One intervention is through the use of dressings and topical agents. This article is a review of the latest dressings and topical agents available in the United States. Recommendations for use are made based on the most current data in the medical literature.

Low-frequency oscillations in arterial blood pressure (Mayer waves) and R-R interval are thought to be linked through the arterial baroreflex. To delve into this relationship, we applied low (10 mmHg) and moderate (30 mmHg) lower body negative pressure (LBNP) in 10-s cycles to 18 healthy young male subjects. They showed no change in average blood pressure with this oscillatory stimulus but did show a significant decrease in R-R interval (P < 0.05) during both levels of LBNP. In addition, we succeeded in augmenting low-frequency blood pressure oscillations in a graded response to oscillatory LBNP level (P < 0.05) while significantly increasing low-frequency R-R interval oscillations (P < 0.05). However, cross-spectral coherence between these increased oscillations was highly variable across individuals and stimulus level. Although nearly all subjects showed significant coherence during basal conditions (n = 17), only seven subjects maintained significant coherence during both levels of LBNP. These results suggest that a complex interaction of regulatory mechanisms determines the link between low-frequency oscillations and the responses to even low levels of LBNP.

Both age and gender influence cardiovascular autonomic control, which in turn may influence the ability to withstand adverse cardiac events and respond to orthostatic stress. The purpose of this study was (1) to quantify age- and gender- related alterations in autonomic control of blood pressure (BP) and (2) to examine the impact of these autonomic alterations on BP response to orthostatic stress. We measured continuous BP and R-R intervals and vasoactive peptide levels in the supine and 60 degrees head-up tilt positions during paced respiration (0.25 Hz) in 89 carefully screened healthy subjects (41 men, 48 women, aged 20 to 83 years). Data were analyzed by gender (age adjusted) and by age group (gender adjusted). During tilt, women had greater decreases in systolic BP than men (-10.2+/-2 versus -1.2+/-3 mm Hg; P=0.02) and smaller increases in low-frequency (sympathetically mediated) BP power (P=0.02). Upright plasma norepinephrine was lower in women (P=0.02). Women had greater supine high-frequency R-R interval power than men (P=0.0001). In elderly subjects, the tilt-induced increase in low-frequency BP power was also diminished (P=0.01), despite higher supine (P=0.02) and similar upright norepinephrine levels compared with younger subjects. Thus, healthy women have less sympathetic influence on BP and greater parasympathetic influence on R-R interval than men. Elderly subjects also have reduced sympathetic influence on BP, but this appears to be more consistent with a reduction in vasomotor sympathetic responsiveness.

It is well documented that excess weight is a major risk factor for many chronic diseases, and, despite considerable expenditure of time, money, and effort, little or no progress has been made in reversing the trend toward increased weight. Although fitness and athletic clubs offer one potential for tackling this problem, few provide information about the efficacy of their weight-loss programs. There is general agreement that an efficacious weight-loss program should reduce body fat, maintain or increase fat-free mass (FFM), and lower total and low-density lipoprotein (LDL) cholesterol. This study was designed to compare changes in body composition and serum cholesterol associated with participation in a fitness club program (EXP) versus changes that occurred when participants pursued a program of their own choosing (CTL). The EXP group participated in the Bally's Total Fitness program that included exercise, behavior modification, and dietary supplements. Although only small differences in body weight were noted between groups, participation in the EXP program led to significant (sixfold) reductions in fat mass, increases in FFM, and improvements in body composition. These data highlight the importance of using measures of body composition rather than scale weight in evaluating the efficacy of weight-loss programs. Additionally, the EXP group achieved significant reductions in total and LDL cholesterol, particularly among individuals with baseline total cholesterol levels above 200 micrograms/dL. It is also worth noting that respective cholesterol levels were maintained for participants with total cholesterol levels between 150 and 199 micrograms/dL and were increased for those with levels at or below 150 micrograms/dL.

Background: The dynamic autonomic processes leading to vasovagal syncope are poorly understood., Methods and Results: We used complex demodulation to continuously assess changes in respiration, R-R interval, and arterial pressure (blood pressure) variability during 60 degree head-up tilt in 25 healthy subjects with tilt-induced vasovagal syncope and 25 age-matched nonsyncopal control subjects. Coherence and transfer function analyses were used to examine the relation between respiration and R-R interval variability before syncope. Baseline blood pressure, R-R, and ventilation were similar between syncope subjects and control subjects. Syncope subjects experienced an increase in tidal volume and decrease in BP beginning 3 minutes before impending syncope (systolic blood pressure <80 mm Hg) necessitated termination of tilt. Approximately 90 seconds before syncope there was a sudden prolongation of R-R interval and increase in amplitude of high and low frequency R-R interval variability, indicating an abrupt enhancement of vagal tone. The increase in respiratory amplitude between 180 and 90 seconds before syncope was not accompanied by changes in R-R interval or R-R variability, suggesting a dissociation between respiration and the respiratory sinus arrhythmia. The coherence analysis showed fewer syncope subjects with coherence between respiratory and R-R interval variabilities and lower transfer magnitudes in syncope subjects compared with control subjects. Nonsyncopal subjects had no change in respiratory, R-R interval, or blood pressure dynamics during matched time periods before the time of syncope., Conclusions: Vasovagal syncope is preceded by a period of hyperpnea and cardiorespiratory decoupling followed by an abrupt increase in cardiovagal tone. Respiratory pumping without inspiratory cardiac slowing may partially counteract preload reduction until sudden bradycardia precipitates syncope.

Previous studies suggest that the autonomic nervous system plays an important role in the generation of complex heart rate dynamics. Therefore, we hypothesized that the complexity (irregularity) of cardiac interbeat intervals would evolve with the maturation of autonomic innervation to the heart. Twelve healthy newborn piglets were implanted with ECG transmitters and studied at one or more different ages up to 33 days of age, the period during which pigs develop functional sympathetic innervation of the heart from the stellate ganglia. Three animals underwent right stellate ganglionectomy, two a left stellate ganglionectomy, two a right cardiac vagotomy and five a sham procedure. The statistic, approximate entropy (ApEn), was used to quantify the regularity of interbeat interval fluctuations. Sham-operated animals showed an increase in the standard deviation (SD) and irregularity (ApEn) of cardiac interval fluctuations with increasing age. Right stellate ganglionectomized piglets had lower interbeat interval ApEn values, but similar SD's by 26-27 days of age compared to sham-operated animals. Left stellate ganglionectomy, which affects cardiac inotropy rather than chronotropy, had no effect on cardiac interval irregularity, while vagotomy had an indeterminant effect. The increasing irregularity of interbeat interval dynamics during autonomic maturation and the apparent attenuation of heartbeat irregularity when right stellate ganglion innervation is interrupted, provides empirical support for the notion that complex heartbeat dynamics in the mature animal are the result of a network of autonomic neural pathways that enables an organism to adapt to stress.

Dental examinations should routinely include examination of the lips by visual inspection and palpation. The primary risk factor for lip cancer is actinic damage. Squamous cell carcinoma of the lip accounts for about nine per cent of all oral cancers, but there has been a downward trend in the number of cases reported from 1973 to 1984. This trend may be due to the increased use of sunscreens. The clinical presentation and management of lip cancer are discussed.

The effects of the cholesterol oxides on low density lipoprotein receptor (LDLR) gene expression were investigated. Cultured rabbit aortic smooth muscle cells were incubated with 1, 2, and 5 micrograms/ml culture medium concentrations of pure cholesterol, 25-hydroxycholesterol (25-OH), 7-ketocholesterol (7-keto), cholestane-3 beta, 5 alpha, 6 beta-triol (triol) and cholesterol-5 alpha, 6 alpha-epoxide (epoxide) for 12 hours and with vehicle only as control. Total mRNAs were extracted and electrophoresed. Northern blot hybridization analyses were performed. The results showed mRNA expressions of LDLR gene were inhibited to 16.1 +/- 4.4%, 33.8 +/- 0.6%, 42.8 +/- 1.8% and 46.9 +/- 3.9% of control by 25-OH, 7-keto, epoxide and triol respectively. Pure cholesterol showed only minimal inhibition. The inhibitions were time dependent. Although cholesterol oxides have been shown to alter many membrane-related functions and the LDLR domain are located in the cell membrane. The findings of this study suggested that the cholesterol oxides exerted their repressive actions on LDLR function primarily by down-regulating LDLR gene expression rather than directly upon cell membrane.

The objective of this study was to determine if ethanol-induced cytochrome P450 2E1 (CYP2E1) was responsible for the changes in hepatic fatty acids observed in rats fed ethanol intragastrically. We hypothesized that if CYP2E1 was responsible for these changes then CYP2E1 inhibitors fed with ethanol should prevent the ethanol-induced changes in fatty acids. We compared the fatty acid composition of the liver in rats fed ethanol alone with that in rats fed ethanol with the CYP2E1 inhibitors, diallyl sulfide and phenethyl isothiocyanate. In each experiment, rats pair-fed isocaloric glucose were included to determine the effect of the inhibitors alone on the hepatic fatty acid composition. The lobular distribution of succinic dehydrogenase was determined histochemically because the lobular distribution of CYP2E1 shifts to the periportal area in livers of rats fed CYP2E1 inhibitors. The CYP2E1 inhibitors ameliorated both the ethanol-induced changes in fatty acids and the shift in succinic dehydrogenase. Rats fed ethanol but no inhibitors had significantly greater hepatic total fatty acids and triglyceride fractions than when inhibitors were fed ethanol. Ethanol altered the fatty acid composition compared with rats fed ethanol with CYP2E1 inhibitors. The ratio of 20:4/18:2 was significantly lower and that of 18:1/18:0 was greater in alcohol-fed rats compared with their pair-fed controls. The CYP2E1 inhibitors inhibited many of the above effects of alcohol. The data suggest that the changes in the fatty acid composition due to ethanol ingestion are the result of CYP2E1-dependent lipid peroxidation and fatty acid metabolism.

Recent data showing gender differences in autonomic control of heart rate and acute estrogen effects on vasodilatation suggest that estrogen may influence autonomic regulation of heart rate and blood pressure. We aimed to determine the effect of postmenopausal estrogen replacement therapy on autonomic control of beat-to-beat heart rate and blood pressure dynamics. Subjects included 20 healthy postmenopausal women aged 60 to 75 years with normal exercise tolerance tests, 10 of whom were taking oral estrogen for 13 +/- 3 (+/- SEM) years. Six healthy premenopausal women were also studied. Continuous electrocardiographic and noninvasive radial artery blood pressure measurements and intermittent forearm blood flow recordings (by venous-occlusion plethysmography) were obtained before and after a 20-minute, 60 degrees head-up tilt and a 420-kcal meal during periods of spontaneous and metronomic breathing (at 0.25 Hz). Low-frequency (0.01- to 0.15-Hz) and high-frequency (0.15- to 0.50-Hz) heart rate and blood pressure spectral powers were compared with a fast Fourier transform. Cardiovascular and heart rate spectral power responses to upright tilt and meal digestion were the same in postmenopausal estrogen users and nonusers. However, during spontaneous breathing the blood pressure spectral power responses to upright tilt and meal ingestion were significantly different between the two groups of women. The low-frequency systolic pressure power response to upright tilt was smaller in estrogen users than nonusers (P = .01). After meal ingestion nonusers had an early postprandial fall (20 to 30 minutes after the meal) and late rise (50 to 60 minutes) in low-frequency systolic and diastolic pressure powers, which were significantly attenuated in estrogen users (P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)

Prostacyclin (PGI2) is synthesized primarily by endothelial cells, is essential for maintenance of vascular integrity, and may play a role in atherogenesis. Human umbilical vein endothelial cells in culture were incubated with either pure cholesterol, 25-hydroxycholesterol, 7-ketocholesterol, cholesterol 5 alpha,6 alpha-epoxide or cholestane-3 beta,5 alpha,6 beta-triol at 10 micrograms/ml culture medium concentration for 12 hours and 24 hours. PGI2 production measured by radioimmunoassay of 6-keto PGF1 alpha, the stable metabolite of PGI2 was inhibited by 39.6%, 27.3%, 40.1% and 31.9% after incubation with 25-hydroxycholesterol, 7-ketocholesterol, cholesterol 5 alpha, 6 alpha-epoxide or cholestane-3 beta,5 alpha,6 beta-triol for 12 hours respectively. Further inhibitory effects were shown after 24 hours of incubation with 25-hydroxycholesterol and 7-ketocholesterol. Platelet adhesion onto endothelial cell monolayers measured by 111In-labeled platelets was enhanced by 104%, 54% and 37% after incubation with cholestane-3 beta, 5 alpha,6 beta-triol, 25-hydroxycholesterol, and 7-ketocholesterol at 10 micrograms/ml concentration for 12 hours respectively. Pure cholesterol at the same concentration had no effect on PGI2 production or platelet adhesion.

The efficiency of receptor-mediated low-density lipoprotein (LDL) uptake and degradation has been implicated in the development of atherosclerosis. It has previously been shown that cholesterol oxides have more effect on the feedback control of cholesterol biosynthesis than does cholesterol per se on a molecule-for-molecule basis. Cholesterol oxides may also modify the expression or function of the LDL receptors, resulting in alteration in cholesterol homeostasis. Rabbit aortic smooth muscle cells were preincubated in 5% lipoprotein-deficient medium for 24 hours and then incubated with 1 or 5 μg/ml purified cholesterol or cholesterol oxides, including 25-hydroxycholesterol, 7-ketocholesterol, cholestane-3β,5α,6β-triol, and cholesterol 5α, 6α-epoxide for 12 to 24 hours. The uptake of (125)I-LDL was significantly suppressed in a dose-dependent fashion to 67% of the control value by 25-hydroxycholesterol at 1 μg/ml and to 53% at 5 μg/ml after the 24-hour incubation period. Other cholesterol oxides also had inhibitory effects on the LDL uptake at 5 μg/ml. At these concentrations cholesterol oxides additionally inhibited cellular degradation of LDL and the fractional turnover rate of LDL was prolonged., (Copyright © 1992. Published by Elsevier Inc.)

Cholesterol in the diet can readily autoxidize and be absorbed and transported in plasma lipoproteins. Cholesterol oxides can also be endogenously produced in tissues via free-radical-induced reactions. Some cholesterol oxides, notably cholestane-3 beta, 5 alpha, 6 beta-triol and 25-hydroxycholesterol, have been shown to cause injury to vascular endothelial and smooth muscle cells, to alter LDL receptor function, to enhance cholesteryl ester accumulation, to inhibit prostacyclin production, and to induce experimental atherosclerosis alone or in combination with cholesterol. An epidemiological study examining relationships between atherosclerosis and plasma levels of cholesterol oxides as independent risk factors may provide additional insights regarding the roles of cholesterol oxides in atherogenesis.

Experimental evidence indicates a relationship between cholesterol alpha-epoxide and skin cancer, and exposure of skin fibroblasts to ultraviolet radiation enduces formation of significant levels of this oxide. Colon cancer is also etiologically linked to cholesterol oxidation products. Higher than normal levels of cholestanetriol have been found in patients with colon cancer and also in those with precancerous disorders such as adenomatous polyps and ulcerative colitis. Higher than normal levels of cholesterol alpha-epoxide have been found in breast fluid aspirates of women with benign breast disease, with or without atypical hyperplasia of the epithelium, and this may be a factor in the increased incidence of breast cancer associated with hyperplasia. Similarly, the observed increased levels of cholesterol alpha and beta-epoxides in prostatic fluid of men with benign prostatic hypertrophy may be associated with subsequent development of prostate cancer. Cholesterol alpha-epoxide has been found to be mutagenic to fibroblasts in culture and to induce morphological transformation in hamster embryo cells and in mouse C3H cells. 25-Hydroxycholesterol and 20 alpha-hydroxycholesterol are potent suppressors of generation and proliferation of tumor-specific cytotoxic T lymphocytes. Although investigations into the role of cholesterol oxidation products in cancer are still in the early stages, evidence to date indicates a potentially significant role in the induction of some types of cancer.

Rabbit aortic endothelial cells in culture were incubated with 10 micrograms/ml of either pure cholesterol or cholestane-3 beta, 5 alpha, 6 beta-triol (triol) for 12 or 24 hours. Cells incubated with triol showed an increased rate of cell death, decreased [3H]-thymidine incorporation and decreased prostacyclin production as compared to either the control or the pure cholesterol group. These effects were more marked at 24 hours than at 12 hours. Pure cholesterol had no significant effects on any of the above parameters at either time interval. These results suggest potential atherogenic mechanisms for cholestanetriol, one of the most biologically active cholesterol oxidation products.

When rat liver cytosol, possessing sterol carrier protein (SCP) activity was incubated with [3H]-squalene-phospholipid liposomes, cofactors, and rat liver microsomes, squalene from the liposomes was converted into sterols. When cytosol was omitted from the incubation mixture, only insignificant amounts of sterols were produced. Liposomes of squalene with either phosphatidylserine or phosphatidylcholine were equally effective as substrates. The liposomes were stable at 4 degrees C for 3 weeks. The ratio of squalene to phospholipid in the liposomes could be varied over a range of 0.004 to 0.23. Multilamellar liposomes with squalene were not effective as a substrate for the conversion of squalene to sterols. The mechanism for transfer of squalene from the liposomes to the enzymes appears to be initial binding of liposomes to microsomes, with subsequent transfer of the substrate to the enzyme site by the SCP in the cytosol. Microsome-liposome complexes prepared in the absence or presence of cytosol are effective in converting squalene to sterols only if cytosol is added again, indicating that cytosol is not required for the binding of liposomes to microsomes.

Activated partial thromboplastin times (APTT's) performed with a semi-automated electrical-conductivity type of clot timer on plasmas from patients with hepatic disease and intravascular coagulation, and on warfarin or heparin therapy, were significantly lower than when done on the same plasmas with either a manual optical method or an automated optical-endpoint instrument. Results of APTT's done on normal plasmas by the three methods were not significantly different. Substitution of different activator-phospholipid reagents resulted in some variability in results, but these differences were less than those between the different done with both the electrical clot timer and the automated optical instrument on prepared plasmas containing 5.0 or 1.0% of factor II, V, VIII, IX, OR X revealed shorter times with the electrical clot timer only in the case of factor II- and factor V-deficient plasmas. APTT's done on normal plasmas to which 0.1 or 0.3 units per ml. of heparin had been added vitro also were shorter with the electrical clot itmer than the automatic optical instrument. Prothrombin times done on normal and abnormal control plasmas and on a series of plasmas from patients on warfarin therapy showed no significant difference between the two methods.

During acetate infusion at a rate of 10 millimoles/kg/hr arterial blood acetate levels rose progressively to maximums of 7.9 +/- 1.7 mM in uremic dogs and 10.8 +/- 1.4 mM in non-uremic dogs. Following cessation of infusion, removal of acetate followed first order kinetics. Acute uremia had no significant effect on mean clearance rates of acetate (1.28 +/- 0.28 L/kg/hr uremics vs 0.92 +/- 0.22 in non-uremics) or upon blood half-life of acetate following infusion (9.7 min. vs 10.9 min.). Plasma pyruvate levels rose during infusion from 1.5 to 4.4 mg/dl in the uremic dogs and following infusion rose further to 6.5 mg/dl. In the non-uremic dogs pyruvate was not significantly elevated until 30 min. post-infusion. Plasma free fatty acids increased from 79 to 131 mumoles/dl during acetate infusion in the uremic dogs, but did not change significantly in the non-uremic group. Plasma cholesterol and triglycerides increased after induction of uremia, but showed no significant changes as a result of acetate infusion in either group. These results suggest that the electrolyte and lipid abnormalities that occur in hemodialyzed uremic patients may be related to the acetate load these patients receive during dialysis.

Rat liver microsomes prepared in Tris buffer exhibited 3 to 10 times higher 3-hydroxy-3-methyl glutaryl CoA reductase specific activity than microsomes prepared with potassium phosphate buffer. This higher activity was observed in rats killed during mid-light cycle, but microsomes from rats killed during mid-dark cycle showed no significant difference in enzyme activity between buffers. When microsomes prepared in the 2 different buffers were preincubated with ATP and MG++, enzyme activity was inhibited to the same extent. The cytosol fraction in each of the 2 different buffer preparations possessed similar phosphatase activity. The higher 3-hydroxy-3-methyl reductase activity in Tris buffer, therefore, does not appear to be due to differences in phosphorylation or dephosphorylation activity.

The lecithin-cholesterol acyltransferase activity of human plasma was found to be inhibited by Rowachol, a proprietary mixture of pure monoterpenes. Menthol, the major ingredient in Rowachol (32%), and a number of other monoterpenes were found to inhibit the enzyme independently. Concentrations of monoterpenes required to achieve 50% inhibition were of the same order of magnitude as the cholesterol concentration present in the reaction mixture.

Rabbit aortic smooth muscle cells in culture were incubated with 0.04-500 M esterastin. Acid cholesteryl ester hydrolase (ACEH) and neutral cholesteryl ester hydrolase (NCEH) activities were inhibited to a comparable degree, with 50% inhibition occurring in the range of 0.4 M esterastin. Cells incubated with cholesteryl oleyl ether showed 50% inhibition of NCEH at 5.0 M, but no inhibition of ACEH over a concentration range of 0.2-20 M. This relative specificity of cholesteryl oleyl ether for NCEH can be employed to study the relative roles of ACEH vs. NCEH in preventing cellular cholesteryl ester accumulation.

A rapid and accurate single step procedure is described for the assay of lecithin-cholesterol acyltransferase activity. After incubation, using radiolabeled cholesterol as the substrate, an ethanolic solution of digitonin is added directly to the incubation mixture to extract the lipids. Excess cholesterol is then added, and the labeled cholesterol-digitonide along with denatured proteins are sedimented by low speed centrifugation, leaving the labeled esterified cholesterol in solution. An aliquot of the supernatant is counted in an aqueous scintillation mixture. The method correlates well with the established thin-layer chromatographic procedure using either lecithin-cholesterol vesicles or heat-inactivated plasma as the substrate for lecithin-cholesterol acyltransferase.

Rat liver microsomal 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase was activated by 50% at a concentration of 0.4 mM 2,3-diphosphoglyceric acid (DPG) and by 11-fold at 10 mM DPG. DPG also prevented the inactivation of HMG-CoA reductase by ATP and Mg++. Rat liver microsomal HMG-CoA reductase prepared in the presence of 1 mM DPG was significantly more active than when prepared in the absence of DPG. Activation of the enzyme by DPG and protection of the enzyme against inhibition by ATP and Mg++ by DPG were also observed with solubilized HMG-CoA reductase.

Adhesion of platelets to collagen fibrils in a stirred system was inhibited by preincubation of platelets with combinations of 2-deoxy-D-glucose and oligomycin or antimycin. The inhibition of adhesion was associated with a decrease in metabolic ATP to 6% of control levels. Without metabolic inhibitors, platelets adherent to collagen fibrils were found to have catabolized approximately 57% of their metabolic ATP, and converted a major part of this to IMP. Storage pool ATP and ADP contents were also diminished in the adherent platelets. Pretreatment with imipramine resulted in 76% inhibition of the release reaction, but only 5% inhibition of adhesion. Imipramine-treated platelets that were adherent to collagen showed significant depletion of metabolic ATP, but markedly diminished conversion of ATP to IMP as compared to control adherent platelets. Inhibition of deamination of platelet AMP by coformycin or erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) did not inhibit adhesion, although platelets adherent to collagen after treatment with these agents showed depletion of metabolic ATP. These studies suggest that adhesion is an energy dependent process, occurring independently of release, and not associated with conversion of ATP to IMP. The energy dependent portions of the adhesion process are probably disc to sphere transformation and pseudopod formation, the ATP threhold requirement is relatively low, and the ATP utilized can probably be regenerated during the adhesion process via glycolysis and oxidative phosphorylation.

Cholesterol undergoes spontaneous autoxidation, leading to the production of potentially atherogenic oxidation derivatives. When 25-hydroxycholesterol (25-OH) or cholestane-3 beta, 5 alpha, 6 beta-triol (triol) was injected intravenously into rabbits, the aortic surfaces showed numerous balloon-like protrusions and crater-like defects indicative of endothelial damage. Alterations in membrane function caused by these cholesterol oxides could be the mechanism for their cytotoxic effect. Carrier-mediated hexose transport by cultured rabbit aortic smooth muscle cells, measured using 2-deoxyglucose, was reversibly inhibited by triol within one hour. A membrane-bound enzyme, 5'-nucleotidase, was inhibited after 24 to 48 hrs incubation with either 25-OH or triol. Endocytosis was also significantly inhibited by both 25-OH and triol. Depletion of membrane cholesterol content by the cholesterol oxides could account for the membrane functional alterations. Cholesterol biosynthesis is markedly inhibited by 25-OH. Triol has a lesser effect on cholesterol biosynthesis, but it is more potent in blocking uptake of cholesterol by arterial cells in culture. Cholesterol oxides may also influence cholesteryl ester accumulation by arterial smooth muscle cells. Incubation of cells with 25-OH resulted in a four-fold increase in cholesterol esterifying activity but no effect on cholesteryl ester hydrolytic activity. The cholesterol oxides appear to be transported in the blood primarily by very low density lipoproteins (VLDL) and low density lipoproteins (LDL). Oxidized LDL has cytotoxic effects and enhances macrophage lipid accumulation. These be effects may be directly related to the cholesterol oxide content of these lipoproteins.

A method has been developed for estimation of human serum lecithin-cholesterol acyltransferase free of interference by endogenous lipoproteins. Precipitation of serum low and very low density lipoproteins by sodium phosphotungstate and magnesium chloride results in complete recovery of lecithin-cholesterol acyltransferase activity in the supernatant. One microliter of the supernatant can be accurately assayed with a highly efficient substrate containing phosphatidylcholine-cholesterol vesicles and apo-high density lipoproteins (HDL), with no interference from endogenous HDL or residual precipitation reagents. Serum levels of the enzyme were found to be reduced in patients with parenchymal liver disease, renal disease, gastrointestinal tumors and anemias.

Bile cholesterol, phospholipids, total bile acids, individual bile acids, and fatty acid compositions of bile neutral lipids and phospholipids were analyzed before, at one month and at six months following jejunoileal bypass surgery in a series of morbidly obese patients. Preoperative mole percentages of cholesterol and lithogenic indices were high, indicating that biles were supersaturated with cholesterol and outside the micellar solubility zone when plotted on triangular coordinates. At the one month post-operative period percentages of cholesterol and lithogenic indices were significantly increased as compared to the pre-operative state. At six months post-operatively these values had decreased to approximately the pre-operative levels. No changes were observed in percentages of lithocholic acid, but deoxycholic acid decreased to markedly low levels at one month and remained low at the six month post-operative interval. Relative proportions of cholic acid increased, and the ratio of cholic to chenodeoxycholic acid was significantly increased at both post-operative intervals. No significant changes were noted in bile neutral lipid or phospholipid fatty acid composition, indicating that no depletion of essential fatty acids had occurred.

Several cholesterol autoxidation derivatives known to be cytotoxic to arterial smooth muscle cells both in vivo and in vitro were shown to inhibit hexose transport in these cells in culture. Cholestane-3 beta, 5 alpha, 6 beta-triol was the most potent inhibitory sterol. The rapid onset of inhibition (15 min) and the reversibility of the effect upon removal of the sterol from the tissue culture medium suggests that the effect may be due to incorporation of the sterol into the plasma membrane. 25-Hydroxycholesterol, a potent inhibitor of sterol biosynthesis in cultured arterial smooth muscle cells, did not affect hexose transport up to 8 hr of incubation. The cytotoxic effect of 25-hydroxycholesterol, therefore, may be a consequence of the reduced sterol biosynthesis caused by this sterol.

The circadian changes in rat adrenal cholesterol ester (CE) metabolism have been studied and related to the circadian changes in adrenal ascorbic acid and corticosterone levels and plasma corticosterone levels. Significant declines in the ratio of CE/C, cholesterol esterase (CEase) and acyl CoA:cholesterol acyl transferase (ACAT) activities occur during the peak and declining phases of adrenal and plasma corticosteroids, suggesting that when there is a decreased need for steroid precursors the amount of stored CE is decreased, and that the enzymes involved in CE metabolism decline in activity. Adrenal ascorbic acid has a biphasic rhythm with peaks at 0900 and 2200 h. The rhythm of ascorbic acid appears to be inverse to that of ACAT activity, suggesting possible relationships between the two parameters.

The conversion of 3H-squalene to sterols by rat liver microsomes and cytosol was inhibited by individual rat and human plasma lipoproteins at various concentrations. This inhibition was also observed with added human high density apolipoprotein, but triglycerides, cholesterol, or cholesteryl esters had no inhibitory effects. Lipoproteins and apo high density lipoprotein (HDL) were demonstrated to bind 3H-squalene in vitro. The binding of 3H-squalene by apo HDL could be reversed by increasing concentration of liver cytosol containing sterol carrier protein.

Cholestane-3 beta, 5 alpha, 6 beta-triol and 25-hydroxycholesterol are two of the most cytotoxic and also relatively abundant of the autoxidation derivatives of cholesterol. Cultured aortic smooth muscle cells which were incubated with 10 micrograms/ml of either sterol for 24 to 48 hr showed a marked decrease of 5'-nucleotidase activity in isolated crude membranes. It was further demonstrated that 5'-nucleotidase activity was also markedly decreased in plasma membrane-enriched fractions when cells were incubated with cholestane-3 beta,5 alpha,6 beta-triol. Na+,K+-ATPase activity in crude membranes showed a significant decrease (32%) only in cells incubated with cholestane-3 beta,5 alpha,6 beta-triol for 48 hr. There was no effect on Na+,K+-ATPase activity in cells incubated for 24 hr with either sterol.

Administration of 2,2'''-([1-methyl-4, 4-diphenylbutylidene] bis(p-phenyl-eneoxy]) bistriethylamine oxalate (SQ 10,591) at 20 mg/Kg daily for 5 days to cholesterol-fed rabbits resulted in no change in aortic microsomal cholesterol esterification with a palmitoyl coenzyme A substrate or of aortic mitochondrial cholesterol esterification with a palmitate substrate. Esterification by both reactions in the adrenal was much higher than in either aorta or testes. Adrenal and testicular mitochondrial esterification and testicular microsomal esterification were inhibited significantly after SQ 10,591 administration. In vitro addition of 0.0001 M SQ 10,591 significantly inhibited both microsomal and mitochondrial cholesterol esterification in aorta, adrenal, and testes.

Acetate-1-14C or acetate-2-14C was infused into the venous dialysis line in 17 chronic stable patients over a 4-hr period of standard hemodialysis. Radioactive CO2 in expired air was measured continuously during dialysis and for 20 hr postdialysis. Significantly more acetate-1-14C (56 +/- 2%) was recovered as 14CO2 in the expired air than was acetate-2-14C (49 +/- 3%). A total of 81% and 71% of the radioactivity was recovered from the expired air and expended dialysate from acetate-1-14C and acetate-2-14C, respectively. Of the remainder, a significant portion was incorporated into plasma lipids and proteins. Incorporation of radioactivity into phospholipids, cholesterol esters, and triglycerides increased during dialysis and continued to increase during the postdialysis period. Free fatty acid radioactivity increased during dialysis but declined afterwards. In the lipoprotein fractions radioactivities remained elevated at 24 hr in the LDL and HDL fractions, but declined in the VLDLs after this time interval.