Relationship between pleural fluid and serum cholesterol levels.

Vaz MA, Teixeira LR, Vargas FS, Carmo AO, Antonangelo L, Onishi R, Light RW.

Division of Respiratory Diseases, Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil.

INTRODUCTION: Since the criteria of Light and colleagues for differentiating transudates and exudates were described, other tests, including the pleural fluid (PF) cholesterol test, have been proposed for the same purpose. However, the factors influencing PF cholesterol levels have not been clearly delineated. PURPOSE: To analyze the relationships among total cholesterol (CHOL), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides (TRIG) in serum (S) and PF. METHODS: PF and S from 99 patients (transudates, 13 patients; exudates, 86 patients) were analyzed for CHOL, HDL, LDL, TRIG, apolipoprotein AI, apolipoprotein B, and protein. The relationship between the PF and S level for each of these measurements was analyzed with linear regression and multiple regression using the ratio of PF to S protein for that measurement as a second independent variable. RESULTS: This study demonstrated that CHOL levels in PF are related to S cholesterol levels and to the permeability of the pleura (r = 0.88; p < 0.001). However, the percentage of CHOL associated with LDL and HDL (56%) in the PF was much lower than that associated with LDL and HDL in S (93%), suggesting that lipoproteins are modified once they enter the pleural space. The PF TRIG was not closely related to its S level or to the PF/S protein ratio (r = 0.49). CONCLUSION: PF cholesterol levels can be closely predicted from the S cholesterol levels and the permeability of the pleura, as reflected by the ratio of PF protein to S protein. Therefore, the CHOL ratio should not provide additional information to that provided by the protein ratio when trying to differentiate transudates from exudates. PF lipoproteins (LDL and HDL) undergo metabolic alterations once they enter the pleural space. PF TRIG levels are not closely related to S levels or to the permeability of the pleura.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11157605&dopt=Abstract cholesterol




Heterocyclic ureas: inhibitors of acyl-CoA:cholesterol O-acyltransferase as hypocholesterolemic agents.

White AD, Creswell MW, Chucholowski AW, Blankley CJ, Wilson MW, Bousley RF, Essenburg AD, Hamelehle KL, Krause BR, Stanfield RL, Dominick MA, Neub M.

Department of Medicinal Chemistry, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.

A series of diaryl-substituted heterocyclic ureas was prepared, and their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in cholesterol-fed animal models in vivo was examined. N-(2,6-Diisopropylphenyl)-N'-tetrazole or isoxazole-substituted heterocyclic ureas proved optimal. A carbon chain of 11-14 carbons substituted 1,3 with respect to the amine provided the optimal side chain. Substitution of the alkyl chain generally lowered activity. Tetrazole urea 2i dosed at 3 mg/kg lowered plasma total cholesterol (TC) 67% in an acute, cholesterol-fed (C-fed) rat model of hypercholesterolemia and 47% in C-fed dogs. Tetrazole 2i, dosed at 10 mg/kg, also lowered TC 52% and raised HDL cholesterol 113% in rats with pre-established hypercholesterolemia.

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Cholesterol at different bilayer concentrations can promote or antagonize lateral segregation of phospholipids of differing acyl chain length.

Silvius JR, del Giudice D, Lafleur M.

Department of Biochemistry, McGill University, Montreal, Quebec.

Fourier-transform infrared-spectroscopic and fluorescence measurements have been combined to examine the effect of cholesterol on the intermixing of short-chain dilauroyl phosphatidylcholine (DLPC) and its bromo-substituted derivative (12BrPC) with longer-chain (C16- or C18-) phosphatidylcholines (PCs) in hydrated lipid bilayers. Infrared spectroscopy of mixtures combining protonated DLPC or 12BrPC with chain-perdeuterated dipalmitoyl PC reveals that cholesterol at lower concentrations in the bilayer modifies the resolved thermal melting profiles for both phospholipid components and, at high bilayer concentrations, produces a convergence of the thermal transitions for the two PC species. Fluorescence-quenching measurements using a short-chain fluorescent PC (1-dodecanoyl-2-[8-[N-indolyl]octanoyl] PC) in ternary mixtures combining 12BrPC, dipalmitoyl or distearoyl PC, and cholesterol confirm that very high cholesterol levels (50 mol %) abolish the lateral segregation of the PC components at 25 degrees C, a temperature where the phospholipids extensively phase-separate in the absence of sterol. By contrast, under these same conditions cholesterol at lower concentrations in the bilayer is found to enhance the tendency of the PC components to exhibit lateral segregation. We show that these seemingly contradictory effects of cholesterol can be readily explained in the light of a ternary phase diagram that is fully consistent with out current understanding of the nature of cholesterol-phospholipid interactions in binary mixtures.

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Cytotoxicity of 7-ketocholesterol toward cultured rat hepatocytes and the effect of vitamin E.

Ohtani K, Miyabara K, Okamoto E, Kamei M, Matsui-Yuasa I.

Faculty of Human Life Science, Osaka City University, Japan.

The effects of 7-ketocholesterol on rat hepatocytes prepared by collagenase perfusion were examined. The viability of cells incubated with 100 microM 7-ketocholesterol was significantly lower than those with cholesterol, although the LDH activity in the cultured medium remained unchanged during the incubation. Hepatocytes treated with 7-ketocholesterol produced large amounts of .NO and O2- in the early stage of incubation. Treatment of the hepatocytes with Carboxy-PTIO, which selectively scavenged .NO, or with L-NMMA, an inhibitor of .NO synthase, increased the cell viability. The addition of 7-ketocholesterol to the culture medium tended to increase the ratio of total sterol to phospholipid of the hepatocytes in a time-dependent manner without changing the content of phospholipid. No lipid peroxidation or oxidation of the cellular SH groups, protein SH and glutathione, was apparent. Vitamin E added 1 h before the addition of 7-ketocholesterol prevented the hepatocytes from cell death by suppressing the incorporation of 7-ketocholesterol into the hepatocytes and by scavenging O2-.

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Relation of dietary carbohydrates to blood lipids in the special intervention and usual care groups in the Multiple Risk Factor Intervention Trial.

Tillotson JL, Grandits GA, Bartsch GE, Stamler J.

Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis 55414, USA.

This chapter explores relations between reported intake of dietary carbohydrates and measurements of plasma lipids at baseline and during trial years 1-6 of the Multiple Risk Factor Intervention Trial. With control for dietary lipids, alcohol, and other factors, total carbohydrate intake at baseline was inversely related to baseline plasma total cholesterol and high-density-lipoprotein (HDL) cholesterol; starch and other simple carbohydrates were unrelated to plasma lipids and sucrose was inversely related to HDL cholesterol. During trial years 1-6, men assigned to the special intervention group increased their intake of starch and other simple carbohydrates as they decreased their fat intake, and lowered their intakes of refined and processed sucrose. Total carbohydrate intake of these men was inversely related to total, low-density-lipoprotein (LDL), and HDL cholesterol. Starch and sucrose intakes were also inversely related to HDL cholesterol. In contrast, intake of other simple carbohydrates was directly related to HDL, and inversely related to plasma total and LDL cholesterol. For men in the highest quintile of intake of other simple carbohydrates compared with men in the lowest quintile, plasma total cholesterol was lower by 3.6 mg/dL, LDL cholesterol was lower by 4.3 mg/dL, and HDL cholesterol was higher by 1.6 mg/dL. Findings were generally similar for men in the usual care group.

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Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis.

Yokoyama I, Ohtake T, Momomura S, Nishikawa J, Sasaki Y, Omata M.

Second Department of Internal Medicine, University of Tokyo, Japan.

BACKGROUND: Reduced coronary flow reserve (CFR) in hypercholesterolemic patients without evidence of ischemia has been reported. However, it remains uncertain whether this abnormality occurs without overt coronary atherosclerosis. This study aimed to clarify whether CFR is impaired even in anatomically normal coronary arteries in hypercholesterolemic patients and to compare CFR between familial hypercholesterolemic (FH) patients and secondary hypercholesterolemic (SH) patients. METHODS AND RESULTS: Twenty-two patients with hypercholesterolemia (11 FH, 11 SH) and 11 control subjects were studied. Baseline myocardial blood flow (MBF) and MBF during dipyridamole loading were measured in segments perfused by angiographically normal coronary arteries with the use of positron emission tomography and 13N-ammonia, and CFR was calculated. Baseline MBF (mL/min per 100 g heart wt) in FH (81.3 +/- 31.4) and SH (70.0 +/- 20.7) patients was not different from that in control subjects (75.0 +/- 34.9). However, MBF during dipyridamole loading was significantly lower in FH patients (129 +/- 19.1) than in control subjects (322 +/- 174, P < .01) and SH patients (210 +/- 71.2, P < .01). CFR in FH patients (1.59 +/- 0.41) was also significantly lower compared with both control subjects (4.22 +/- 1.42, P < .01) and SH patients (3.00 +/- 0.96, P < .01). CFR in SH patients was also significantly lower than that in control subjects (P < .05). CFR correlated significantly with both plasma total cholesterol (r = .67, P < .01) and LDL cholesterol concentrations (r = .69, P < .01). CONCLUSIONS: CFR was decreased even in anatomically normal coronary arteries in hypercholesterolemic patients. This abnormality was more prominent in FH patients.

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[Is the recent decrease in cholesterolemia in the Czech Republic convincing evidence?]

[Article in Czech]

Skodova Z, Pisa Z, Poledne R, Grafnetter D, Kaucka J, Cicha Z, Pikhartova J, Berka L, Hoke M, Vojtisek P, Emrova R, Wiesner E, Valenta Z, Bobak M, Paclt M.

IKEM, Praha.

BACKGROUND: The objective of the study was to evaluate the 8-year trend of serum cholesterol levels in six districts of the Czech Republic, to assess whether the reduction of mean values of total cholesterol recorded during the period between 1985 and 1992 was convincing and to discuss possible causes and consequences of this development. METHODS AND RESULTS: Three cross-sectional surveys of risk factors were implemented in independent random 1% samples of the population aged 25-64 years. In 1985 1256 men (respondence rate 81.5%) and 1317 women (85%) were examined, In 1988 1357 men (85.2%) and 1412 women (88.4%), in 1992 1142 men (73.2%) and 1211 women (76.7%). A detailed check of the deviations in estimations during different time intervals from reference values provided evidence that the analytical method did not have an impact on the revealed changes. In men the mean total cholesterol level was 6.21 (95% confidence limit 6.14-6.28 mmol/l in 1985; 6.29 (6.23-6.35) mmol/l in 1988; 5.99 (5.91-6.06) mmol/l in 1992. In women the mean value of the total cholesterol level was 6.19 (6.12-6.25) mmol/l in 1985; 6.23 (6.17-6.30) mmol/l in 1988; 5.95 (5.88-6.02) mmol/l in 1992. According to variance analysis (ANOVA) the serum cholesterol in 1992 was lower by 0.22 mmol/l (p < 0.0001) than in 1985 and by 0.28 mmol/l (p < 0.0001) lower than in 1988. The drop of cholesterol between 1988-1992 may have been caused by dietary changes recorded in the population. According to nationwide data after 1990 there was a marked drop of the consumption of meat and meat products, milk and dairy products and animal fats, while the consumption of vegetable fats increased. Despite these dietary improvements, in six districts in 1992 fats accounted for 37% of the energy intake, the P/S ratio was only 0.41 in men and 0.46 in women. In these districts in 1992 and 1993 a decline of the standardized mortality rate from IHD in men was recorded. CONCLUSIONS: During an eight-year period the mean serum cholesterol level of men and women decreased significantly in six districts of the Czech Republic. This change was probably associated with a restricted intake of foods which have an impact on the serum cholesterol level.

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Involvement of trihydroxyconjugated bile salts in cholesterol assimilation by bifidobacteria.

Tahri K, Grill JP, Schneider F.

Universite Henri Poincare-Nancy I, Laboratoire de Chimie Biologique I, BP 239, 54506 Vandoeuvre les Nancy Cedex, France.

To determine the conditions of cholesterol assimilation,various strains of Bifidobacterium species were cultured in the presence of cholesterol and bile salts. During culturing, Bifidobacterium breve ATCC 15700 assimilates cholesterol in the presence of oxgall at pH values lower than 6. This strain was selected to study the influence of conjugated (taurocholic acid) and deconjugated (cholic acid) bile salts on cholesterol assimilation. B. breve ATCC 15700 assimilated cholesterol(up to 51%) when cultures were undertaken in the presence of taurocholic acid, whereas less than 13% of the initial amount ofcholesterol was measured in the cells in the presence of cholic acid.Cultured in the presence of six individual di- or trihydroxyconjugated bile salts, bifidobacteria strains assimilated cholesterol. This assimilation appeared to be more important in the presence of trihydroxyconjugated bile salts (tauro- and glycocholic acids). It is concluded thattrihydroxyconjugated bile salts are involved in the assimilation of cholesterol by bifidobacteria.

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Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins.

Beentjes JA, van Tol A, Sluiter WJ, Dullaart RP.

Department of Endocrinology, University Hospital Groningen, The Netherlands.

Growth hormone (GH) deficiency and acromegaly may be associated with increased cardiovascular risk. Little is known about alterations in high density lipoproteins (HDL) in these conditions. Lecithin:cholesterol acyl transferase (LCAT) has the ability to esterify free cholesterol (FC) in HDL. Cholesteryl ester transfer protein (CETP) is able to transfer cholesteryl esters (CE) from HDL to very low and low density lipoproteins (VLDL and LDL). During phospholipid transfer protein (PLTP)-mediated HDL remodelling, small pre beta-HDL particles are generated which serve as acceptors for cellular cholesterol and provide the initial LCAT-substrate. We documented plasma lipids, LCAT, CETP and PLTP activity levels as well as plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) in 12 adult men with acquired GH deficiency, 12 acromegalic men and 24 healthy male subjects. All GH deficient and acromegalic patients received conventional hormonal replacement therapy if necessary. VLDL + LDL cholesterol and plasma triglycerides were higher in GH deficient (P < 0.01 and P < 0.05) and acromegalic patients (P < 0.05 and P < 0.01) than in healthy subjects. HDL cholesterol and HDL CE were lower (P < 0.05 for both) and the HDL FC/CE ratio was higher (P < 0.01) in these patient groups compared to healthy subjects. Plasma LCAT, CETP and PLTP activity levels were lower in acromegalic patients (P < 0.01 for all) and CETP activity was lower in GH deficient patients (P < 0.01) compared to healthy subjects. Plasma EST and CET were decreased in both acromegalic (P < 0.01 for both) and GH deficient patients (P < 0.05 for both). Multiple regression analysis demonstrated independent negative relationships of plasma insulin-like growth factor I with plasma LCAT (P = 0.0001), CETP (P = 0.009) and PLTP activity levels (P = 0.021). Plasma LCAT (P = 0.0001) and CETP activity (P = 0.0001) were also negatively associated with (substitution therapy for) adrenal insufficiency. In conclusion, GH deficient and acromegalic patients show abnormalities in HDL, consistent with impaired LCAT action. Decreases in plasma EST and CET in such patients, as well as a low PLTP activity in acromegaly suggest that reverse cholesterol transport may be impaired, contributing to increased cardiovascular risk.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11164439&dopt=Abstract cholesterol