Plasma cholesterol concentration and death from coronary heart disease: 10 year results of the Whitehall study.

Ten year mortality from coronary heart disease in 17,718 middle aged men was related to their initial plasma cholesterol concentrations. The relative risk of death from coronary heart disease declined with age, but the absolute excess risk did not. The risk gradient was continuous over the whole range of cholesterol concentrations, the lowest mortality being among men with concentrations below the lowest decile. It seems that, as with blood pressure, the average cholesterol concentration in the blood pressure, the average cholesterol concentration in the population is too high: lowest concentrations are prognostically the best. A quarter of all deaths from coronary heart disease related to cholesterol occurred among men with concentrations above the top decile, but 55% occurred among men with concentrations in the middle three fifths of the distribution; this figure of 55% could be reduced only by a policy aimed at lowering concentrations in the whole population.     

Influence of cholesterol on survival after stroke: retrospective study.

OBJECTIVE: To investigate the association between serum cholesterol concentration and cerebrovascular disease. DESIGN: Retrospective study. SETTING: Acute stroke unit of inner city general hospital. SUBJECTS: 977 patients with acute stroke. MAIN OUTCOME MEASURES: Serum total cholesterol concentration, type of stroke investigated by computed tomography or magnetic resonance imaging, three month outcome (good (alive at home) or bad (dead or in care)), long term mortality. RESULTS: After adjustment for known prognostic factors, higher serum cholesterol concentrations were associated with reduced long term mortality after stroke (relative hazard 0.91 (95% confidence interval 0.84 to 0.98) per mmol/l increase in cholesterol) independently of stroke type, vascular territory and extent, age, and hyperglycaemia. Three month outcome was also influenced independently by serum cholesterol (P = 0.024). CONCLUSIONS: Our data suggest an association between poor stroke outcome and lower serum cholesterol concentration. Until a prospective controlled study has confirmed the benefits of lowering cholesterol concentration in elderly subjects, the application of cholesterol lowering guidelines cannot be justified as secondary prevention of acute stroke.     

A high-throughput metabolomics method to predict high concentration cytotoxicity of drugs from low concentration profiles

A major source of drug attrition in pharmacological development is drug toxicity, which eventually manifests itself in detrimental physiological effects. These effects can be assessed in large sample cohorts, but generating rich sets of output variables that are necessary to predict toxicity from lower drug dosages is problematic. Currently the throughput of methods that enable multi-parametric cellular readouts over many drugs and large ranges of concentrations is limited. Since metabolism is at the core of drug toxicity, we develop here a high-throughput intracellular metabolomics platform for relative measurement of 50?C100 targeted metabolites by flow injection-tandem mass spectrometry. Specifically we focused on central metabolism of the yeast Saccharomyces cerevisiae because potential cytotoxic effects of drugs can be expected to affect this ubiquitous core network. By machine learning based on intracellular metabolite responses to 41 drugs that were administered at seven concentrations over three orders of magnitude, we demonstrate prediction of cytotoxicity in yeast from intracellular metabolome patterns obtained at much lower drug concentrations that exert no physiological toxicity. Furthermore, the ¹³C-determined intracellular response of metabolic fluxes to drug treatment demonstrates the functional performance of the network to be rather robust, until growth was compromised. Thus we provide evidence that phenotypic robustness to drug challenges is achieved by a flexible make-up of the metabolome.     

Vesicular cholesterol in bile. Relationship to protein concentration and nucleation time

A study was done to determine whether the nucleation time was related to the amount of cholesterol carried in vesicles. Bile was obtained from cholesterol gallstone patients and controls. Gel-exclusion chromatography was used to separate vesicles and micelles in the native bile using an eluting buffer containing 10 mM sodium cholate. The percent of total cholesterol carried in vesicles in gallbladder bile of stone patients was significantly greater than that in control patients. Total cholesterol concentration in gallbladder bile of stone patients was significantly greater than in controls. This difference was due to the fact that vesicular cholesterol concentration was significantly greater in the gallbladder bile of stone patients compared to controls. Micellar cholesterol concentrations were similar in the two groups. Nucleation time was related significantly to vesicular cholesterol concentration in correlation analysis and, as previously shown, so was total protein concentration. This study supports the importance of vesicular cholesterol in solid crystal formation and demonstrates for the first time that the rate of cholesterol monohydrate crystal formation is directly related to the amount of cholesterol transported in vesicles.     

Regulation of gallbladder cholesterol concentration in the hamster. Role of hepatic cholesterol level

The goal of this investigation was to determine how alterations in hepatic cholesterol metabolism influence the cholesterol content of gallbladder bile in hamsters. Although the rate of hepatic cholesterol synthesis was varied over 600-fold, there was no direct relationship between the rate of cholesterol synthesis and the cholesterol content of gallbladder bile. However, expansion of the hepatic cholesterol pool by 42-fold resulted in an 11-fold increase in gallbladder bile cholesterol. Examination of four subfractions of the hepatic cholesterol pool revealed that the cholesterol content of gallbladder bile was most consistently correlated with the free cholesterol level in both hepatic tissue and hepatic microsomes from all experimental groups. In most groups of animals in which gallbladder bile cholesterol was increased, plasma lipoprotein cholesterol levels were also increased. It was concluded that in hamsters, under these experimental conditions, changes in the cholesterol content of gallbladder bile were directly related to alterations in cholesterol content of the liver and most closely related to alterations in the free cholesterol content of that tissue.     

Pedigree analysis of HDL cholesterol concentration in baboons on two diets.

Using complex segregation analysis, we examined the effects of genetic factors and diet on serum concentrations of high-density-lipoprotein cholesterol (HDL-C) in baboons. In analyses of 710 baboons in 23 sire families, we found evidence for a major gene as well as a polygenic contribution to HDL-C concentration in baboons fed a basal (chow) diet and also in the same animals after challenge with a high-cholesterol, saturated-fat diet. There was evidence for a polygenic contribution to the change in HDL-C concentration in response to the dietary challenge, but there was no evidence for a major gene effect.     

Relation of high-density lipoprotein cholesterol concentration to type of diabetes and its control.

Serum cholesterol and high-density lipoprotein (HDL) cholesterol concentrations were measured in 192 diabetics (94 with juvenile-onset and 98 with maturity-onset diabetes) and 177 non-diabetic controls. Hb A1C, an index of blood sugar control, was also measured in the diabetics. Serum cholesterol concentrations were similar in all the diabetics and controls, but HDL cholesterol concentrations were lower in patients with maturity-onset diabetes than in those with juvenile-onset diabetes and controls. There was no correlation in diabetics between HDL cholesterol and Hb A1C. We conclude that HDL cholesterol concentrations are abnormally low in patients with maturity-onset diabetes but essentially normal in those with juvenile-onset diabetes. They are not related to diabetic control.     

Serum cholesterol concentration and death from suicide in men: Paris prospective study I.

OBJECTIVE: To investigate whether low serum cholesterol concentration or changing serum cholesterol concentration is associated with risk of suicide in men. DESIGN: Cohort study with annual repeat measurements of serum cholesterol concentration (for up to four years). SETTING: Paris, France. SUBJECTS: 6393 working men, aged 43-52 in 1967-72, who had at least three measurements of serum cholesterol concentration. MAIN OUTCOME MEASURES: Individual change over time in serum cholesterol concentration (estimated using within person linear regression method); death from suicide during average of 17 years'' follow up after last examination. RESULTS: 32 men committed suicide during follow up. After adjustment for age and other factors, relative risk of suicide for men with low average serum cholesterol concentration (< 4.78 mmol/l) compared with those with average serum cholesterol concentration of 4.78-6.21 mmol/l was 3.16 (95% confidence interval 1.38 to 7.22, P = 0.007). Men whose serum cholesterol concentration decreased by more than 0.13 mmol/l a year had multivariate adjusted relative risk of 2.17 (0.97 to 4.84, P = 0.056) compared with those whose cholesterol remained stable (change of < or = 0.13 mmol/l a year). CONCLUSION: Both low serum cholesterol concentration and declining cholesterol concentration were associated with increased risk of death from suicide in men. Although there is some evidence in favour of a concomitant rather than a causal effect for interpreting these associations, long term surveillance of subjects included in trials of lipid lowering treatments seems warranted.     

Influence of fasting and cholesterol feeding on the cholesterol synthesis in rats in vivo.

An inhibition of the cholesterol synthesis located between lanosterol and cholesterol could be shown in fasting rats in vivo with glucose, palmitate, acetate, and mevalonate as tracer substances. The same type of inhibition of the cholesterol synthesis was observed after cholesterol feeding. No indication was obtained for any other inhibiting effect located between acetyl-coenzyme A and lanosterol by these in vivo experiments.