Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up.

OBJECTIVES: We compared the ability of very high levels of nonfasting cholesterol and triglycerides to predict risk of myocardial infarction and total mortality. DESIGN: Prospective study from 1976 to 1978 until 2007. SETTING: Danish general population. PARTICIPANTS: Randomly selected population of 7581 women and 6391 men, of whom 768 and 1151 developed myocardial infarction and 4398 and 4416 died, respectively. Participation rate was 72%, and follow-up was 100% complete. Less than 2% of participants were taking lipid-lowering therapy. RESULTS: Compared to women with cholesterol <5 mmol L(-1) , multivariate-adjusted hazard ratios for myocardial infarction ranged from 1.3 [95% confidence interval (CI): 0.9-1.8] for a cholesterol level of 5.0-5.99 mmol L(-1) to 2.5 (95%CI: 1.6-4.0) for cholesterol ≥ 9 mmol L(-1) (trend: P < 0.0001). Compared with women with nonfasting triglycerides <1 mmol L(-1) , hazard ratios for myocardial infarction ranged from 1.5 (95%CI: 1.2-1.8) for triglycerides of 1.0-1.99 mmol L(-1) to 4.2 (95%CI: 2.5-7.2) for triglycerides ≥ 5 mmol L(-1) (p<0.0001). In men, corresponding hazard ratios ranged from 1.2 (95%CI: 1.0-1.5) to 5.3 (95%CI: 3.6-8.0) for cholesterol (P < 0.0001) and from 1.3 (95%CI: 1.0-1.6) to 2.1 (95%CI: 1.5-2.8) for triglycerides (P < 0.0001). Increasing cholesterol levels were not consistently associated with total mortality in women (trend: P = 0.39) or men (P = 0.02). By contrast, compared with women with triglycerides <1 mmol L(-1) , multivariate-adjusted hazard ratios for total mortality ranged from 1.1 (95%CI: 1.0-1.2) for triglycerides of 1.0-1.99 mmol L(-1) to 2.0 (95%CI: 1.5-2.9) for triglycerides ≥5 mmol L(-1) (trend: P < 0.0001); corresponding hazard ratios in men ranged from 1.1 (95%CI: 1.0-1.2) to 1.5 (95%CI: 1.2-1.7) (P < 0.0001). CONCLUSIONS: Stepwise increasing levels of nonfasting cholesterol and nonfasting triglycerides were similarly associated with stepwise increasing risk of myocardial infarction, with nonfasting triglycerides being the best predictor in women and nonfasting cholesterol the best predictor in men. Even more surprisingly, only increasing levels of nonfasting triglycerides were associated with total mortality, whereas increasing cholesterol levels were not.

Glucose metabolism in glucose-intolerant older people during chromium supplementation.

The effects of chromic chloride (CrCl3) administered orally for 12 weeks to five elderly subjects with glucose intolerance were assessed. Pretreatment and posttreatment, the hyperglycemic clamp technique was employed to determine glucose utilization, beta-cell sensitivity to glucose, and tissue sensitivity to insulin. In addition, erythrocyte insulin binding was studied. Urinary chromium excretion increased approximately 5 fold indicating good compliance with supplementation. The oral glucose tolerance curves following supplementation were lowered from 60 to 120 minutes but only the 60-minute values were significantly lowered. In agreement with this was significantly increased glucose utilization during the hyperglycemic clamp studies. Tissue sensitivity to insulin, receptor affinity, and total insulin binding were unchanged by supplementation while beta-cell sensitivity to glucose increased following supplementation (P less than 0.04), and explained the increased glucose utilization. HDL and LDL and total cholesterol levels were slightly lower after chromium supplementation, but no change reached statistical significance. The LDL/HDL cholesterol ratio was unchanged. This study shows small but statistically significant effects of CrCl3 on carbohydrate metabolism. The clinical relevance of these effects, that is, their prophylactic or therapeutic significance, remains to be determined.

Teacher interactions in mainstream social studies and science classes.

This investigation was designed to change teacher-student interactions in middle school social studies and science classes. Eighteen of 35 teacher volunteers received a six-session inservice emphasizing teacher effectiveness variables. Results indicated significant differences between experimental and control teachers on a pre-post contrast, as well as on a follow-up (maintenance) contrast. Differential effects on the science and social studies teachers were seen. Similarities and differences related to student type, independent of the intervention, were obtained.

Novel mutations in leukotriene C4 synthase and risk of cardiovascular disease based on genotypes from 50,000 individuals.

BACKGROUND: Atherosclerosis is an inflammatory condition where cysteinyl leukotrienes have been identified to play an important role. Furthermore, cysteinyl leukotrienes may also affect thrombus formation. Using prospective, cross-sectional and case-control designs, we tested the hypothesis that hitherto unknown genetic variation, likely to affect the function of leukotriene C(4) synthase, is associated with risk of venous thromboembolism, ischemic stroke and myocardial infarction. METHODS AND RESULTS: Resequencing the gene coding for leukotriene C(4) synthase in an extreme risk population with more than 1500 individuals revealed 17 new mutations, of which four are likely to change protein function (211G>A (minor allele frequency, 0.0001), IVS3 + 1G>A (0.002), 374G>A (0.0006) and 451_453+10del (0.0007)). Based on genotyping 50,000 individuals, age and sex adjusted odds ratios for venous thromboembolism were 2.0 (95% CI, 1.3-3.5) for IVS3+1G>A heterozygotes vs. wild type, and 1.9 (1.5-2.7) for any mutation heterozygote vs. wild type. Corresponding values were 2.0 (1.3-3.2) and 1.5 (1.1-2.1) for ischemic stroke, and 1.0 (0.8-1.3) and 1.2 (1.0-1.4) for myocardial infarction. CONCLUSIONS: Four novel mutations that are likely to change the function of leukotriene C(4) synthase were associated with increased risk of venous thromboembolism and ischemic stroke. These findings need confirmation in other independent studies. In addition, the mechanism behind these findings deserves further investigation.

Nonfasting hyperlipidemia and cardiovascular disease.

Most humans are in the nonfasting or postprandial state in the majority of a 24 hour cycle; however, lipids, lipoproteins, and apolipoproteins are usually measured in the fasting state. Recent studies demonstrate that these values at most change minimally in response to normal food intake, changes that are clinically unimportant. Also, elevated levels of nonfasting triglycerides as a marker of elevated remnant lipoprotein cholesterol associate strongly with increased risk of myocardial infarction, ischemic stroke, and early death. The mechanism behind these findings likely involves entrance of remnant lipoproteins into the arterial intima with subsequent retention leading to atherogenesis, while low HDL cholesterol levels may be an innocent bystander. Finally, nonfasting levels of total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, HDL cholesterol, apolipoprotein A1, total cholesterol/HDL cholesterol, and apolipoprotein B/apolipoprotein A1 all associate with increased risk of cardiovascular disease. These new data open the possibility that nonfasting rather than fasting lipid profiles can be used for cardiovascular risk prediction. If implemented, this would simplify blood sampling for lipid measurements for millions of patients worldwide. Furthermore, the results also highlight the need for randomized double-blind trials of new and established drugs to reduce nonfasting triglycerides and remnant lipoprotein cholesterol, with the ultimate aim of reducing risk of cardiovascular disease and early death.

Glucocorticoid activation of Na+/H+ exchange in renal brush border vesicles: kinetic effects.

Administration of the synthetic glucocorticoid dexamethasone to adrenalectomized rats increased Na+/H+ exchange activity in isolated renal brush border membrane vesicles. Treatment altered the initial rate of Na+ uptake by increasing Vmax (19.90 +/- 2.17 vs. 27.32 +/- 1.50 nmol.mg protein-1.5 s-1) and not the apparent affinity KNa+ (8.33 +/- 1.11 vs. 7.94 +/- 1.60 mM). Dexamethasone treatment resulted in a proportional increase in 1 mM Na+ uptake at every intravesicular pH measured. When these data were analyzed by the Hill equation, it was found that dexamethasone treatment did not change the apparent number of H+ binding sites (1.24 vs. 1.26) or the [H+]0.5 (0.33 vs. 0.32 microM) but increased the apparent Vmax (0.98 vs. 0.55 nmol.mg protein-1.2 s-1). It was also found that dexamethasone injections of 60 micrograms/100 g body wt resulted in maximum stimulation of exchange activity and that a significant increase in amiloride-sensitive Na+ uptake was detected within 12 h after a single dose of dexamethasone.

Glucocorticoids increase the Na+-H+ exchange and decrease the Na+ gradient-dependent phosphate-uptake systems in renal brush border membrane vesicles.

The glucocorticoid dexamethasone, but not the mineralocorticoid aldosterone, increased amiloride-sensitive Na+-H+ exchange activity in rat proximal tubule brush border vesicles. Na+ uptake, independent of amiloride, was not affected. The glucocorticoid decreased the Na+ gradient-dependent phosphate uptake. Uptake in the absence of a Na+ gradient was not inhibited. Dexamethasone did not affect the Na+ gradient-dependent D-glucose uptake. These findings are consistent with the effects of glucocorticoids in stimulating acid secretion and causing phosphaturia in man and animals and may identify the locus of action and suggest the mechanisms by which the hormones act.

beta-Adrenergic regulation of protein phosphorylation and its relationship to exocrine secretion in dispersed rat parotid gland acinar cells.

The possible role of cyclic AMP-mediated phosphorylation events in the regulation of exocrine secretion after beta-adrenergic stimulation was examined in vitro in dispersed acinar cell aggregates from rat parotid gland. l-Isoproterenol, a beta-adrenergic agonist, stimulated endogenous activity of cyclic AMP-dependent protein kinase, alterations in the 32P content of 3 parotid phosphoproteins (increased 32P in 2, Mr = 27,000 and 14,000; decreased 32P in the remaining, Mr = 13,600), and amylase secretion in a dose-dependent manner. All responses were half-maximal within a range of l-isoproterenol concentrations of approximately 4 X 10(-8) to 5 X 10(-7) M. Examination of the time course of these 3 processes revealed that by 30 s after addition of l-isoproterenol, significant elevations in cyclic AMP-dependent protein kinase activity and alterations in the 32P content of the 3 parotid proteins had occurred, whereas secretion of amylase from cells was first detected 1-2 1/2 min after hormonal stimulation. Dibutyryl cyclic AMP (2 mM) elicited the same changes in parotid protein 32P content as l-isoproterenol. Our results support the concept of a role for cyclic AMP-regulated protein phosphorylation in the sequence of cellular events leading to exocrine protein secretion from the rat parotid gland following beta-adrenergic stimulation.

Na+-H+ exchange and Na+-dependent transport systems in streptozotocin diabetic rat kidneys.

The streptozotocin-induced diabetic rat was used to test the hypothesis that Na+-H+ exchange activity in the proximal tubule luminal membrane would be increased in association with renal hypertrophy, altered glomerular hemodynamics, enhanced filtered load and tubular reabsorption of Na+, and stimulated Na+ pump activity in the basolateral membrane, previously reported characteristics of this experimental animal model. Amiloride-sensitive H+ gradient-dependent Na+ uptake and Na+ gradient-dependent H+ flux were increased in brush-border membrane vesicles from the streptozotocin-treated animals. Na+ gradient-dependent uptakes of phosphate, D-glucose, L-proline, and myoinositol were decreased in the drug-induced diabetic animals. These membrane transport alterations were not found when the streptozotocin-diabetic animals were treated with insulin.

Rapid colorimetric determination of activity of subtilisin enzymes in cleaning products.

A new colorimetric method is described for the determination of enzymatic activity of subtilisin in cleaning products. The procedure is more rapid and precise than the casein digestion methods commonly used to assay protease activity. The principle of the colorimetric method depends on the determination rate of p-nitrophenol released on hydrolysis of N-CBZ-L-leucine-p-nitrophenyl ester at pH 8.0 by subtilisin, with correction for any nonenzymatic (spontaneous) hydrolysis of the substrate. Because of the broad range of hydrolytic activity of this enzyme, and the difficulties in predicting its proteolytic activity, this hydrolytic rate was chosen as a general indicator of subtilisin enzyme behavior. The slope for 7 replicate standard curves generated over a 6 week period exhibited a relative standard deviation of 7.5%, and 8.0% for 20 replicates with an enzyme cleaning product. Papain does not interfere with this assay.