Genetic analysis of indicators of cholesterol synthesis and absorption: Lathosterol and phytosterols in Dutch twins and their parents

Significant familial aggregation was observed for plasma levels of lathosterol (an indicator of whole-body cholesterol synthesis) and plant sterols campesterol and β-sitosterol (indicators of cholesterol absorption) in 160 Dutch families consisting of adolescent mono- and dizygotic twin pairs and their parents. For lathosterol a moderate genetic heritability in parents and offspring (29%) was found. In addition, shared environment also contributed significantly (37%) to variation in plasma lathosterol concentrations in twin siblings. However, a model with different genetic heritabilities in the two generations (10% in parents and 68% in offspring) fitted the data almost as well. For plasma plant sterol concentrations high heritabilities were found. For campesterol heritability was 80% and for β-sitosterol it was 73%, without evidence for differences in heritability between sexes or generations. No influence of common environmental influences shared by family members was seen for either campesterol or β-sitosterol. Taken together, these results confirm and expand the hypothesis that individual differences in plasma levels of noncholesterol sterols are moderately (lathosterol) to highly (plant sterols) heritable

Anomalous Power Law Distribution of Total Lifetimes of Branching Processes Relevant to Earthquakes

We consider a branching model of triggered seismicity, the ETAS (epidemic-type aftershock sequence) model which assumes that each earthquake can trigger other earthquakes (``aftershocks''). An aftershock sequence results in this model from the cascade of aftershocks of each past earthquake. Due to the large fluctuations of the number of aftershocks triggered directly by any earthquake (``productivity'' or ``fertility''), there is a large variability of the total number of aftershocks from one sequence to another, for the same mainshock magnitude. We study the regime where the distribution of fertilities $\mu$ is characterized by a power law $\sim 1/\mu^{1+\gamma}$ and the bare Omori law for the memory of previous triggering mothers decays slowly as $\sim 1/t^{1+\theta}$, with $0 < \theta <1$ relevant for earthquakes. Using the tool of generating probability functions and a quasistatic approximation which is shown to be exact asymptotically for large durations, we show that the density distribution of total aftershock lifetimes scales as $\sim 1/t^{1+\theta/\gamma}$ when the average branching ratio is critical ($n=1$). The coefficient $1<\gamma = b/\alpha<2$ quantifies the interplay between the exponent $b \approx 1$ of the Gutenberg-Richter magnitude distribution $\sim 10^{-bm}$ and the increase $\sim 10^{\alpha m}$ of the number of aftershocks with the mainshock magnitude $m$ (productivity) with $\alpha \approx 0.8$. More generally, our results apply to any stochastic branching process with a power-law distribution of offsprings per mother and a long memory.Comment: 16 pages + 4 figure

Autoantibodies against MDA-LDL in subjects with severe and minor atherosclerosis and healthy population controls

Autoantibodies against oxidized low-density lipoprotein (LDL) have been reported to be associated with atherosclerosis. However, data are not consistent. We compared the titres of autoantibodies to malondialdehyde-modified LDL in three groups, a case group with angiographically documented severe coronary stenosis (> 80% stenosis in at least 1 vessel, n = 47), a hospital control group with minor stenosis on the coronary angiography (< 50% stenosis in all three major vessels, n = 47) and a healthy population control group with no history of coronary heart disease (n = 49). Age ranged from 26 to 68 years. Subjects were frequency-matched for gender distribution and storage time of the blood samples. No relevant differences in autoantibody titre between case and control groups were found. The mean autoantibody titres (± S.D.) were 1.44 ± 1.82, 1.46 ± 1.40 and 1.62 ± 1.95 for cases, hospital controls and population controls, respectively. No correlations were found between autoantibody titre and age, number of cigarettes smoked and LDL or total cholesterol. Autoantibody titres were correlated wit

Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S]

Atherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab, monoclonal antibodies against cholesterol-regulating proprotein convertase subtilisin/kexin type 9 and angiopoietin-like protein 3, may provide more benefit. We investigated the effect of such lipid-lowering interventions on atherosclerosis in APOE*3-Leiden.CETP mice, a well-established model for hyperlipidemia. Mice were fed a Western-type diet for 13 weeks and thereafter matched into a baseline group (euthanized at 13 weeks) and five groups that received diet alone (control) or with treatment [atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks. We measured effects on cholesterol levels, plaque composition and morphology, monocyte adherence, and macrophage proliferation. All interventions reduced plasma total cholesterol (37% with atorvastatin to 80% with triple treatment; all P < 0.001). Triple treatment decreased non-HDL-C to 1.0 mmol/l (91% difference from control; P < 0.001). Atorvastatin reduced atherosclerosis progression by 28% versus control (P < 0.001); double treatment completely blocked progression and diminished lesion severity. Triple treatment regressed lesion size versus baseline in the thoracic aorta by 50% and the aortic root by 36% (both P < 0.05 vs. baseline), decreased macrophage accumulation through reduced proliferation, and abated lesion severity. Thus, high-intensive cholesterol-lowering triple treatment targeting all apoB-containing lipoproteins regresses atherosclerotic lesion area and improves lesion composition in mice, making it a promising potential approach for treating atherosclerosis.Cardiolog

The BCR-ABL1 Inhibitors Imatinib and Ponatinib Decrease Plasma Cholesterol and Atherosclerosis, and Nilotinib and Ponatinib Activate Coagulation in a Translational Mouse Model

Cardiolog

The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice

Cardiolog

Results, meta-analysis and a first evaluation of UNOxR, the urinary nitrate-to-nitrite molar ratio, as a measure of nitrite reabsorption in experimental and clinical settings

Diabetes mellitus: pathophysiological changes and therap

Maintenance of bile acid synthesis and cholesterol 7α-hydroxylase activity in cultured rat hepatocytes

Addition of foetal-bovine serum to rat hepatocytes cultured in Williams E medium resulted in improved maintenance of bile-acid-synthetic capacity and cholesterol 7α-hydroxylase activity as compared with cultures supplemented with rat or newborn-bovine serum or cultures in a hormonally defined serum-free medium. Minimally, 5% (v/v) foetal-bovine serum was necessary to maintain these liver-specific functions. Serum factor(s) responsible for these effects were not dialysable or associated with lipoproteins, but were removed by charcoal extraction. Chemicals/CAS: Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Culture Medi

Lack of predictability of classical animal models for hypolipidemic activity: A good time for mice?

Hypolipidemic drugs that are efficacious in man are not always active in classical animal models of dyslipidemia. Inhibitors of HMG-CoA reductase (statins) do not lower plasma cholesterol in rats, but yet this species was alone in providing activity for fibrate-type drugs. Nicotinic acid possesses many desirable features with regard to clinical use, but most of these actions are lacking in rats and monkeys. The metabolism of low density lipoproteins in hamsters is widely thought to be similar to that in humans, yet neither statins or fibrates lower plasma lipids in these specieS. With the advent of mouse models expressing specific human genes (or disruption of genes) it is now possible to re-examine the effect of established drugs and to characterize new hypolipidemic compounds with respect to site and mechanism of action. Drug responses observed in humans are now being seen in such mouse models (e.g. HDL elevation with fenofibrate in mice with the human apo A-I gene). Moreover, mice are now being screened for compounds that lower plasma (human) Lp(a), or lower plasma cholesterol in the absence of LDL receptors. It is proposed that these new genetic mouse models may afford a more focused examination of drug action and provide, for new compounds, better prediction of the human response