Effect of crilvastatin, a new cholesterol lowering agent, on unesterified LDL-cholesterol metabolism into bile salts by rat isolated hepatocytes.

1. The aim of these experiments was to determine the effect of crilvastatin, a new cholesterol lowering agent, on the metabolism of unesterified low density lipoprotein (LDL)-cholesterol by rat freshly isolated hepatocytes. This preclinical model was developed as an alternative to in vivo experiments, to mimic the metabolic effects of a molecule on its target cells and to define optimal conditions for future experimentation on human hepatocytes. 2. Cells were obtained from normolipidaemic or hypercholesterolaemic rats, hypercholesterolaemia was nutritionally induced. Incubations were performed in a medium containing 600 microM taurocholate and 50 microM or 300 microM crilvastatin. 3. This molecule was shown in vitro to be carried by physiological transporters, i.e., albumin-bile salt micellar associations and LDL. Crilvastatin induced a significance increase in the synthesis and secretion by hepatocytes of bile salts resulting from the metabolism of unesterified LDL-cholesterol in both normolipidaemic and hypercholesterolaemic rats. Stimulation involved non-conjugated as well as tauro- and glyco-conjugated bile salts. These findings corroborate preliminary studies showing in vivo that crilvastatin enhances the secretion of bile acids by stimulating the uptake and incorporation of LDL-cholesterol by the liver.

Differences in hypolipidaemic effects of two statins on Hep G2 cells or human hepatocytes in primary culture.

1. The objective of this study was to compare in cultured human hepatocytes or Hep G2 cells, changes in the fate of unesterified low density lipoprotein (LDL)-cholesterol induced by crilvastatin, a new cholesterol lowering drug and a reference statin, simvastatin. 2. The experiments were carried out for 20 h, each well contained 4.2 x 10(5)/cm2 Hep G2 cells or 0.5 x 10(5)/Cm2 human hepatocytes, 130 microM ursodeoxycholate, 0.68 microCi or 1.59 microCi unesterified human [14C]-LDL-cholesterol, crilvastatin or simvastatin at 0 or 50 microM (both cell types) or 300 microM (Hep-G2 cells). Incubation with the two drugs resulted in increased amounts of unesterified [14C]-LDL-cholesterol taken by the two cell types, compared to control. 3. Crilvastatin 50 microM led to significantly higher quantities of [14C]-glyco-tauro-conjugated bile salts, compared to simvastatin. Statins reduced the apo B100 level secreted by the two cell types (simvastatin) or human hepatocytes (crilvastatin). Crilvastatin enhanced both the level of apo A1 secreted by the Hep G2 cells and the level of APF, a high density lipoprotein (HDL) and biliary apoprotein. 4. Crilvastatin not only acts by stimulating LDL-cholesterol uptake by hepatocytes, but also by enhancing the catabolism of LDL-cholesterol in bile salts and probably by stimulating HDL and/or bile component secretion. Such a mechanism was not previously described for HMG CoA reductase inhibitors. Our results on APF show that this apoprotein could be considered also as an indicator of changes in bile and/or HDL compartments. 5. The human hepatocyte model appeared to be a suitable and relevant model in the pharmacological-metabolic experiments carried out in this study. It led to more consistent data than those obtained with Hep G2 cells.

Biomechanical interpretations of some bony structures in the skull.

For the causal understanding of some evolutive morphological particularities at the level of the lateral wall of orbits (in mammals and in man), the authors have resorted to biomechanical interpretations of bony structures at the cranium level. To this effect some stress factors as well as the modeling effect on the local bone morphogenesis have been analysed.

Contributions to the evolutionary study of the liver afferent veins.

The extra- and intrahepatic venous afferent devices have been followed up in their evolution in all the classes of vertebrates and in man. There were studied 319 cases in 19 vertebrate species, in situ by the method of corrosion preparates with acid-resistant plastic materials or radiographies. The extraparenchymal afferent venous device shows an evolution characterized by the maintenance and improvement of the visceral hepatic venous system and by the gradual freeing of somatic parietal afferences, substantiating new anatomical notions like "liver visceralization", "hepatic parietal territories" and allowed the ascertainment of an evolutionary phyletic line of the liver based on the progressive diminution of the hepatic parietal territory. The basic characteristic type of intrahepatic distribution of the portal vein was sketched beginning with the testudine reptiles and was maintained including man. The liver segmentary angioarchitecture appeared already in birds. These findings allowed the homologation of the cleaved liver with the unitary liver of mammals and man as well as the homologation of the hepatic organ of mammals, birds and of some reptiles, and the understanding of the emergence variation of the portal vein ventrocranialis dexter.

Foetus and newborn skeleton preparation. Technical note.

The artisanal preparation of foetus and newborn skeleton is described. The essential phases of the technique are circumstantially presented.

Contribution to the clinical anatomy of the vertebral column. Considerations on the stability and the instability at the height of the "vertebral units".

Based on the findings with human cadaver material and the literature data, the concept of "vertebral unit" is discussed as a basic morphofunctional and pathogenic unit of the vertebral column. The vertebral structures collaborating to the stabilization of the vertebral units are described and a review is made of the possibilities of installation of a vertebral instability. An attempt is made to define the vertebral stability and instability.

Some peculiarities of osteomedullary interrelations at the level of the lateral wall of the maxillary sinus.

Several structural aspects in the lateral wall of the maxillary sinus are shown, revealing the existence of some peculiarities of the osteomedullary relationships at this level, as for instance: a) a great density of vascular canals, b) a marked collagen density and a high degree of polymerization of the ground substance pleading for a great stability of the osseous structure, and c) a relative cellular scarcity inside the marrow-like spaces as an expression of a reduced reactive ability of bone marrow. It is considered that these peculiarities are not merely determined by specific functional needs of the bone as a tissue, but mainly by subordination of the latter to the requirements of the higher-ordered structural and functional levels served by a certain osseous zone.

A quantitative study of the human lumbar spine mobility in sagittal plane.

A method using lateral radiographs in different flexion and extension positions in order to study the mobility of the lumbar spine is described. The vertebra parameters and their relationships are presented, for one vertebra in various spine positions and for the lumbar vertebrae in a given spine position; these may be taken as objective criteria for detection of a quantitatively abnormal mobility.

Cholesterol-lowering effect of soyabean lecithin in normolipidaemic rats by stimulation of biliary lipid secretion.

The purpose of the present study was to assess the role of the liver in the plasma-cholesterol-lowering effect of soyabean lecithin. Normolipidaemic rats were fed on lecithin-enriched or control diets with the same amount of protein. The lecithin diets contained 200 g/kg high-fat commercial semi-purified soyabean lecithin (230 g/kg total lipids as soyabean phosphatidylcholine) or 200 g/kg high-fat purified soyabean lecithin (930 g/kg total lipids as soyabean phosphatidylcholine). The control diets were a lowfat diet (40 g fat/kg) and a high-fat triacylglycerol-rich diet (200 g fat/kg). The high-fat diets were isoenergetic. The cholesterol-lowering effect of the lecithin-enriched diets was associated with significantly lower levels of plasma total- and HDL-cholesterol and significantly higher levels of bile phosphatidylcholine (PC), bile salts and cholesterol. These findings suggest that the liver plays a major role in the reduction of plasma cholesterol, the increased biliary lipid being provided by both HDL and the hepatic microsomal pools of PC and cholesterol.