The anti-atherosclerotic properties of F 12511, a novel acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, were studied in rabbits that were fed a cholesterol-free casein-rich diet and ...developed endogenous hypercholesterolemia and fibrofatty preatheroma lesions. After 6 weeks of casein feeding, an endothelial abrasion was performed in the abdominal aorta; at week 8, a control group was maintained on this diet while F 12511 (8 mg/kg/d) was administered as a diet admixture for the subsequent 24 weeks. Total plasma cholesterol level rose to 250-300 mg/dl in both groups before starting the treatment; F 12511 time-dependently reduced total plasma cholesterol by 50%, and also decreased by 50% the incidence of lesions and macrophage accumulation in uninjured aorta (thoracic arch, celiac bifurcation). Residual lesions in the treated group were characterized by few macrophages, essentially under the endothelium, and by a larger content of smooth muscle cells. Quantitative image analysis of serial sections of mechanically injured abdominal aorta revealed a 20% surface covered by preatheroma lesions in the placebo group; F 12511 significantly reduced this surface. These data suggest that the combination of endogenous hypercholesterolemia with endothelial injury in the rabbit may offer a useful model to study atherosclerosis; lipid lowering by F 12511 reduces the incidence of vascular lesions and macrophage infiltration and may reinforce the fibrous skeleton of the atheroma.
The pharmacological profile of F 12511 (
S)-2′,3′,5′-trimethyl-4′-hydroxy-α-dodecylthio-phenylacetanilide, a new inhibitor of acyl-CoA: cholesterol acyltransferase (EC 2.3.1.26; ACAT), was evaluated ...by using different
in vitro and
in vivo models.
In vitro, F 12511 was shown to be a highly potent inhibitor of ACAT activity in microsomal preparations from various animal species as well as of cholesterol esterification in relevant human cell lines in culture. The concentrations of F 12511 required to produce 50% inhibition of ACAT activity (IC
50 values) in microsomal preparations ranged from 41nM for hypercholesterolemic rabbit intestine to 223 nM for normocholesterolemic hamster liver. In whole cell assays using hepatic (Hep G2), intestinal (CaCo-2) and macrophagic (THP-1) cell lines, F 12511 inhibited ACAT activity with IC
50 values of 3, 7, and 71 nM, respectively.
In vivo, orally administered F 12511 displayed high potency and efficacy as an antihypercholesterolemic compound in different cholesterol-fed animals (rat, guinea-pig, rabbit). For instance, in guinea-pigs the dose required to reduce plasma cholesterol levels by 30% (ED
30 value) was 0.008 mg.kg
-1. In rabbits, an animal species prone to atherosclerosis, the hypocholesterolemic effect was accompanied by a dose-related reduction in the incidence of aortic fatty streaks that reached asymptote at 2.5 mg.kg
-1 and by an improvement of the impaired endothelial function. When given orally to chow-fed hamsters, F 12511 elicited a dose-related decrease in plasma cholesterol from 9% at 0.63 mg.kg
-1 up to 31% at 40 mg.kg
-1 associated with a preferential reduction in atherogenic lipoproteins, very low density lipoproteins (VLDL) and low density lipoproteins (LDL). Moreover, in the same dose range, F 12511 decreased hepatic cholesteryl ester concentrations and reduced liver
ex vivo ACAT activity. By using a bioassay, ACAT inhibitory activity was present in plasma of treated hamsters 1 hr after oral administration of F 12511. Hence, the results in chow-fed hamsters are consistent with systemic and direct hepatic effects of F 12511. In guinea-pigs, an adreno-sensitive species, F 12511 did not impair the adrenal function (adrenocorticotrophic hormone challenge) at doses up to 2.5 mg.kg
-1, far higher than those eliciting hypocholesterolemic effects in the same species. In conclusion, the results suggest that F 12511, a powerful and systemic ACAT inhibitor, constitutes an appropriate tool to determine whether the inhibition of ACAT constitutes an effective therapy for the treatment of hypercholesterolemia and of atherosclerosis in man.
In 1987 a potters' quarter was discovered to the east of the ancient town of Sagalassos (SW Turkey). A wide variety of ceramic products was manufactured locally, including a series of tableware ...(Sagalassos red slip ware). Following a late Hellenistic antecedent, mass production of this tableware started during the early Augustan period and lasted into the first half of the 7th century ad. This contribution aims at illustrating some of the technological and organizational choices made by the potters when mass production was initialized.
L’histoire, l’histoire de l’art et l’archéologie s’imbriquent à travers les figures exceptionnelles de Jacques Le Goff et Tonio Hölscher alors que la fécondité des catégories territoriales révèlent ...ici Babylone, la Méditerranée ou encore le Saint-Empire romain germanique. L’actualité de la recherche s’écrit aussi dans une confrontation de la discipline à l’histoire des corps et des dieux, comme elle redéfinit ses objets et ses moyens en se fondant sur le canon de la Grèce antique, ou en prenant de front la question de la situation des savoirs et de la migration du savant : Erwin Panofsky par Johanne Lamoureux. Ce numéro est en vente sur le site du Comptoir des presses d'universités.
The growth and evolution of the interphase, due to contact with the ambient atmosphere or electrolyte, are followed using
7
Li magic-angle spinning nuclear magnetic resonance (MAS NMR) in the case of ...two materials amongst the most promising candidates for positive electrodes for lithium batteries: LiFePO
4
and LiMn
0.5
Ni
0.5
O
2
. The use of appropriate experimental conditions to acquire the NMR signal allows observing only the «diamagnetic» lithium species at the surface of the grains of active material. The reaction of LiMn
0.5
Ni
0.5
O
2
with the ambient atmosphere or LiPF
6
(1 M in Ethylene Carbonated/DiMéthyl Carbonate (EC/DMC)) electrolyte is extremely fast and leads to an important amount of lithium-containing diamagnetic species compared to what can be observed in the case of LiFePO
4
. The two studied materials display a completely different surface chemistry in terms of reactivity and/or kinetics of the surface towards electrolyte. Moreover, these results show that MAS NMR is a very promising tool to monitor phenomena taking place at the interface between electrode and electrolyte.
Antithrombotic potency of recombinant hirudins rHV2, rHV2-Lys47 and rHV2-Arg47 was studied in a model of experimental thrombosis induced by tissue factor in the rat. Venous thrombosis was induced by ...i.v. injection of 25 mg/kg tissue factor followed by stasis of the inferior vena cava. In this model natural recombinant hirudins, rHV2 and rHV2-Lys47 injected 5 min before thrombo-plastin totally inhibited thrombosis in the same micrograms range as heparin or natural hirudin extracted from leeches. However, the mutant variant rHV2-Arg47 gave a maximal 60% inhibition of thrombosis. Variants rHV2-Lys47 (30 micrograms/kg) and rHV2-Arg47 (157 micrograms/kg) injected 5 min before thromboplastin prevented by 90 to 100% the drop in platelet count observed during the disseminated intravascular coagulation induced by thromboplastin injection. Recombinant hirudins were less anticoagulant than heparin as measured by an APTT on rat plasma. After rat tail transection, rHV2-Lys47 caused a 2-fold smaller prolongation of the bleeding time than an equivalent antithrombotic dose of heparin. Plasmatic elimination of rHV2-Lys47 from rat plasma after i.v. injection had a fast distribution phase with a half-life of 3 min during which 90% of injected rHV2-Lys47 was lost and was followed by a slower elimination phase. Thus recombinant hirudin rHV2-Lys47 appears as a promising potent antithrombotic agent for the prevention of thrombin-dependent venous thrombosis and disseminated intravascular coagulation.
The relative value of two different MRI procedures for the assessment of infratentorial extension in multiple sclerosis (MS) was studied. Multislice spin-echo techniques were used overall. Procedure ...A consisted of parasagittal T1-weighted images (500/30) and axial T2-weighted images (2500/30, 2500/120). Procedure B consisted of parasagittal T2-weighted images (1600/35, 1600/90). In the parasagittal T2-weighted images clear visualization of MS lesions is achieved because signal intensities of CSF and normal nervous tissue are nearly identical. All images were performed with a 0.5 Tesla MR system. Data were obtained in 98 patients with definite (N = 30) or probable MS (N = 68). Areas with abnormal signal intensity in the infratentorial regions (brainstem, cerebellum, and/or cervical spinal cord) were identified in 44% of the patients with procedure A and in 64% with procedure B. The standard application of the combination of both procedures improves the sensitivity of the MR examination for the diagnosis of MS, the delineation of infratentorial lesions and the correlation between clinical and MR data without excessively increasing imaging time.
One of the aims of the new excavation programme in the potters’ quarter, which started in 1997, was the integration of archaeometrical knowledge in order to study every single aspect of the pottery ...manufacturing process of Sagalassos in detail. As a result of this field work, the source of the clays used for the slip of the local tableware or Sagalassos red slip ware (SRSW) was identified. The slip layer was already characterised by Viaeneet al. (1993). In this study, the slip layer of 18 samples of SRSW was petrographically and geochemically investigated. The composition of the slip was
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