HDL steady state levels are not affected, but HDL apoA-I turnover is enhanced by Lifibrol in patients with hypercholesterolemia and mixed hyperlipidemia.

Lifibrol (4-(4'-tert-butylphenyl)-1-(4'carboxyphenoxy)-2-butanol) is a new hypocholesterolemic drug effectively reducing total cholesterol, LDL cholesterol, and apolipoprotein (apo) B in experimental animals and in humans. In contrast to fibrates and HMG-CoA reductase inhibitors the cholesterol and triglyceride lowering effect of Lifibrol is not accompanied by increases in HDL cholesterol and apoA-I levels. We examined the impact of Lifibrol on the metabolism of HDL apoA-I in patients with hyperlipoproteinemia, using endogenous labeling with stable isotopes. Kinetic studies were performed in five male hypercholesterolemic individuals (type IIa), before and on treatment with 450 mg of Lifibrol daily for 4 weeks and in five male individuals suffering from mixed hyperlipidemia (type IIb), before and on therapy, for 12 weeks. Lifibrol reduced total cholesterol by 14% (P=0.02) and LDL cholesterol by 16% (P=0. 014) in all patients, and decreased triglycerides by 34% in type IIb patients. During Lifibrol therapy, HDL cholesterol and ApoA-I concentrations did not change. Tracer kinetics revealed that the fractional catabolic rate (FCR) of HDL apoA-I increased by 22% (P=0. 013). This increase in the apoA-I FCR was accompanied by a 23% increase in HDL apoA-I production rate (P=0.006). We conclude that Lifibrol, although not changing HDL steady state concentrations, enhances the turnover of apoA-I containing HDL particles.

Lifibrol enhances the low density lipoprotein apolipoprotein B-100 turnover in patients with hypercholesterolemia and mixed hyperlipidemia.

Lifibrol (4-(4'-tert-butylphenyl)-1-(4'carboxyphenoxy)-2-butanol), a new hypocholesterolemic drug, effectively reduces total cholesterol (CH), low density lipoprotein (LDL)-CH, and apolipoprotein (apo) B in experimental animals and in humans. The impact of Lifibrol on the metabolism of apoB-100 containing lipoproteins in patients with hyperlipoproteinemia using endogenous labeling with stable isotopes is examined. Kinetic studies were performed in four male hypercholesterolemic individuals (type IIa) before and on treatment with 450 mg of Lifibrol daily for 4 weeks, and in five male individuals suffering from mixed hyperlipidemia (type IIb) before and on therapy for 12 weeks. Kinetic parameters were estimated by multicompartmental modeling. Lifibrol therapy reduced total CH by 16% (P = 0.012) in all patients, increased triglycerides (TG) by 11% (not significant) in type IIa patients and decreased TG by 34% (P = 0.059) in type IIb patients. During Lifibrol therapy, LDL apoB-100 concentrations decreased by 19% (P = 0.011) in all patients. The decrease in LDL apoB concentrations with Lifibrol therapy was due to an overall increase (75%, P = 0.006) of the fractional catabolic rates (FCR) of LDL apoB. This increase was partially attenuated by a 33% increase in LDL apoB production rate (PR) (P = 0.041). The overall production of apoB increased only slightly. Our data suggest that the major mechanism by which Lifibrol lowers LDL-CH is an increase in receptor-mediated catabolism of LDL rather than a decrease in hepatic apoB production.

Twenty-five thousand-year-old triple burial from Dolní Vestonice: an ice-age family?

In 1986 a paleolithic triple burial was discovered near Dolní Vestonice (Czech Republic). The occurrence of anatomic variants in all three skeletons gave rise to speculations that the buried individuals may have been closely related. To test this hypothesis the skeletons were submitted to a systematic kinship analysis based on odontologic and other non-metric traits. Statistical tests showed that the coincident occurrence of several rare traits in the individuals is highly unlikely to occur at random. This and further data included in the analysis therefore suggest that the three individuals buried together were genetically related and actually belonged to one family.

HDL-mediated efflux of intracellular cholesterol is impaired in fibroblasts from Tangier disease patients.

To further elucidate the cellular mechanisms leading to HDL deficiency in Tangier disease, HDL-mediated cholesterol efflux was studied in cultured skin fibroblasts from Tangier patients. Both Tangier and control fibroblasts show specific saturable binding of HDL3 to the cell membrane (Bmax = 70 and 52 ng/mg protein, respectively; Kd = 8.8 and 10.6 micrograms/mL, respectively). There was no appreciable uptake of HDL3 by Tangier and control fibroblasts, indicating that cholesterol efflux from fibroblasts occurs at the cell membrane. When cellular cholesterol was labeled to equilibrium by [14C]cholesterol incubation for 48 hours at 37 degrees C, HDL3-mediated cholesterol efflux from Tangier fibroblasts was only 50% of control fibroblasts. To define this abnormality in HDL3-mediated cholesterol efflux more precisely, several additional experiments were performed. First, membrane desorption of cholesterol was determined after cell membranes were labeled with [14C]cholesterol for 3 hours at 15 degrees C. With this labeling protocol, there was no difference in HDL3-mediated cholesterol efflux between control and Tangier fibroblasts. Second, efflux of newly synthesized sterols was determined after incorporation of the precursor [14C]mevalonolactone. Under these conditions, specific HDL3-mediated efflux of sterols was almost absent in Tangier fibroblasts. Third, cells were labeled by incubation with reconstituted [3H]cholesteryl-linoleate-LDL. Efflux of LDL-derived cholesterol was only slightly reduced for the first 4 hours of incubation. After 12 hours, there was no difference between control and Tangier cells. The combined data indicate that the reduced efflux of cholesterol from Tangier fibroblasts observed after homogeneous labeling is due to severely reduced efflux of newly synthesized sterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Fast atom bombardment mass spectrometry of N-acetylated neoglycolipids of the 1-deoxy-1-phosphatidylethanolamino-lactitol-type.

N-Acetylated neoglycolipids (neoGL) of the 1-deoxy-1-phosphatidylethanolamino-lactitol-type (Lac-PtdEtn) carrying lactose, sialyllactose, disialyllactose, II3sialylgangliotetraose, II3,IV3disialylgangliotetraose, lacto-N-tetraose, IV6sialyllacto-N-tetraose, lacto-N-triaose, and bloodgroup A determinant as carbohydrate moieties were synthesized either chemically or enzymatically by glycosylation or deglycosylation of the parent compounds. The neoGL were then analyzed by fast atom bombardment mass spectrometry (FAB MS) with positive (FAB(+)) and negative ion (FAB(-)) detection. The resulting spectra showed intense pseudomolecular ions and characteristic fragmentations. FAB(-) spectra of the N-acetylated Lac-PtdEtn-type neoGL showed pseudomolecular ions (M-H)- of one magnitude higher intensity compared to those from the corresponding non-acetylated compounds. The main fragment ions were obtained from successive cleavage of the sugar units, thereby indicating the monosaccharide sequence. In FAB(+) spectra of the title compounds clearly detectable pseudomolecular ions were observed. The most prominent peaks, however, were obtained from cleavage of phosphatidic acid. The N-acetyl-ethyleneamine moieties of the corresponding glycosyl-Etn-fragments most probably formed five membered rings and thereby mesomery-stabilized cations. Secondary ions resulting from loss of the respective terminal sugars demonstrated the monosaccharide sequence.

An investigation into the glycolipid metabolism of alpha-N-acetylgalactosaminidase-deficient fibroblasts using native and artificial glycolipids.

Deficient activity of lysosomal alpha-N-acetylgalactosaminidase represents a recently recognized lysosomal disorder whose neurologic manifestation in infancy is infantile neuroaxonal dystrophy. The lysosomal enzyme defect, inherited as an autosomal recessive trait, was first identified in the two brothers, GD and BD. Metabolic modification of glycolipids with terminal alpha-GalNAc was studied in fibroblasts from these patients. [Ceramide-3H]Forssman-glycosphingolipid (GSL), the fluorescent C6-NBD-lyso-Forssman-glycolipid (GL) and a 14C-labelled neoglycolipid containing the blood group A trisaccharide were synthesized and used as probes in degradation studies with cell homogenates and with cells in culture. Assays of each of these substrates with fibroblast homogenates of the patients demonstrated the profound deficiency of alpha-N-acetylgalactosaminidase activity compared with controls. Residual activities in the patients' fibroblast homogenates were detected with all glycolipid substrates; those amounted to 6.3 +/- 3.7% (BD) and 12.8 +/- 6.3% (GD) of the mean activity in controls for [3H]Forssman-GSL, and to 2.2 +/- 0.8% (BD) and 3.6 +/- 1.8% (GD) for C6-NBD-lyso-Forssman GL, respectively. alpha-N-Acetylgalactosaminidase deficiency in intact cells was confirmed by TLC analyses, which showed impaired glycolipid modification in cell extracts obtained following addition of [3H]Forssman GSL and C6-NBD-lyso-Forssman GL to the culture media of fibroblasts from the patients.

The origins of ceramic technology at dolni vecaronstonice, czechoslovakia.

A typology was established for more than 5000 ceramic artifacts at Dolni Vestonice, Czechoslovakia. Conjectured methods of manufacture were confirmed by radiography. The compositions and mineralogy of the artifacts were identical to those of the local soil, loess. A firing temperature range of 500 degrees to 800 degrees C was measured and compared with those of hearths and kilns. The mechanism of sintering was impurity-initiated, liquid-phase sintering. Many fracture sections show evidence of thermal shock, although thermal expansion of the loess is low. The making, firing, and sometimes exploding of the figurines may have been the prime function of the ceramics at this site rather than being manufactured as permanent, portable objects.