Effect of ciprofibrate treatment on biliary lipids in patients with hyperlipoproteinaemia

Abstract. Treatment with hypolipidaemic drugs such as clofibrate increases secretion of biliary cholesterol and induces supersaturation of bile, leading to an increased risk of gallstone formation. Ciprofibrate is a phenoxyisobutyrate derivative with lipid-lowering effects in hyperlipoproteinaemia. We analysed serum lipid levels and biliary lipid composition and cholesterol saturation of gallbladder bile in nineteen hyperli-poproteinaemic patients before and after 6 weeks treatment with ciprofibrate, 100 mg daily. In addition, hepatic secretion rates of biliary lipids were determined in eight of the patients. Ten of the patients were also studied after 1 year of treatment.
Short-term treatment reduced the serum cholesterol levels by about 20% ( P < 0·001) and the serum triglycerides by about 40% ( P < 0·001). The relative cholesterol concentration and cholesterol saturation of bile were not significantly increased for the group as a whole, nor in patients with familial hypercholesterolaemia ( n = 9), or with other types of hyperlipidaemia ( n = 10). During treatment, however, fourteen patients had saturated bile compared with nine before treatment. An increase in cholesterol saturation was the consequence of an increased hepatic secretion of cholesterol whereas the secretion rates of bile acids and phospholipids were unaffected.
After 1 year of treatment the serum lipid concentrations were reduced to about the same level as after 6 weeks, whereas biliary lipid composition and cholesterol saturation had returned to pre-treatment values.
In contrast to clofibrate ciprofibrate exerts hypolipidaemic effects without consistently increasing the relative cholesterol concentration in bile. In some patients it leads to a transient rise in cholesterol saturation of gallbladder bile. This effect is due to an enhanced secretion of cholesterol probably because of a mobilization of tissue cholesterol.     

Unscheduled DNA synthesis in normal human skin after single and combined doses of V-A, UV-B and UV-A with methoxsalen (PUVA)

The aim of this study was to measure unscheduled DNA synthesis (UDS) by autoradiography in normal htiman skin (1) after high dose UV-A, (2) after low dose UV-A applied before or after erythemogenic doses of UV-B, (3) after high dose PUVA and (4) after therapeutic doses of PUVA applied before and after erythemogenic doses of UV-B. Single high dose UV-A exposure induced rougbly 60% of the amount of UDS induced by equally erythemogenic doses of UV-B. Single low dose UV-A exposure did not induce UDS, nor did it significantly alter the amount of UV-B induced UDS when combined with UV-B exposure. Single high dose PUVA did not lead to UDS and had no influence on UV-B induced UDS when combined with UV-B exposure. Our findings indicate: (1) erythemogenic doses of UV-A induce a considerable DNA excision repair; (2) low dose UV-A neither augments UV-B induced DNA repair nor does it inhibit the repair process; (3) no UDS was shown to occur after either high or therapeutic doses of PUVA. This was unexpected since psoralen-DNA monoadducts have been shown to be repairable by a mechanism similar to excision repair of pyrimidine dimers. It is therefore assumed tbat PUVA as performed for therapeutic purposes either preferentially induced interstrand crosslinks not repairable via the classical repair mechanism or the repair of monoadducts was below resolution in this study; (4) therapeutic PUVA doses apparently do not interfere with excision repair of UV-B induced DNA lesions.     

6-Sulfatoxymelatonin excretion and self-reported sleep in good sleeping controls and 55–80-year-old insomniacs

The pineal hormone melatonin is thought to play a role in sleep initiation and maintenance. This was examined in a large sample of good sleeping controls ( n =52) and sleep maintenance insomniacs ( n =56), aged 55–80 y. Subjects collected 5 d of self-reported sleep diary measures, and 12-h urine samples (08.00–20.00 and 20.00–08.00 h) for analysis of the urinary melatonin metabolite, 6-sulphatoxymelatonin (aMT.6S). Insomniacs reported a significantly greater amount of wake after sleep onset, less sleep in total, less efficient sleep and poorer quality sleep compared to controls. However, no significant differences in melatonin excretion were observed between controls and insomniacs, with both groups showing similar mean (SEM) 12-h night-time [30.9 (2.9) vs. 30.6 (3.3) nmoles, respectively] as well as 24-h total [38.7 (3.4) vs. 36.7 (3.8)] aMT.6S excretion levels. No significant correlations were observed with any sleep parameters nor any effects of medication (anti-inflammatory agents, hormone replacement therapy, and an undifferentiated group of medications). The present results do not support a simple relationship between total melatonin production and self-reported sleep quality and duration in the aged.     

Bile acid metabolism in hypothyroid subjects: response to substitution therapy

Bile acid kinetics and biliary lipid composition were determined in ten hypothyroid patients before and after treatment with L-thyroxine. Hypothyroid patients had normal synthesis rates of cholic acid and chenodeoxycholic acid. Hormone treatment, which lowered plasma cholesterol by about 35%, stimulated the formation of chenodeoxycholic acid by about 40% but did not significantly change the synthesis of cholic acid or total primary bile acids. The mean relative biliary concentration of deoxycholic acid was decreased from 30% to 19% and that of chenodeoxycholic acid was concomitantly increased. Cholesterol saturation of bile was decreased by treatment in six of the patients, but the mean value before treatment (135 +/- 13%) was not significantly different from that obtained after treatment (108 +/- 9%). It is suggested that the hypocholesterolaemic effect of thyroid hormones is not primarily due to an increased degradation of cholesterol to bile acids. Similar to what is observed in heterozygous familial hypercholesterolaemia, the defective receptor mediated degradation of plasma low density lipoproteins in hypothyroidism is thus apparently associated with a quantitatively normal catabolic rate of cholesterol to bile acids.     

Chimaeric cultures of human marrow stroma and murine leukaemia cells: evidence for abnormalities in the haemopoietic microenvironment in myeloid malignancies and other infiltrating marrow disorders

Summary. PGM-1 is a transplantable C3H/HeJ leukaemia which is not viable in unstimulated in vitro culture, differentiates into mature granulocytes and macrophages in response to soluble cytokines, and undergoes self-renewing cell divisions in coculture with selected human bone marrow stromal cell lines. When PGM-1 cells were cultured on pre-established adherent layers from primary human marrow samples, their fate depended on the source of the human marrow. Adherent layers from healthy marrow donors or patients with reactive marrow alterations had no or very little capacity to maintain PGM-1 cells in an immature colony-forming state. However, in coculture with adherent layers from patients with myeloid leukaemia or, to a lesser extent, lymphoblastic leukaemia or marrow-infiltrating lymphoma the colony-forming potential was retained. There was no correlation between the remission status of the patient and the PGM-1 activity of the adherent layer. Consistent morphological differences between active and inactive stromal layers were not observed.
The PGM-1 coculture system enables the detection of a hitherto undescribed regulatory abnormality in bone marrow malignancies. Whether the PGM-1 supporting activity is mediated through differences in the production of a cytokine with close homology to complement factor Bb which has recently been shown to induce self-renewal in immature PGM-1 cells, requires further investigation.     

Acute lymphoblastic leukaemia in childhood: cell proliferation without rest

The percentage of non-cycling blast cells in children with untreated acute lymphoblastic leukaemia (ALL) was investigated by staining smears for statin, a nuclear protein specifically present in non-growing resting cells. Results were compared with purified normal CD34-positive progenitors. A low fraction of ALL and CD34-positive cells expressed statin (2.0 ± 3.8% and 2.8 ±3.1%, respectively), the growth fraction assessed by staining for the nucleolar antigen p120 was 94% in both ALL and CD34-positive cell samples. From this analysis it can be concluded that the compartment of non-replicating cells in ALL as well as in normal CD34-positive precursor cells collected from peripheral blood is very small and that most cells are cycling.     

Molecular Approaches to the Characterization of Cell and Blood/Biomaterial Interactions

In order to address questions related to cell/biomaterial interactions with respect to cell function and production of extracellular matrix proteins that support or maintain cell/tissue specific properties, we have developed molecular approaches for analysis of in vivo implanted materials and in vitro studies. In an explant of a human left ventricular assist device (LVAD), intact total cellular RNA could be isolated in sufficient quantities for hybridization analyses with gene-specific probes to evaluate cell growth, cytoskeletal organization, and production of extracellular matrix proteins. Cells harvested from a 132-day implanted LVAD exhibited proliferative activity and expressed genes for fibronectin and collagen types I, III, and IV. In vitro studies revealed that endothelial cells cultured on two different segmented polyurethane biomaterials (Biomer and Tecoflex 60D) exhibited different patterns of gene expression that reflected differences in cell growth rates, morphology, and composition of the extracellular matrix. These methodologies provide a valuable approach for a detailed evaluation of: (1) the biocompatibility of cells colonizing implanted cardiac assist devices; and (2) the functionality of cells seeded onto biomaterials.     

The mandible and osteoporosis(2)

Transverse sections, 3–4 cm long, were obtained post mortem from the radii and from edentulous mandibles of fifty patients (twenty-four females and twenty-six males) aged 46–92 years. The mineral density of the sections was measured by roentgen absorption. A significant negative correlation was found between the mineral density and age (P<0.01). A statistically significant correlation was found between the variation of the mineral density of the mandible and that of the radius (P<0.01).