An evaluation of the prognostic significance of antigen CD95(Fas/APO-1) expression on the cells of patients with a myelodysplastic syndrome, acute myeloid leukemia and chronic myeloleukemia

AIM: The expression of CD95(Fas/APO-1) antigen was studied on bone marrow cells of 19 MDS patients, peripheral blood blast cells of 15 acute myeloid leukemia (AML) patients, blast cells and granulocytes of 68 patients with chronic myeloid leukemia (CML)--24 in chronic, 9 in accelerated phase and 35 in blastic crisis (BC)--by indirect surface immunofluorescence assay using flow cytometry (FACScan, Becton Dickinson, USA). RESULTS: CD95(Fas/APO-1) antigen was revealed on bone marrow cells of 8 out of 19 (36.8%) MDS patients; the percentage of antigen-positive cells was 38.1 +/- 19.2%; on 45.5 +/- 22.8% of cells in 6(45%) of 15 AML patients. Fas/APO-1 antigen was totally absent in CML chronic stage; its expression was found in 34% (12 of 35) of our patients with CML BC on peripheral blood blasts and in 56% (5 of 9) on peripheral blast cells of CML patients in acceleration phase. CONCLUSION: The data on overall survival of CD95-positive MDS patients suggest that the presence of Fas antigen is a favorable prognostic sign for patients with MDS. The patients from CD95-negative group represent a risk group both for survival and AML transformation. In CML BC group the survival does not depend upon Fas-antigen expression.     

Increase of aminotransferases

Elevated aminotransferases activities are frequent in medical practice. In acute elevations, the mains causes are generally easily found (viral, drug-induced, toxic, ischemic). In moderate or prolonged elevations, the most frequent causes are steatosis (alcoholic, diabetes, obesity) and chronic hepatitis (viral B, D, C, drug-induced and auto-immune diseases.     

Synthesis of new bifunctional compounds which selectively alkylate guanines in DNA

The aim of this work was to develop new bifunctional alkylating agents which damage DNA in a selective manner. In order to extend our previously published work on conformationally restricted nitrogen mustards containing one piperidine ring, new bispiperidine derivatives were designed with varying lengths of carbon chain between the two rings and structure-activity relationships in these systems were studied. Thus samples of new bispiperidine salts 22-26 with chloromethyl groups at the 2-positions and a bridge between the two nitrogen atoms of 2-6 carbon atoms were synthesized. The analogous new bis(p-nitrophenylcarbamates) 17-21 were also prepared. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation with different distances between the two alkylating sites. The bispiperidines 22-24 were shown to alkylate guanines at the 7-position in the major groove of DNA more selectively than melphalan. The bispiperidine 22 with the shortest two carbon bridge was the most reactive but it was less cytotoxic than melphalan in a human colon carcinoma cell line (IC50 value approximately 30 microM) and in a human chronic myeloid leukaemia cell line (IC50 value approximately 12 microM). The most cytotoxic compound in the latter cell line was the carbamate 17, with an IC50 value of approximately 0.3 microM, and carbamates 17, 19 and 20 were most potent in a panel of human ovarian carcinoma cell lines. These compounds also showed circumvention of acquired cisplatin resistance in three paired cell lines. The carbamates 17-21, however, were less efficient at alkylating and cross-linking naked DNA than the bispiperidines 22-26.     

Large-cell change of hepatocytes in cirrhosis may represent a reaction to prolonged cholestasis

The deaths of 10 heroin body packers are reported and contrasted to those of cocaine body packers. Only one was a woman, and all were traveling to or from Colombia. Drug packets deteriorated in the gastrointestinal tract and caused the deaths of eight victims. Accomplices removed drug packets from two of these smugglers after death occurred. One died of peritonitis stemming from a small-bowel obstruction caused by the drug packets, and one died from the recreational use of heroin (nasally ingested). The heroin recovered was < or = 881 g, and the drug purity of the contraband in three cases was between 65% and 73%. Blood concentrations of morphine were < 1.0 mg/L in four victims; no morphine was detected in the smuggler who died of peritonitis. However, two victims had blood morphine concentrations of 4.4 mg/L and 6.7 mg/L, respectively, and three had morphine concentrations of 35.8, 39.4, and 52.6 mg/L, respectively. Fatal heroin body packing differs from cocaine body packing in that individuals may have extremely high drug levels in their blood and their accomplices appear to be more likely to abandon them in a remote location after attempting to remove the drug packets after death has occurred.     

Cognitive testing

Melorheostosis is a very rare bone disease of unknown etiology characterised by linear hyperostosis and associated with fibrosis of soft tissues and the skin. This uncommon sclerosing bone dysplasia was first described by Leri and Joanny in 1922, and since then, until 1993, approximately 300 cases were reported in the literature. Linear scleroderma is a localised proliferation of connective tissue and has rarely been associated with melorheostosis. In this paper, we present a new case of melorheostosis with linear scleroderma which, to the best of our knowledge, is the first case reported in Turkey.     

Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding

To elucidate cellular mechanisms of insulin resistance induced by excess dietary fat, we studied conscious chronically high-fat-fed (HFF) and control chow diet-fed rats during euglycemic-hyperinsulinemic (560 pmol/l plasma insulin) clamps. Compared with chow diet feeding, fat feeding significantly impaired insulin action (reduced whole body glucose disposal rate, reduced skeletal muscle glucose metabolism, and decreased insulin suppressibility of hepatic glucose production [HGP]). In HFF rats, hyperinsulinemia significantly suppressed circulating free fatty acids but not the intracellular availability of fatty acid in skeletal muscle (long chain fatty acyl-CoA esters remained at 230% above control levels). In HFF animals, acute blockade of beta-oxidation using etomoxir increased insulin-stimulated muscle glucose uptake, via a selective increase in the component directed to glycolysis, but did not reverse the defect in net glycogen synthesis or glycogen synthase. In clamp HFF animals, etomoxir did not significantly alter the reduced ability of insulin to suppress HGP, but induced substantial depletion of hepatic glycogen content. This implied that gluconeogenesis was reduced by inhibition of hepatic fatty acid oxidation and that an alternative mechanism was involved in the elevated HGP in HFF rats. Evidence was then obtained suggesting that this involves a reduction in hepatic glucokinase (GK) activity and an inability of insulin to acutely lower glucose-6-phosphatase (G-6-Pase) activity. Overall, a 76% increase in the activity ratio G-6-Pase/GK was observed, which would favor net hepatic glucose release and elevated HGP in HFF rats. Thus in the insulin-resistant HFF rat 1) acute hyperinsulinemia fails to quench elevated muscle and liver lipid availability, 2) elevated lipid oxidation opposes insulin stimulation of muscle glucose oxidation (perhaps via the glucose-fatty acid cycle) and suppression of hepatic gluconeogenesis, and 3) mechanisms of impaired insulin-stimulated glucose storage and HGP suppressibility are not dependent on concomitant lipid oxidation; in the case of HGP we provide evidence for pivotal involvement of G-6-Pase and GK in the regulation of HGP by insulin, independent of the glucose source.     

Enzymatic activity of pig heart mitochondrial malate dehydrogenase monomolecular films by surface exchange technique

A technique for studying the catalytic activity of enzymes spread as a film at an air-water interface, by exchanging the subphase under the film to remove unspread enzyme molecules, was developed, and its effectiveness was studied using surface-spread mitochondrial malate dehydrogenase. Mitochondrial malate dehydrogenase formed stable films which gave reproducible pi-A curves. The enzyme activity was measured by the oxidation rate of reduced nicotinamide adenine dinucleotide (NADH) in the presence of the substrate oxalacetic acid. Oxalacetic acid and NADH were injected into the subphase. The catalytic activity of the enzyme was dependent on the surface pressure of the film. The maximum catalytic activity was observed at a surface pressure of 4.4 dynes/cm. The activity was higher at intermediate surface pressures than at very low or very high surface pressures. A high bulk catalytic activity was observed in the unstable region, i.e., at a high degree of compression, of the film. The catalytic activity of the surface-spread enzyme was only a fraction of an equivalent amount of enzyme in solution.