Synthesis and antiviral activity evaluation of 3'-fluoro-3'-deoxyribonucleosides: broad-spectrum antiviral activity of 3'-fluoro-3'-deoxyadenosine

Five 3'-fluorinated ribonucleosides were prepared and evaluated for their inhibitory properties against different viruses. The synthesis of these compounds was achieved by treatment of 2',5'-di-O-tritylated nucleoside analogues possessing a xylo-configuration with diethylaminosulfur trifluoride, followed by deprotection. 3'-Fluoro-3'-deoxyadenosine was active against a broad range of viruses, encompassing both DNA viruses [pox (vaccinia)], single-stranded (+) RNA viruses [picorna (polio, Coxsackie B), toga (sindbis, Semliki Forest)] and double-stranded RNA viruses (reo). In its antiviral activity spectrum 3'-fluoro-3'-deoxyadenosine clearly differed from those adenosine analogues that are known as inhibitors of S-adenosylhomocysteine hydrolase. 3'-Fluoro-3'-deoxyadenosine also proved effective in vivo, in inhibiting tail lesion formation in mice inoculated intravenously with vaccinia virus.     

Physical inactivity, excess adiposity and premature mortality

The purpose of this report is to review the evidence that physical inactivity and excess adiposity are related to an increased risk of all‐cause mortality, and to better identify the independent contributions of each to all‐cause mortality rates. A variance‐based method of meta‐analysis was used to summarize the relationships from available studies. The summary relative risk of all‐cause mortality for physical activity from the 55 analyses (31 studies) that included an index of adiposity as a covariate was 0.80 [95% confidence interval (CI) 0.78–0.82], whereas it was 0.82 [95% CI 0.80–0.84] for the 44 analyses (26 studies) that did not include an index of adiposity. Thus, physically active individuals have a lower risk of mortality by comparison to physically inactive peers, independent of level of adiposity. The summary relative risk of all‐cause mortality for an elevated body mass index (BMI) from the 25 analyses (13 studies) that included physical activity as a covariate was 1.23 [95% CI 1.18–1.29], and it was 1.24 [95% CI 1.21–1.28] for the 81 analyses (36 studies) that did not include physical activity as a covariate. Studies that used a measure of adiposity other than the BMI show similar relationships with mortality, and stratified analyses indicate that both physical inactivity and adiposity are important determinants of mortality risk.     

Translocation of BCR to chromosome 9: A new cytogenetic variant detected by FISH in two Ph-negative,BCR-positive patients with chronic myeloid leukemia

Leukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: I) Cytogenetics showed a normal 46.XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2 (patient I) or b3a2 (patient 2) configuration, and 3) fluorescence in situ hybridization (FISH) demonstrated relocation of the 5′ BCR sequences from one chromosome 22 to one chromosome 9. The ABL probe hybridized to both chromosomes 9 at band q34, while two other probes which map centromeric and telomeric of BCR on 22q 11 hybridized solely with chromosome 22. For the first time, a BCR-ABL rearrangement is shown to take place on 9q34 instead of in the usual location on 22q 11. A rearrangement in the latter site is found in all Ph-positive CML and in almost all investigated CML with variant Ph or Ph-negative, BCR-positive cases. The few aberrant chromosomal localizations of BCR-ABL recombinant genes found previously were apparently the result of complex and successive changes. Furthermore in patient 2, both chromosomes 9 showed positive FISH signals with both ABL and BCR probes. Restriction fragment length polymorphism (RFLP) analysis indicated that mitotic recombination had occurred on the long arm of chromosome 9 and that the rearranged chromosome 9 was of paternal origin. The leukemic cells of this patient showed a duplication of the BCR-ABL gene, analogous to duplication of the Ph chromosome in classic CML. In addition they had lost the maternal alleles of the 9q34 chromosomal region. The lymphocytes of patient 2 carried the maternal chromosome 9 alleles and were Ph-negative as evidenced by RFLP and FISH analyses, respectively. © 1993 Wiley-Liss, Inc.     

Kupffer cell depletion in vivo results in preferential elimination of IgG aggregates and immune complexes via specific Fc receptors on rat liver endothelial cells.

In the present study we have investigated the clearance kinetics and tissue distribution of monomeric (m) IgG and soluble aggregates of IgG (AIgG) and immune complexes (IC) in normal and Kupffer cell (KC) depleted rats. In normal rats, clearance of mIgG occurred in a biphasic manner with a first half-life (T1/2) (T1) of 36.3 +/- 6.3 min and a second T1/2 (T2) of 168.4 +/- 4.7 min. AIgG composed of 20-27 IgG molecules per aggregate were cleared significantly faster than mIgG with a T1 of 2.5 +/- 0.1 min and a T2 of 32.5 +/- 5.6 min. KC depletion did not have a significant effect on the clearance rate of mIgG (T1: 33.4 +/- 8.9 min; T2; 159.5 +/- 12.5 min), while clearance of AIgG was delayed significantly with T1 4.8 +/- 0.7 min and T2 41.2 +/- 3.2 min. Eight minutes after injection, 77% of AIgG was found in the liver in normal rats while 62% was found in the liver of KC-depleted rats. Double immunofluorescence studies indicated that AIgG in the liver was associated with KC and endothelial cells (EC) in normal rats. In KC-depleted rats, AIgG was strongly associated with EC. A similar staining pattern was observed when IgG-immune IC were administered. The clearance of AIgG in KC-depleted rats was inhibited fully by pre-administration of high concentrations of IgG but not by pretreatment with IgA. asialofetuin (ASFe) or ovalbumin (OVA). Aggregated F(ab')2IgG was cleared with a comparable rate to mIgG from the circulation, again suggesting Fc gamma receptor-mediated elimination of AIgG by EC. There was a reduced degradation of AIgG in rats depleted of KC as compared with normal rats. These data suggest binding and degradation of AIgG by EC in vivo.     

Influence of pH on the binding of suramin to human serum albumin

The pH dependence of the binding of suramin to albumin has been studied by means of equilibrium dialysis and circular dichroism. Dialysis experiments have revealed that the association constants of the high and low affinity binding sites are strongly influenced by the pH. At pH 6.0 K1 = 1.4 x 10(6) M-1/n1 = 2.0 and K2 = 1.3 x 10(5) M-1/n2 = 1.0; at pH 9.2 K1 = 2.0 x 10(5) M-1/n1 = 2.0. At the high pH no low affinity sites could be demonstrated any more. The pH dependence of the induced ellipticity of the suramin-albumin complex at low molar drug-to-protein ratio r = 0.1 can be superimposed upon the neutral-to-base (N-B) transition of albumin alone. By means of the Linderstr?m-Lang equation for electrostatic interaction and a two-state model for the N-B transition of albumin, evidence is obtained of a link of the pH dependent binding behaviour of suramin to albumin and the neutral-to-base transition of albumin. The possible correlation of this link with transport processes of suramin in the body and with selective uptake of suramin in cells and parasites is discussed.