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The interaction between DNA and two peptide-acridine conjugates containing one (1) or two (2) moieties of the Ser-Pro-Lys-Lys (SPKK) minor groove-binding peptide motif has been studied by a combination of hydrodynamic, biochemical and spectroscopic methods including diffusion-enhanced luminescence energy transfer (DELET) measurements with a Tb(III) lanthanide chelate as donor. Viscometric titrations do not reveal any significant difference between the two hybrid molecules which both unwind (by about 15 degrees) and extend the DNA similarly. DELET measurements show that the acridinyl chromophore of compounds 1 and 2 is much more accessible than that of a simple monointercalating drug such as acridine orange or ethidium. The accessibility factor increases proportionally with the peptide length, reflecting the extent of perturbation imposed upon the intercalating chromophore by the binding to DNA of the peptide moiety of the hybrids. Experiments with the osmium tetroxide-bispyridine reagent indicate that the two hybrid compounds both affect the local conformation of DNA rendering certain thymine residues conspicuously accessible to the probe. The drug-induced sites of hyperreactivity towards OsO4 in DNA are very similar with the exception of a short run of three T residues which is attacked more strongly in the presence of tetrapeptide-acridine conjugate 1 than with the octapeptide-acridine conjugate 2. These results are fully in agreement with previous footprinting studies and support the view that a minimum of two SPKK motifs is required to mimic the AT-specific minor groove binding antibiotic netropsin. On the basis of the DNA-binding properties of these two peptide-acridine hybrids, we present DNA-binding models in which the acridinyl moiety of compound 1 protrudes slightly outside the double helix but remains more or less parallel to the plane of the base-pairs. In contrast, with compound 2, where the octapeptide SPKKSPKK is bound to the minor groove, we postulate that the chromophore lies only partially overlapped with the base pairs in the intercalation site and, in addition, the heterocyclic chromophore is significantly tilted with respect to the double helix axis. Electric linear dichroism and DELET measurements with chromatin reveal that the presence of histone proteins affects the intercalative binding of compound 2 while it has practically no effect on the binding of compound 1.

The interaction between a tandem repeat of the SPKK peptide motif and calf thymus DNA or several polynucleotides has been investigated by circular dichroism. The octapeptide SPKKSPKK does not induce any important changes in the CD spectra of the polynucleotides poly(dG).poly(dC), poly(dG-dC).poly(dG-dC) and poly(dA).poly(dT) while the spectrum of calf thymus DNA is slightly modified. Binding of this basic peptide to the alternating copolymer poly(dA-dT).poly(dA-dT) results in a marked psi-type condensation in a manner similar to that induced by the entire C-terminal domain of histone H1.

In this paper we define two types of formal biological entities corresponding to biological levels of organization, the biolons and the orgons, the properties of which are phenomenologically analyzed and discussed. We examine then, in a rather speculative manner, how some characteristics of these entities may suggest analogies between properties of biological systems and some special features of quantum systems. These analogies are principally related to the specific roles played by these entities (relatively to matter-energy, for orgons, and to information, for biolons) in a biological system. They are funded on the formal equivalence between the temporal variations associated to the development of the orgons and the biolons, respectively, and the statistical distribution over the available energy levels of the two main types of quantum entities, the fermions and the bosons (the former being associated to the constitution of matter and the latter to the effects of interactions). This formal comparison leads us to put into correspondences the developmental duration in biological systems with the energetic structuration in quantum ones and the related characteristic times of the former with the temperature of the latter. We discuss briefly these correspondences.

A case of bone marrow necrosis associated with a serologically documented recent Parvovirus B 19 infection which preceded the development of PH1+ acute lymphoblastic leukemia is reported. No conclusions can be drawn on the basis of a single case but the question of the role of human Parvovirus B19 in the pathogenesis of bone marrow necrosis is discussed. It is suggested that the virus may act as a co-factor for the induction of bone marrow necrosis, in some cases.

Unlabelled: Amiodarone (Am) pneumonitis is currently a common and potentially severe adverse reaction, the accurate diagnosis of which remains difficult to establish., Objectives: To determine the contribution of bronchoalveolar lavage (BAL) in the diagnostic workup of patients suspected of having Am pneumonitis., Methods: Diagnosis of Am pneumonitis was established on the basis of (1) development of recent symptoms and pulmonary opacities while receiving the drug, (2) exclusion of other possible causes, and (3) improvement following cessation of Am and/or steroid therapy. (4) Confirmatory changes were obtained by histopathologic examination in eight cases. BAL was performed in each patient at the time of initial evaluation., Results: Am pneumonitis was diagnosed in 15 consecutive patients between 1985 and 1991. The disease was associated with significant morbidity and mortality. Six patients died; four died of Am pneumonitis. A neutrophilic BAL was found in nine patients (average PMN = 26.6 percent). A mixed pattern (lymphocytic + neutrophilic) was seen in four patients (average: Ly = 19.9 percent; PMN = 11.9 percent). Two patients had a normal BAL. No patient had a lymphocytic pattern. A low CD4+/CD8+ ratio was seen in two patients. A literature survey indicated 70 cases of Am pneumonitis with detailed information on BAL. The BAL pattern was mixed in 23 (33 percent), neutrophilic in 18 (26 percent), lymphocytic in 15 (21 percent), and normal in 14 (20 percent). No correlation was found between BAL pattern and prognosis. Also, BAL pattern was related neither to daily or total dose of Am nor to duration of treatment with Am., Conclusion: The cellular profile of BAL in Am pneumonitis is highly variable, and no cellular pattern of BAL seems to be predictive of a detrimental outcome or of irreversible fibrosis. Aside from excluding other illnesses, and due to its extreme variability, the contribution of BAL differential in the initial workup of patients suspected of having Am pneumonitis is limited.

The sequence selectivity of binding to DNA by an acridine-linked peptide ligand has been investigated by means of footprinting methodologies. The ligand conjugates an anilino-acridine intercalating chromophore with the potentially minor groove binder octapeptide SPKKSPKK. This basic peptide corresponds to a highly conserved DNA recognition motif found in histone H1 and several other nonhistone proteins. Three complementary techniques using DNase I, hydroxyl radicals and osmium tetroxide as sequencing probes have been employed to evaluate both the sequence specificity of binding and the drug-induced conformational changes in DNA. The results converge to demonstrate the AT-selectivity and support a model in which the peptide moiety lies in the minor groove. DNA-binding sites of the conjugate are restricted to a few alternating AT-sequences proximal to GC-rich regions. Binding to homooligomeric runs of A and T is clearly disfavoured by the hybrid whereas such sequences represent preferred binding sites for the unsubstituted basic peptide. These differences reflect the influence of the anilino-acridine chromophore, which evidently contributes to the DNA recognition process allowing the peptide only to contact defined DNA sequences.

The synthesis of two peptidic derivatives, including an anilinoacridine chromophore (related to the antileukemic drug amsacrine) and either the tetrapeptide SPKK (a nucleic acid-binding unit) (1) or the octapeptide SPKKSPKK (2), has been carried out. The interaction of both drugs with DNA has been studied. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the tetrapeptidic or octapeptidic portion is located in the DNA minor groove. Compound 1 fully intercalates into DNA. In contrast, minor groove binding of the octapeptide SPKKSPKK seems to partially modify the intercalative properties of the acridine moiety of 2. In vitro cytostatic and cytotoxic activities against a murine leukemia cell line (L1210), as well as inhibition of [3H]thymidine incorporation, are reported. Compound 1, which is a better inhibitor of DNA synthesis than 2, is also 2.8-fold more potent in terms of growth inhibition. Both drugs are efficient cytostatic agents, but are weakly cytotoxic. The DNA-binding abilities of the two molecules are well correlated to their biological properties. Thus, DNA can be considered as the primary target for these new ligands.

We show how a simple nonlinear dynamical system (the discrete quadratic iteration on the unit segment) can be the basis for modelling the embryogenesis process. Such an approach, even though being crude, can nevertheless prove to be useful when looking with the two main involved processes: (i) on one hand the cell proliferation under successive divisions; (ii) on the other hand, the differentiation between cell lineages. We illustrate this new approach in the case of Caenrhabditis elegans by looking at the early stages of embryogenesis, up to several hundreds of cells ("lima bean" larval stage). We show how the many results that have been obtained by several groups can be interpreted in terms of values for the parameters controlling the dynamical system. Furthermore, we can extend the model to the cases of genetic mutations. More precisely the teratogenetic and lethal effects are associated with abnormal variation of teh control parameters with time.

During experimental treatment of human immunodeficiency virus (HIV-1) infection using high doses of acyclovir (ACV) (600 mg IV every 8 h), cyclosporin, and several courses of plasmapheresis (PE) (60 ml/kg), ACV pharmacokinetics in three patients have been measured. The results with or without PE were not significantly different: half-time of elimination 3 vs. 2.3 h, volume of distribution 1.8 vs. 1.14 liter/kg, and total clearance 404 vs. 314 ml/min. The clearance and the fraction of elimination due to PE were 5.27 ml/min and 2.5%, respectively. These findings suggest that supplemental doses of ACV are not needed when plasmapheresis is performed.

Epidemiological features of multiple myeloma were studied over a seven-year period (1980-86) in the department of Côte d'Or (population 478,000). The crude annual incidence rates were 3.7/100,000 for males and 4.0/100,000 for females. The corresponding age-standardized rates were 2.5 and 2.1. The sex ratio was 1.2. Cumulative rates were 0.3% for both sexes. Age and specific incidence were low before 50 and increased with advancing age up to 85 years in males and females. There was no significant variation in incidence over the seven-year period. The risk of multiple myeloma was slightly higher in urban than in rural areas (the variations were not significant). The period between the beginning of the symptoms and the diagnosis was often short, less than one month in 56% of the cases. When compared to other population based registries the incidence rates are similar to those reported all over the world (except for registries with a high proportion of blacks in the population). Cases have been staged according to Durie and Salmon classification: 32% of the cases were classified as Stage I. This result suggests that globally cases diagnosed in a well-defined population are less severe than those reported in hospital statistics. Survival showed significant differences: there were better rates for patients under 75 and for patients at stage I and II compared with stage III patients. Percentage and morphology of plasma cells also influenced prognosis.

By the registry of hematopoietic malignancies in Côte d'Or we studied the 177 cases of myeloproliferative disorders diagnosed between 1980 and 1986, divided into 4 groups: chronic myelogenous leukemia, idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia. The global standardized rates based on the world population were 3.5 per 100,000 in men and 1.9 in women (sex ratio = 1.8). The mean age for myeloproliferative disorders was 61 +/- 16 years. Incidence was slightly higher in urban than in rural areas (NS). The most common means of detection were routine hemogram, fatigue and thrombosis. Five-year survival curves showed large differences in prognosis, from 30% for chronic myelogenous leukaemia to 83% for polycythaemia vera.