Neural plasticity in vivo: opioid sensitivity of memory develops gradually after a septal lesion

Neuronal plasticity can manifest itself in alterations in the sensitivity of memory to the effects of drugs. After the production of a brain lesion, the memory processing of a passive-avoidance task in mice gradually becomes sensitive to the effect of morphine, i.e., an improvement in retention performance is seen after 6 weeks, but not after 1 or 2 weeks. The results presented demonstrate that, even if they lead to no discernible changes in behaviour, plastic processes can still be detected by means of behavioural tests.     

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.     

A novel nucleotide-containing antigen for human blood γδ T lymphocytes

The stimulation of human γδ T cells by mycobacteria occurs through recognition of four distinct nonpeptide phosphorylated antigens termed TUBag1–4. Among these latter, TUBag4 has already been biochemically characterized as a γ-X derivative of 5′-deoxythymidine triphosphate (Constant, P., Davodeau, F., Peyrat, M. A., Poquet, Y., Puzo, G., Bonneville, M. and Fournié, J.-J., Science 1994. 264: 267). However, despite chemical synthesis of weakly stimulatory nucleotide-containing analogs, these mycobacterial compounds remained the sole nucleotide-containing antigens actually isolated from natural sources. Here, we present the complete isolation of the TUBag3 antigen from Mycobacterium fortuitum and demonstrate that this nonpeptide molecule contains a 5′-UTP nucleotide moiety. On selected Vγ9/Vδ2 clones, T cell responses can be triggered with nanomolar concentrations of TUBag3. Like crude mycobacterial extracts, this purified nucleotide conjugate elicits a strong polyclonal response of γδ PBL from healthy donors. Furthermore, we present evidence that this compound is distinct from the recently synthesized γ-isopentenyl 5′-UTP, a nucleotide conjugate of isopentenyl pyrophosphate that was found to be stimulatory for human γδ T cells (Tanaka, Y., Morita, C. T., Tanaka, Y., Nieves, E., Brenner, M. B. and Bloom, B. R., Nature 1995. 375: 155). Since it appears that both mycobacterial nucleotide antigens are molecules structurally related to peculiar precursors of nucleic acid synthesis, we propose that TUBag-reactive T cells might be specifically devoted to surveillance of proliferating cells.     

Complex Ph1 translocation in chronic myeloid leukemia

This report describes a new case of chronic myeloid leukemia with an unusual Philadelphia chromosome translocation involving chromosomes No. 4,9, and 22; t(4,9,22) (q31;q34;q11).     

Interleukin-4 Cellular Gene Therapy and Osteoprotegerin Decrease Inflammation-Associated Bone Resorption in Collagen-Induced Arthritis

To evaluate the respective action of IL-4, an anti-inflammatory cytokine, and OPG, an inhibitor of bone resorption, on the inflammatory process and the associated bone resorption in collagen-induced arthritis (CIA). After CIA induction, DBA/1 mice were treated with OPG or with IL-4 DBA/1 transfected fibroblasts or both OPG + IL-4. CIA significantly improved in IL-4 groups. OPG had no effect on arthritis clinical scores but histologic scores were reduced in OPG, IL-4, and OPG + IL-4 groups vs. nontreated CIA mice. OPG increased significantly BMD and decreased by 45% D-pyridinolin levels. Moreover association of IL-4 and OPG exerted an additive effect of BMD and resorption marker (-68%). Production of IFN-gamma in the supernatants of spleen cells was reduced in IL-4 treated mice. OPG had a moderate effect on IFN-gamma, but potentiated the inhibitory effect of IL-4. OPG and IL-4 prevent bone loss in CIA-mice model and could have additive effects on IFN-gamma secretion.     

Virion-bound ICAM-1 and activated LFA-1: a combination of factors conferring resistance to neutralization by sera from human immunodeficiency virus type 1-infected individuals independently of the disease status and phase

The role of the supplementary interaction between virion-bound host ICAM-1 and LFA-1 on target cells in sensitivity to neutralization of human immunodeficiency virus type 1 (HIV-1) is poorly studied. Serum samples from four long-term nonprogressors (LTNPs) and sequential sera from one progressor were used to assess neutralization sensitivity of isogenic ICAM-1-negative and ICAM-1-bearing HIV-1(NL4-3), a prototype of T-cell-line-adapted viruses. We found that virus neutralization sensitivity to the studied sera is not modified by the additional interaction between virally embedded ICAM-1 and LFA-1 under an inactive state. However, expression on the target cell surface of an activated LFA-1 form renders ICAM-1-bearing virus particles, but not viruses devoid of ICAM-1, more refractory to neutralization by sera from three out of four LTNPs and all sequential sera from the person who has experienced a progression of the HIV-1-associated disease. Although no conclusive correlation could be drawn between virus susceptibility to neutralization and the disease status or stages of HIV-1 infection, these findings demonstrate that other nonspecific virus-cell interactions mediated by virion-anchored host proteins and their normal cognate ligands on target cells represent factors that can affect the mechanism of HIV-1 neutralization.     

Differential effects of interleukin-1α and β on the arachidonic acid cascade in human synovial cells and chondrocytes in culture

The effects of interleukin-1 and were tested on the [³H]-arachidonic acid release and the prostaglandin synthesis by human cultured synovial cells and chondrocytes. Both forms of interleukin-1 stimulated the arachidonic acid release but interleukin-1 was more potent than IL-1. Human synovial cells and chondrocytes synthesized three types of prostaglandins upon stimulation with interleukin-1 or : prostaglandin E₂, F₂ and 6-keto-prostaglandin F₁. Regarding the synthesis of these prostaglandins, IL-1 was again more potent than IL-1. A comparison between interleukin-1-stimulated synovial cells and chondrocytes revealed neither significant quantitative nor qualitative differences in both the arachidonic acid release and the prostaglandin synthesis.     

A cellular model for myeloma cell growth and maturation based on an intraclonal CD45 hierarchy

Summary: Multiple myeloma (MM) is a plasma cell malignancy mainly characterized by the accumulation of malignant plasma cells within the bone marrow. This review shows that the biology of CD45 illuminates that of MM and, more specifically, provides a better delineation of a tumor cell ‘hierarchy’ of clinical interest. We show that in MM, as in normal plasma cell differentiation, there is an intraclonal CD45 hierarchy that is a gradient of CD45 expression on myeloma cells directly related to their proliferation rate and differentiation status. This CD45 hierarchy allows for the design of a cellular model for MM‐cell growth and maturation in which CD45 bright myeloma cells represent the proliferating compartment and CD45 low myeloma cells the quiescent compartment. This model includes an aberrant phenotype that is annihilation rather than decline of CD45, annihilation reflecting the terminal phase of the disease and/or an aggressive presentation of MM. Data from the literature suggest that CD45 bright myeloma cells are targeted by interleukin (IL)‐6, whereas CD45 negative myeloma cells with a high clonogenic capacity are targeted by insulin/insulin‐like growth factor 1 (IGF‐1). This model will be useful for both a better understanding of the basic biology of MM and a better stratification of and therapeutic approach to the patients. Finally, this model presents MM as a self‐renewing plasma cell disease, although the first oncogenic events such as 14q32 translocations clearly occur earlier in a B cell.