Cocaine tolerance: Interactions among random-ratio and random-interval reinforcement-schedule parameters and repeated exposure to cocaine

Food-deprived pigeons were trained to peck a key under either a three-component multiple random-ratio 5, random-ratio 25, random-ratio 125 schedule or a three-component multiple random-interval 10-sec, random-interval 30-sec, random-interval 125-sec schedule of food presentation. Following determination of acute effects of cocaine (1.0-13.0 mg/kg), are-sponse-rate-reducing dose was given before each daily session. Once performance under conditions of daily administration had become stable, other doses occasionally were substituted for the usual daily dose so that dose effects could be assessed. Tolerance, i.e., a rightward shift in the dose-effect curve was observed in all subjects. For subjects studied under the random-ratio schedules, however, the robustness of the tolerance usually was related to the schedule-parameter value; tolerance was great at lower random values. By contrast, subjects whose responding was maintained by random-interval schedules were less likely to show tolerance that was schedule-parameter dependent. The results also provide suggestive evidence that dose may be an important factor in determining effects of repeated cocaine exposure; repeated administration of larger doses may be less likely to result in tolerance than similar exposure to smaller doses.     

Long-term structural alterations to endothelial cells in vein-to-artery grafts: a quantitative electron microscopic study

The intracellular structure of endothelium lining vein-to-artery grafts in rats was analysed, using transmission electron microscopy and morphometry, to determine the ultrastructural adaptations of endothelial cells in this altered vascular environment. Autogenous 4-mm sections of iliolumbar veins were inserted microsurgically into the left common iliac arteries of 16 male Wistar rats. At 3, 6, 26 and 52 weeks the cytoplasmic-vesicular, mitochondrial and rough endoplasmic reticular contents of endothelial cells lining the grafts, the opposite iliac arteries and the remaining ilio-lumbar veins were analysed morphometrically. There was a significant increase in the amount of all these cytoplasmic structures in endothelial cells at 3, 6 and 26 weeks; at 52 weeks there was also a significant increase in the volumes of mitochondria and cytoplasmic vesicles, but not in rough endoplasmic reticulum. It was concluded that the ultrastructure of endothelial cells lining these grafts is changed chronically after graft insertion, and we propose that this may be attributable to altered haemodynamic stresses within the graft.     

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.     

Fluorescence spectroscopy monitoring of the conformational restraint of formaldehyde- and glutaraldehyde- treated infectious bursal disease virus proteins

Interaction of native proteinaceous antigens during the recognition and the effector phases of an immune response leads to antigenic conformational modifications which may elicit additional specific immune response. Protein cross-linking and conformation restraining formaldehyde and glutaraldehyde have been extensively used in vaccine preparation, but the relative efficiencies of conformational restraint at concentrations similar to those used in vaccine preparation have not been investigated. We addressed this issue by comparing the extent of conformational restraint of virus proteins in formaldehyde- and glutaraldehyde-treated virus preparations by monitoring the fluorescence intensities (I₃₂₀) of infectious bursal disease virus preparations (IBDV) and those of untreated virus during thermal denaturation. Formaldehyde was found to cause no detectable conformational restraint at 0.01% and only very weak restraint at 1%, while glutaraldehyde caused very strong conformational restraint at 0.01%. It is proposed how conformational restraint of proteinaceous antigens may alter ensuing immunity.     

Selective gap-junctional communication capacity of transformed and non-transformed rat liver epithelial cell lines

To investigate whether a selective intercellular communicationexists between transformed epithelial cells and their counterparts,the homologous and heterologous communication capacities offour rat liver epithelial cell lines were compared with theirexpression of transformed phenotypes. All four cell lines showedreasonably good homologous junctional communication capacity,as measured by the dye-transfer assay. In heterologous co-cultures,the non-transformed cell line IAR 20 did not communicate withthe transformed cell lines IAR 6–1 or IAR 27 F. Thesetwo cell lines showed a high degree of transformed phenotypessuch as cell morphology, growth in soft agar and expressionof -glutamyltrans-peptidase activity. Another cell line IAR27 E, showed the least degree of transformation and it communicatedwith IAR 20 cells. Thus, it appears that there is an inversecorrelation between the extent of expression of transformedphenotypes by rat liver epithelial cells and their ability tocommunicate with non-transformed counterparts. There was noheterologous intercellular communication between any combinationof IAR 27 E, IAR 27 F and IAR 6–1 cell lines.     

Phase I study of 4′-deoxydoxorubicin (esorubicin) in children with malignant solid tumors

Summary 4 -Deoxydoxorubicin was given to 15 patients with drug-resistant pediatric malignant solid tumors with the objectives of determining the maximum tolerated dosage and dose-limiting toxicity. Maximum tolerated dosage was 36 mg/m₂ given IV once every 3 weeks. Dose limiting toxicity was myelosuppression, which was severe and prolonged. Therapeutic benefits were not observed for these patients.