Forced Contact between Antigen-Presenting Cells and T Cells: Consequences for T-Cell Activation

It is still not known how T cells are activated, which T-cell surface structures transmit activation signals, and if antigen-presenting cells possess activation structures for T cells. We have studied whether the T-cell receptor (TcR) must be engaged for T-cell activation to occur. By using membrane-incorporated monoclonal antibodies, we artificially forced T cells to bind to antigen-presenting cells in a mixed lymphocyte reaction system and thereby bypassed the need for TcR engagement and also made it possible for any surface molecule on antigen-presenting cells to deliver a stimulatory signal to the T cells. Theoretically, T cells would become polyclonally activated by this procedure. However, we found that they did not, even though they were intimately bound to the antigen-presenting cell, thus demonstrating that the TcR must participate in antigen/MHC binding in order for the T cells to become activated. This study does not exclude the possibility that antigen-presenting cells possess structures that can activate T cells.     

Benzodiazepines: abuse and new use.

Both abuse and new uses for benzodiazepines are reviewed. The pharmacology of benzodiazepines is summarized and statistics regarding their general use are given. The question of benzodiazepine abuse is reviewed in some detail and the question of rebound, recurrence of symptoms and physiological withdrawal is differentiated. Benzodiazepines are regarded as a very safe class of drugs and the abuse potential is felt to be negligible provided that they are prescribed for appropriate conditions and monitored carefully. The dangers of alternatives to benzodiazepines such as alcohol or barbiturates is emphasized. New uses for benzodiazepines are reviewed including the use of benzodiazepines in panic disorder, as well as an adjunct in the therapy of mania and some psychotic states. Rational prescribing of benzodiazepines is encouraged and the attitude that these are dangerous and addictive drugs is discouraged and put into perspective.     

Structural modeling of functional neural pathways mapped with 2-deoxyglucose: effects of acoustic startle habituation on the auditory system

This paper describes the first application of structural modeling to neuroscience. Structural modeling (also known as path analysis) is a method to assess the relative impact of directional links in a system and how these interrelations may change under different conditions. The objective was to demonstrate how structural modeling can be used to determine the functional interrelationships between brain structures that form the auditory system. Using structural modeling, changes in auditory system 2-DG uptake were examined during long- and short-term habituation of the acoustic startle reflex. Models were based on the anatomical connections between central auditory system structures. Using functional 2-DG data, the correlations between these structures were calculated and numerical weights were computed for each anatomical link. The analysis revealed that the lemniscal path was dominant during short-term habituation, while during long-term habituation this influence was modified through extra-lemniscal pathways. The models are discussed in the context of previous findings to demonstrate how structural modeling can not only complement, but also extract more information from 2-DG mapping experiments.     

Activation-induced changes in evoked and slow brain potentials: effect of cocaine in rabbits previously subchronically treated by cocaine

To study the type of adaptive modification (tolerance vs. sensitization) in different organism's indices following intermittent cocaine (COC) administrations, acute COC (2 mg/kg, SC)-induced changes in heart and breathing rate, response to increasing noxious stimulation, spontaneous EEG and event-related evoked and slow brain potentials (ERP) registered from the occipital cortex and hippocampal CA1 region were investigated in naive rabbits and one subchronically treated with COC (6 injections at a same dose). Tolerance developed for bradycardia, depression of noxious responsiveness, cortical desynchronization and increase of main components of cortical ERP, typical to acute COC, while the changes in breathing and hippocampal ERP were stable. These changes as well as a significant increase due to COC administrations of the basal values of an animal's noxious responsiveness and increase in relative changes in main component of cortical ERP (N205) are considered as a consequence of adaptive changes in neurophysiological/neurochemical substrate accepting COC action and mediating phenomena tolerance-sensitization and dependence typical to the drug.     

A phase I-II trial of 4'-deoxydoxorubicin (esorubicin) in refractory or relapsed acute leukemia

In a phase I-II study, 21 patients with relapsed or refractory acute leukemia were treated with 4'-deoxydoxorubicin (esorubicin), the 4'-deoxy derivative of doxorubicin. Four of 14 evaluable patients with acute nonlymphocytic leukemia (ANLL) in relapse or refractory to other anthracyclines achieved partial response (28.5%). Pharmacokinetics were similar to those of the parent compound, doxorubicin. Esorubicin has activity in ANLL and has pharmacologic properties comparable to those of other anthracyclines. Dose-limiting toxicity occurs in the form of mucositis, which may limit its use in combination with other antileukemic drugs.     

Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietary salt intake and chronic diuretic infusion.

We studied the effects of dietary NaCl intake on the renal distal tubule by feeding rats high or low NaCl chow or by chronically infusing furosemide. Furosemide-treated animals were offered saline as drinking fluid to replace urinary losses. Effects of naCl intake were evaluated using free-flow micropuncture, in vivo microperfusion, and morphometric techniques. Dietary NaCl restriction did not affect NaCl delivery to the early distal tubule but markedly increased the capacity of the distal convoluted tubule to transport Na and Cl. Chronic furosemide infusion increased NaCl delivery to the early distal tubule and also increased the rates of Na and Cl transport above the rates observed in low NaCl diet rats. When compared with high NaCl intake alone, chronic furosemide infusion with saline ingestion increased the fractional volume of distal convoluted tubule cells by nearly 100%, whereas dietary NaCl restriction had no effect. The results are consistent with the hypotheses that (a) chronic NaCl restriction increases the transport ability of the distal convoluted tubule independent of changes in tubule structure, (b) high rates of ion delivery to the distal nephron cause tubule hypertrophy, and (c) tubule hypertrophy is associated with increases in ion transport capacity. They indicate that the distal tubule adapts functionally and structurally to perturbations in dietary Na and Cl intake.