Increased extracellular dopamine in the nucleus accumbens of the rat during associative learning of neutral stimuli

Brain microdialysis was used to study changes in dopamine in the nucleus accumbens and the dorsal striatum during associative learning between two neutral stimuli, flashing light and tone, presented on a paired schedule during stage 1 of a sensory preconditioning paradigm. The tone was subsequently paired with mild footshock using standard aversive conditioning procedures and the formation of a conditioned association between the flashing light and the tone in stage 1 was assessed by measuring the ability of the flashing light to elicit the same conditioned response as the tone when presented at test. The first experiment used behavioural monitoring only, to establish stimulus parameters for subsequent microdialysis experiments. Animals receiving paired presentation of the light and tone in stage 1 showed a conditioned suppression of licking to the light as well as to the tone, indicating that associative learning between the flashing light and the tone had occurred during stage 1, whilst in a separate group of animals given the same stimuli over the same time period but on an explicitly non-paired schedule, the conditioned emotional response was seen to the tone, but not to the light, showing that no association had been formed between the two stimuli during stage 1. In dialysis experiments using the same procedure, we measured a two-fold rise in dopamine in the nucleus accumbens during paired presentation of flashing light and tone, but not during non-paired presentation of the two stimuli. On subsequent test presentation of the two stimuli, we saw increases in accumbal dopamine on presentation of the tone in both groups, reflecting the formation of an association with the footshock in both. However the flashing light elicited an increase in dopamine only in the group which had received paired presentation at stage 1. Thus accumbal dopamine release at test is correlated to the ability of the stimulus to evoke a conditioned response measured behaviourally. Hypotheses of the behavioural function of the mesolimbic dopamine system centre on its role in mediating the effects of biological reinforcers, both rewarding and aversive, conditioned and unconditioned. The present results, showing increases in extracellular dopamine in the nucleus accumbens when an association is formed between two stimuli of which neither is a biological reinforcer nor, prior to formation of the association, affects dopamine levels, suggest a role for accumbal dopamine in the modulation of associative learning in general, not only that involving reinforcement.     

Diagnostic utility of specific microbiological markers for periodontal diseases

Specific detection of marker organisms Porphyromonas gingivalis, Prevotella intermedia, and Actinobacillus actinomycetemcomitans with an immunoassay provided 2 types of useful information directly into private clinical practice: 1) persistence of P. gingivalis in patients undergoing regular treatment allowed rapid identification of pockets requiring further treatment without waiting for measurable progression of lesions and 2) presence of A. actinomycetemcomitans in adults at any stage of diagnosis or treatment identified patients who may prove to have difficult-to-manage periodontitis. We made these findings in 253 patients (234 in specialist periodontal practices [F-ME 55; MHM 179] and 19 in general dental practice [EWM]). The search for useful diagnostic markers overlaps only partly with the search for periodontal pathogens. The P. gingivalis marker and the A. actinomycetemcomitans marker identify 2 different patterns of infection that appear to reflect 2 different underlying problems. Demonstration of pocket-dependent infection with P. gingivalis in treated patients provides an outcome marker for sites not converting to marker-negative sites at detection levels of the immunoassay. This information facilitates selection of sites and patients requiring adjustment of treatment regimens. Detection of A. actinomycetemcomitans in adult patients is significantly associated with periodontitis characterized as refractory. Positive identification of A. actinomycetemcomitans with the immunoassay supports clinical decision-making by drawing attention to adult patients who require closer monitoring and intensive persistent treatment. Successful application of immunoassay detection of microbiological markers is based on continuous patient monitoring to support clinical decisions; it does not replace careful clinical judgment.     

Antagonistic activity against Helicobacter infection in vitro and in vivo by the human Lactobacillus acidophilus strain LB

The purpose of the present study was to examine the activity of the human Lactobacillus acidophilus strain LB, which secretes an antibacterial substance(s) against Helicobacter pylori in vitro and in vivo. The spent culture supernatant (SCS) of the strain LB (LB-SCS) dramatically decreased the viability of H. pylori in vitro independent of pH and lactic acid levels. Adhesion of H. pylori to the cultured human mucosecreting HT29-MTX cells decreased in parallel with the viability of H. pylori. In conventional mice, oral treatment with the LB-SCS protected against infection with Helicobacter felis. Indeed, at both 8 and 49 days post-LB-SCS treatment (29 and 70 days postinfection), inhibition of stomach colonization by H. felis was observed, and no evidence of gastric histopathological lesions was found. LB-SCS treatment inhibits the H. pylori urease activity in vitro and in H. pylori that remained associated with the cultured human mucosecreting HT29-MTX cells. Moreover, a decrease in urease activity was detected in the stomach of the mice infected with H. felis and treated with LB-SCS.     

Blood pressure control programs on and off the worksite

Cows on high and low feeding levels were submitted to palpation of the ovaries and recording of the presence and size of follicles at various days of the cycle. A mid-cycle rise in follicular activity was apparent and for which the nonovulating ovary was responsible. High level feeding stimulated ovarian activity in each of the 2 ovaries throughout the cycle and follicular activity commenced earlier in the ovulating ovary on high level feeding than on low level feeding. A larger number of inseminations per conception was required by cows on high level feeding on low level feeding. The effect of ovarian activity on fertility is discussed.     

Antitumor effect of N alpha-benzyloxycarbonyl-N,N-bis-(2-halogenethyl)-hydrazide derivatives of amino acids

The antitumor effect of some N alpha-benzyloxycarbonyl-N,N-bis-(2-halogenethyl)hydrazide derivatives of lysine, glycine, cystine, phenylalanine and p-chlorophenylalanine, was studied. Six of eight newly synthesized compounds show considerable antitumor effect on solid Walker carcinosarcoma 256 (about 95% tumor growth inhibition). Three of these compounds under study increased the lifespan of mice with leukemia L1210. The investigation of the effect of N alpha-benzyloxycarbonyl,D,L-phenylalanine-N,N-bis(2-chloroethyl)hydrazine on various mouse tumors showed remarkable growth inhibition of the Ehrlich ascites carcinoma, sarcoma 37, colon adenocarcinoma akatol and lesser antitumor effect also on solid adenocarcinoma 755, Lewis lung carcinoma and melanoma B16. All investigated compounds exhibited depression of leukocyte count--their toxicity being, however, lower than that of sarcolysine in parallel experiments.     

Antigen-specific cytolysis by neutrophils and NK cells expressing chimeric immune receptors bearing zeta or gamma signaling domains

TCR- and IgG-binding Fc receptors (Fc gamma R) mediate a variety of critical biologic activities including cytolysis via the structurally related zeta- and gamma-chains. In previous studies, we have described chimeric immune receptors (CIR) in which the ligand-binding domain of a heterologous receptor or Ab is fused directly to the cytoplasmic domain of the TCR zeta-chain. Such zeta-CIRs efficiently trigger cytotoxic function of both T and NK cells in a target-specific manner. In this report, we compared the ability of both zeta- and gamma-CIRs to activate the cytolytic function of two distinct classes of Fc gamma R-bearing effectors, NK cells and neutrophils. Mature neutrophils expressing zeta- and gamma-CIR were generated in vivo from murine hemopoietic stem cells following transplantation of syngeneic mice with retrovirally transduced bone marrow or in vitro from transduced human CD34+ progenitors following differentiation. Both zeta- and gamma-based CIRs were capable of activating target-specific cytolysis by both NK cells and neutrophils, although the zeta-CIR was consistently more efficient. The experimental approach described is a powerful one with which to study the role of nonlymphoid effector cells in the host immune system and permits the rational design of immunotherapeutic strategies that rely on harnessing multiple immune cell functions via CIR-modified hemopoietic stem cells or progenitors.