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We have demonstrated that it is possible to condition the feeding behavior induced by either 2-deoxy-D-glucose (a chemical that induces glucopenia) or tolbutamide (an oral hypoglycemic agent). Such behavioral conditioning is also accompanied by a conditioning of neuroendocrine responses. A model for both overt and covert conditioned responses is proposed.
Despite the widespread adoption of reduced-intensity conditioning (RIC) for myeloma, there are few data comparing outcomes with RIC with myeloablative conditioning (MAC). We report the outcomes of patients undergoing allogeneic transplantations for myeloma and reported to the EBMT. A minimum data set was available on 320 RIC and 196 MAC allografts performed between 1998 and 2002. The RIC patients were older (51 vs 45 years) with more progressive disease (28% vs 21%) and more had received a prior transplant (76% vs 11%). In addition, there was a longer time to transplantation and an increased use of peripheral blood and T-cell depletion. For RIC and MAC, respectively, the nonrelapse mortality (NRM) at 2 years was 24% and 37% (P = .002); overall survival, 38.1% and 50.8% (not significant [ns]); and progression-free survival (PFS), 18.9% and 34.5% (P = .001). On multivariate analysis, RIC was associated with a reduction in NRM (HR, 0.5), but this was offset by an increase in relapse risk (HR, 2.0), and the conditioning intensity did not impact on overall survival or retain significance for PFS. These data suggest that there is a continuing need to investigate dose intensity in the conditioning for myeloma allografts.
The present study investigated fear-potentiated startle and autonomic learning in brain-lesioned patients in a classical fear-conditioning paradigm. Startle blink and skin conductance responses of 30 patients who underwent unilateral temporal lobectomy because of drug-resistant epilepsy were compared with those of 32 healthy controls. As expected, temporal lobectomy patients showed a general impairment in fear conditioning relative to controls. This impairment did not differ with respect to the affected hemisphere. Moreover, while fear-conditioned startle potentiation in healthy controls was independent of contingency awareness, skin conductance discrimination was only observed for those participants who correctly recognized the stimulus contingencies. Patients who acquired a declarative memory of the contingencies also showed intact skin conductance discrimination but failed to exhibit fear-potentiated startle. The present findings support a two-levels-of-learning account of human fear conditioning and also demonstrate that the amygdala is crucially involved in fear learning.
The authors showed that conditional effects of the stimulation environment modulate both the ictal and interictal behaviors of rats subjected to amygdala kindling. Rats received 53 stimulations to the left basolateral amygdala in 1 conditional stimulus (CS) context (CS+) and 53 sham stimulations (the stimulation lead was attached but no current was delivered) in another context (CS-), quasirandomly over 54 days. Three kinds of conditional effects were observed. First, after several stimulations, less ambulatory activity, more freezing, and less rearing reliably occurred in the CS+ context than in the CS-context. Second, after 45 stimulations, all of the rats chose the CS- context over the CS+ context in a conditioned place preference test. Third, when the rats were finally stimulated in the CS- context, their motor seizures were less severe: Latencies were longer, motor seizures were shorter, convulsive patterns were of a lower class, and there were fewer falls.
Properties of a conditioned inhibitor (CI) were studied using the conditioned emotional response (CER) method. The classical defensive response (suppression of the on-going barpressing for food) was first established using 3 min of the white noise conditioned stimulus (CS) and foot shock unconditioned stimulus (US). Then the conditioned inhibitor, a 4 min house light offset, was introduced. During the last 3 min the CI was presented together with CS and not paired with the shock. The rapidly of CER training and also the efficacy of the CI training were both positively correlated with the CS intensity. The final effect of the CI + CS complex enhanced barpressing, whereas the CS alone suppressed it as before. The extinction of the CER resulted in the recovery of the regular barpressing rate during the CS and the CI + CS complex. Presentations of free shocks resulted in a temporary reinstatement of the suppressing effect of the CS and the enhancing effect of the CI + CS. The efficacy of inhibitory training depended on the alimentary motivation level.
Preconditioning experience with the unconditional stimulus (UCS) retards subsequent excitatory conditioning. Three experiments demonstrated that this UCS retardation effect is attenuated by associative manipulations of contextual stimuli of the UCS preexposure environment. The UCS retardation effect was reduced by (a) altering contextual stimuli between preexposure and conditioning (Experiment 1), (b) latently inhibiting contextual stimuli prior to UCS preexposure (Experiment 2), and (c) extinguishing contextual stimuli subsequent to UCS preexposure (Experiment 3). Although UCS preexposure retarded excitatory conditioning, the results of Experiment 4 demonstrated that UCS preexposure facilitated inhibitory conditioning. These results indicate that an association between contextual stimuli and the preexposed UCS contributes to the effects of preconditioning UCS experience on subsequent learning.
The goal of this work was to test the involvement, in fear conditioning, of afferents to the lateral nucleus of the amygdala originating from the auditory thalamus, auditory cortex, and perirhinal area. The acoustic startle reflex was used as the behavioral index of conditioning because it is reliably enhanced in the presence of a conditioned stimulus (CS) previously paired with a footshock. Auditory and visual CSs were used to assess the modality specificity of lesions to the above brain areas. Pre- or posttraining lesions of the entire auditory thalamus including the ventral, dorsal, and medial divisions of the medial geniculate body, the posterior intralaminar nucleus, and the suprageniculate nucleus, completely blocked fear-potentiated startle to the auditory CS, but had no effect on fear-potentiated startle to the visual CS. Posttraining lesions mostly restricted to the ventral and dorsal divisions of the medial geniculate body specifically disrupted fear-potentiated startle to the auditory CS. However, retraining in rats sustaining ventral and dorsal medial geniculate body lesions led to reliable fear-potentiated startle to the auditory CS. Posttraining lesions mostly restricted to the medial division of the medial geniculate body, posterior intralaminar, and suprageniculate nuclei did not disrupt fear-potentiated startle. These results indicate that the auditory thalamus is specifically involved, through either its direct or indirect amygdaloid afferents, in fear conditioning to auditory CSs. Pre- or posttraining lesions mostly restricted to the primary auditory cortex did not reliably attenuate fear-potentiated startle to the auditory or visual CSs. Extensive posttraining lesions of the perirhinal area (including secondary auditory cortices), but not its rostral aspect alone, blocked fear-potentiated startle to both CSs. However, reliable potentiated startle was observed to both CSs following similarly extensive pretraining lesions of the perirhinal area. Because post- but not pretraining lesions of the perirhinal area blocked fear-potentiated startle nonspecifically, at least with regard to auditory and visual CSs, the results are consistent with the involvement of the perirhinal area in general memory functions such as information storage or retrieval. Alternatively, the secondary auditory and/or perirhinal cortices might function as multimodal sensory relays to the amygdala.
Current research suggests there are genetic differences in susceptibility to drug abuse. One way to examine this relationship is to study inbred strains, such as Lewis (LEW) and Fischer 344 (F344) rats, that show differential biochemical and behavioral effects in response to psychoactive drugs. In the present study several behavioral effects of cocaine were compared in these strains, including conditioned place preference (CPP), conditioned taste aversion and locomotor activity. Cocaine CPP was greater in LEW rats than in F344 rats. In contrast, cocaine conditioned taste aversion did not differ between LEW and F344 rats, or did the locomotor activity levels seen after the first cocaine administration. LEW rats, however, showed enhanced locomotor activity to repeated cocaine administrations at all doses tested, an effect not seen in F344 rats. These data suggest that differences in the development of cocaine CPP in LEW and F344 rats are not due to differences in detection of or in inability to condition to cocaine. Rather, these differences in CPP may reflect strain differences in the response to repeated cocaine administrations and may be related to previously observed biochemical differences between the two rat strains.
Conditioned switching over of heterogeneous instrumental reactions was elaborated in four dogs. The action of a fan served as a switch from alimentary to a defensive situation. In the alimentary situation, the animal, in response to a conditioned stimulus, pressed the pedal with its right foreleg and, in a defensive situation, in response to the same signal, lifted the left paw attached to the lever. In some dogs the switching over was elaborated quite rapidly and easily, while in others it was achieved only on some days of the experiment. In the course of elaboration of the switching over, the animals responded to the trigger signal with bieffector reactions. The basic features of the dynamics of switching over elaboration revealed for classic conditioned reflexes also proved valid for instrumental conditioned reflexes.
The oxidation of benzene under sulfate-reducing conditions was examined in column and batch experiments under close to in situ conditions. Mass balances and degradation rates for benzene oxidation were determined in four sand and four lava granules filled columns percolated with groundwater from an anoxic benzene-contaminated aquifer. The stoichiometry of oxidized benzene, produced hydrogen carbonate and reduced sulfate correlated well with the theoretical equation for mineralization of benzene with sulfate as electron acceptor. Mean retention times of water in four columns were determined using radon ((222)Rn) as tracer. The retention times were used to calculate average benzene oxidation rates of 8-36 microM benzene day(-1). Benzene-degrading, sulfide-producing microcosms were successfully established from sand material of all sand filled columns, strongly indicating that the columns were colonized by anoxic benzene-degrading microorganisms. In general, these data indicate a high potential for Natural Attenuation of benzene under sulfate-reducing conditions at the field site Zeitz. In spite of this existing potential to degrade benzene with sulfate as electron acceptor, the benzene plume at the field site is much longer than expected if benzene would be degraded at the rates observed in the column experiment, indicating that benzene oxidation under sulfate-reducing conditions is limited in situ.
In these investigations, the influence of a range of experimental parameters on the isothermal characteristics of hen egg white lysozyme (HEWL) and human serum albumin (HSA) adsorbed to several different adsorbents has been examined. The adsorbents were selected to encompass the same basic types of silica support matrices, but with the ligand properties and surface characteristics adjusted so that the dominant mode of interaction between the protein and the ligand involved either electrostatic binding (i.e. as ion-exchange interaction with polyaspartic acid immobilised onto glycidoxypropyl-modified Fractosil 1000), mixed-mode binding with both hydrophobic and electrostatic effect contributing to the protein-ligand interaction (i.e. as dye-affinity interactions with Cibacron Blue F3G-A immobilised onto Lichroprep DIOL or onto glycidoxypropyl-modified Fractosil 1000), or lone pair coordination binding (i.e. as immobilised metal ion affinity (IMAC) interactions with Cu2+ ions complexed with iminodiacetic acid immobilised onto glycidoxypropyl-modified Fractosil 1000). In each case, the adsorbents exhibited similar ligand densities and had the same particle size ranges and silica surface pretreatment. The effect of the ionic strength of the adsorption buffer and temperature on the isothermal adsorption behaviour under batch equilibrium binding conditions of the two test proteins were determined. Consistent with previous observations with soft gel ion exchangers and triazine dye-based adsorbents that are used in packed bed chromatographic systems, the capacities of the silica-based ion-exchange adsorbents, as well as the Cibacron Blue F3G-A dye affinity adsorbents, for both HSA and HEWL were reduced as the salt concentration was increased under batch equilibrium binding conditions. Moreover, with both of these classes of adsorbents, as the ionic strength was increased under constant temperature conditions, the isothermal adsorption dependencies progressively approximated more closely a Langmuirean model of independent binding site interactions, typical of a mono-layer binding process. In contrast, with the silica-based immobilised metal ion affinity adsorbents as the ionic strength was increased the adsorption behaviour appeared to follow a Freundlich model, indicative of positive cooperativity in the binding process. In parallel experiments, the effect of changes in temperature under iso-ionic strength conditions was examined. With increasing temperature, different patterns of isothermal adsorption behaviour for both test proteins were observed, with the magnitude of these trends depending on the type of interaction involved between the immobilised ligand and the protein. Utilising first order Van't Hoff relationships to analyse the experimental data for these protein-ligand interactions, the apparent changes in enthalpy and entropy for these interactions have been derived from the dependency of the change in the apparent Gibbs free energy on 1/T.
The concept of conditional stability constant is extended to the competitive binding of small molecules to heterogeneous surfaces or macromolecules via the introduction of the conditional affinity spectrum (CAS). The CAS describes the distribution of effective binding energies experienced by one complexing agent at a fixed concentration of the rest. We show that, when the multicomponent system can be described in terms of an underlying affinity spectrum [integral equation (IE) approach], the system can always be characterized by means of a CAS. The thermodynamic properties of the CAS and its dependence on the concentration of the rest of components are discussed. In the context of metal/proton competition, analytical expressions for the mean (conditional average affinity) and the variance (conditional heterogeneity) of the CAS as functions of pH are reported and their physical interpretation discussed. Furthermore, we show that the dependence of the CAS variance on pH allows for the analytical determination of the correlation coefficient between the binding energies of the metal and the proton. Nonideal competitive adsorption isotherm and Frumkin isotherms are used to illustrate the results of this work. Finally, the possibility of using CAS when the IE approach does not apply (for instance, when multidentate binding is present) is explored.
Both nitroreduction and ring-oxidation appear to be important pathways for the in vivo metabolic activation of 1-nitropyrene (1-NP), a tumorigenic environmental contaminant. Previous studies, however, suggest that ring-oxidation is primarily responsible for the S9-mediated mutagenicity of 1-NP in Chinese hamster ovary (CHO) cells. In this study, an anaerobic rat liver S9 metabolizing system was used to facilitate the nitroreduction of 1-NP to a mutagen in repair-proficient CHO-K1-BH4 cells and excision-repair-deficient CHO-UV5 cells, and results using this system were compared with those obtained from the aerobic S9 metabolism of 1-NP. Anaerobic S9 metabolism of 2.5-15 micrograms/ml of 1-NP produced 15 +/- 3 mutants/10(6) cells/microgram 1-NP/ml with CHO-UV5 cells and 3 +/- 1 mutants/10(6) cells/microgram 1-NP/ml with CHO-K1-BH4 cells (different at P less than 0.001). When the assays were conducted with CHO-K1-BH4 cells, the number of mutants produced by 1-NP using aerobic treatment conditions was similar to that found using anaerobic conditions. In contrast, the aerobic incubations resulted in significantly fewer 1-NP-induced mutants than the anaerobic treatments when the assays were conducted with CHO-UV5 cells. Examination of the metabolites produced during these incubations indicated that under anaerobic conditions 1-NP was efficiently converted to 1-aminopyrene, while aerobic metabolism resulted in the formation of 1-NP phenols and dihydrodiols. DNA adduct analysis by 32P-postlabeling revealed that 1-NP treatment using the anaerobic procedure produced CHO-cell adducts by the reduction of 1-NP to N-hydroxy-1-aminopyrene, while aerobic incubations resulted in adducts produced by other metabolic pathways, probably involving ring-oxidation. These findings indicate that the S9-mediated metabolism of 1-NP under anaerobic conditions produces mutations and DNA adducts in CHO cells that are the result of nitroreductive metabolism. The results with aerobic S9 metabolism were consistent with the previous conclusion that this system mediated the mutagenicity of 1-NP in CHO cells mainly through the generation of ring-oxidized metabolites. The combination of the anaerobic and aerobic S9 metabolism procedures provides a new approach for evaluating the mutagenicity of nitropolycyclic aromatic hydrocarbons in mammalian cells.
This paper addresses and answers "no" to the question of whether the literal molecular-dynamically-derived species velocities prevailing at a solid surface bounding a two-component fluid continuum undergoing molecular diffusion constitute the appropriate species-velocity boundary conditions to be imposed upon the fluid continuum. In a broader context, generic boundary condition issues arising from the presence of different length scales in continuum-mechanical descriptions of physical phenomena are clarified. This is achieved by analyzing a model problem involving the steady-state diffusion of a dilute system of Brownian spheres (the latter envisioned as tractable models of solute "molecules") through a quiescent viscous solvent continuum bounded laterally by solid plane walls. Both physicochemical (potential energy) and hydrodynamic (steric) wall interaction effects experienced by the Brownian spheres are explicitly accounted for in our refined, microscale continuum model of the diffusion process. Inclusion of these "solid-wall-fluid" (s-f ) boundary-generated forces [above and beyond the usual "fluid-fluid" (f-f ) intermolecular forces implicit in the conventional Fick's law macroscale continuum description] serves to simulate the comparable s-f molecular boundary forces modeled in molecular dynamics simulations of the diffusional process. A singular perturbation framework is used to clarify the physical interpretation to be ascribed to "continuum-mechanical boundary conditions." In this same spirit we also clearly identify the origin of the physical concept of a "surface field" as well as of the concomitant surface transport conservation equation for strongly adsorbed species at solid walls. Our analysis of such surface phenomena serves to emphasize the fact that these are asymptotic, surface-excess, macroscale concepts assigned to a surface, rather than representing literal molecular material entities physically confined to the surface. Overall, this paper serves to illustrate the manner in which molecular simulations need to account for these different length scales and corresponding scale-dependent concepts if such analyses are to avoid drawing incorrect inferences regarding the molecular origins of continuum-mechanical boundary conditions.
BACKGROUND: Previous studies have characterized alopecia in captive rhesus macaques (Macaca mulatta) by a mixed partial to complete alopecia in a bilateral symmetric pattern. METHODS: In this study, coat condition assessments were related to exogenous and endogenous factors in captive rhesus macaques under different housing conditions in order to identify disturbances in environmental factors controlling or influencing hair growth. Additionally, the degree of alopecia was investigated in relation to adrenal endocrine function as an indicator of social stress using faecal glucocorticoid measurements. RESULTS: Hair loss was found to vary with season and sex, was most pronounced in adult females during the winter and spring months. Generally, infants were not affected, but alopecia developed during adolescence. However, the housing system, available enclosure space and variations in group size and composition also appeared to influence coat condition. Levels of immunoreactive cortisol metabolites (11-oxoetiocholanolone) in faeces were significantly negatively correlated with alopecia, suggesting a relationship between hypothalamic-pituitary-adrenal (HPA) axis activity and hair loss in captive rhesus macaques. CONCLUSIONS: Although the present study demonstrates the influence of the HPA axis on coat condition, it is not known if hair loss is caused by abnormal behaviour or hormonal imbalances of the HPA axis itself. Our data suggest that alopecia in rhesus macaques is a highly complex multicausal disorder.
Anaerobic and aerobic chemostat cultures of Saccharomyces cerevisiae were performed at a constant dilution rate of 0.10 h(-1). The glucose concentration was kept constant, whereas the nitrogen concentration was gradually decreasing; i.e., the conditions were changed from glucose and energy limitation to nitrogen limitation and energy excess. This experimental setup enabled the glycolytic rate to be separated from the growth rate. There was an extensive uncoupling between anabolic energy requirements and catabolic energy production when the energy source was present in excess both aerobically and anaerobically. To increase the catabolic activity even further, experiments were carried out in the presence of 5 mM acetic acid or benzoic acid. However, there was almost no effect with acetate addition, whereas both respiratory (aerobically) and fermentative activities were elevated in the presence of benzoic acid. There was a strong negative correlation between glycolytic flux and intracellular ATP content; i.e., the higher the ATP content, the lower the rate of glycolysis. No correlation could be found with the other nucleotides tested (ADP, GTP, and UTP) or with the ATP/ADP ratio. Furthermore, a higher rate of glycolysis was not accompanied by an increasing level of glycolytic enzymes. On the contrary, the glycolytic enzymes decreased with increasing flux. The most pronounced reduction was obtained for HXK2 and ENO1. There was also a correlation between the extent of carbohydrate accumulation and glycolytic flux. A high accumulation was obtained at low glycolytic rates under glucose limitation, whereas nitrogen limitation during conditions of excess carbon and energy resulted in more or less complete depletion of intracellular storage carbohydrates irrespective of anaerobic or aerobic conditions. However, there was one difference in that glycogen dominated anaerobically whereas under aerobic conditions, trehalose was the major carbohydrate accumulated. Possible mechanisms which may explain the strong correlation between glycolytic flux, storage carbohydrate accumulation, and ATP concentrations are discussed.
Using a conditioned suppression procedure, the effects of three contingent relationships between conditioned (CS) and unconditioned (US) stimuli were investigated. A traditional positive (if CS-then US) contingency suppressed response rate during the CS relative to responding during stimulus-free minutes of the session. A negative (if CS-then no US) contingency resulted in suppressed responding during CS-off minutes, and rate increases during the CS. A no-contingency control procedure, during which CS and US were randomly related, almost totally suppressed responding throughout the session and showed no differential effects of the CS on response rate. An analysis of changes in response rate during the minute after US-offset revealed acceleration under the no-contingency condition and, to a somewhat lesser degree, under the negative contingency. Both conditioned suppression and non-suppression are analyzed in terms of the temporal relationship between CS and US.
The paper reports a study comparing performance on obligation and causal conditionals in the explicit standard order conditional selection task. Analysis indicated that both general and specific reasoning strategies are used when a request is given to disprove obligation conditionals, contradicting the prevalent view that only one of the two kinds of strategy is used and confirming the 1993 suggestions of Evans and later ones by Evans and Over. The incidence of general reasoning strategies in this situation is reduced, compared to that for other kinds of conditional in a disproof task probably because a specific reasoning strategy is available that is easier to use.