Rapid avoidance acquisition in Wistar-Kyoto rats.

The relationship between trait stress-sensitivity, avoidance acquisition and perseveration of avoidance was examined using male Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. Behavior in an open field was measured prior to escape/avoidance (E/A) acquisition and extinction. E/A was assessed in a discrete trial lever-press protocol. The signal-shock interval was 60s with subsequent shocks delivered every 3s until a lever-press occurred. A 3-min flashing light safety signal was delivered contingent upon a lever-press (or failure to respond in 5 min). WKY rats displayed phenotypic low open field activity, but were clearly superior to SD rats in E/A performance. As avoidance responses were acquired and reached asymptotic performance, SD rats exhibited "warm up", that is, SD rats rarely made avoidance responses on the initial trial of a session, even though later trials were consistently accompanied with avoidance responses. In contrast, WKY rats did not show the "warm up" pattern and avoided on nearly all trials of a session including the initial trial. In addition to the superior acquisition of E/A, WKY rats demonstrated several other avoidance features that were different from SD rats. Although the rates of nonreinforced intertrial responses (ITRs) were relatively low and selective to the early safety period, WKY displayed more ITRs than SD rats. With removal of the shocks extinction was delayed in WKY rats, likely reflecting their nearly perfect avoidance performance. Even after extensive extinction, first trial avoidance and ITRs were evident in WKY rats. Thus, WKY rats have a unique combination of trait behavioral inhibition (low open field activity and stress sensitivity) and superior avoidance acquisition and response perseveration making this strain a good model to understand anxiety disorders.

Chronic stress and neural function: accounting for sex and age.

Cognitive responses to stress follow the temporally dependent pattern originally established by Selye (1) wherein short-term stressors elicit adaptive responses whereas continued stress (chronic) results in maladaptive changes--deleterious effects on physiological systems and impaired cognition. However, this pattern for cognitive effects appears to apply to only half the population (males) and, more specifically, to young, adult males. Females show different cognitive responses to stress. In contrast to impaired cognition in males after chronic stress, female rodents show enhanced performance on the same memory tasks after the same stress. Not only cognition, but anxiety, shows sex-dependent changes following chronic stress--stress is anxiolytic in males and anxiogenic in females. Moreover, behavioral responses to chronic stress are different in developing as well as aging subjects (both sexes) as compared to adults. In aged rats, chronic stress enhances recognition memory in both sexes, does not alter spatial memory, and anxiety effects are opposite to young adults. When pregnant dams are exposed to chronic stress, at adulthood the offspring display yet different consequences of stress on anxiety and cognition, and, in contrast to adulthood when the behavioral effects of stress are reversible, prenatal stress effects appear enduring. Changing levels of estradiol in the sexes over the lifespan appear to contribute to the differences in response to stress. Thus, theories of stress dependent modulations in CNS function--developed solely in male models, focused on peripheral physiological processes and tested in adults--may require revision when applied to a more diverse population (age- and sex-wise) at least in relation to the neural functions of cognition and anxiety. Moreover, these results suggest that other stressors and neural functions should be investigated to determine whether age, sex and gonadal hormones also have an impact.

Clinical validation of the "in silico" prediction of immunogenicity of a human recombinant therapeutic protein.

Antibodies elicited by protein therapeutics can cause serious side effects in humans. We studied immunogenicity of a recombinant fusion protein (FPX) consisting of two identical, biologically active, peptides attached to human Fc fragment. EpiMatrix, an in silico epitope-mapping tool, predicted promiscuous T-cell epitope(s) within the 14-amino-acid carboxy-terminal region of the peptide portion of FPX. On administration of FPX in 76 healthy human subjects, 37% developed antibodies after a single injection. A memory T-cell response against the above carboxy-terminus of the peptide was observed in antibody-positive but not in antibody-negative subjects. Promiscuity of the predicted T-cell epitope(s) was confirmed by representation of all common HLA alleles in antibody-positive subjects. As predicted by EpiMatrix, HLA haplotype DRB1*0701/1501 was associated with the highest T-cell and antibody response. In conclusion, in silico prediction can be successfully used to identify Class II restricted T-cell epitopes within therapeutic proteins and predict immunogenicity thereof in humans.

Blockage of glucocorticoid, but not mineralocorticoid receptors prevents the persistent increase in circulating basal corticosterone concentrations following stress in the rat.

Exposure to a single session of intense inescapable stressors results in elevations of plasma corticosterone levels selective to the trough of the circadian rhythm that last for several days after stressor cessation. In the present study, we examined whether this stress-induced alteration in the regulation of the circadian trough is dependent upon glucocorticoid and/or mineralocorticoid receptor activation during stress. Pre-treatment with the mineralocorticoid receptor (MR) antagonist, spironolactone (RU-28318; 50 mg/kg, s.c.), and/or the glucocorticoid receptor (GR) antagonist, mifepristone (RU-38486; 50 mg/kg, s.c.) 1 h before inescapable stress (40, 2.0-mA tail-shocks delivered over a 1 h period) had no effect on the acute plasma corticosterone response to inescapable stress. Treatment with the MR antagonist alone did not affect the appearance of basal corticosterone elevations in stressed rats. However, the elevated trough plasma corticosterone levels were no longer evident in rats treated previously with the GR antagonist either alone or in combination with the MR antagonist. GR activation during stressor exposure appears to be necessary for the development of subsequent basal corticosterone elevations.

[Respiratory filters and pneumonia: many unresolved questions]. / Beatmungsfilter und Pneumonie in der Intensivmedizin: viele ungelöste Fragen.

BACKGROUND AND OBJECTIVE: The use of heat and moisture exchanging filters (HMEF) instead of conventional heated humidifiers is a cost-effective method in intensive care medicine. It was the objective of this paper to investigate the evidence for HMEF from the viewpoint of prevention of pneumonia and to investigate the appropriate changing intervals as well as filter materials. METHOD: Randomised controlled trials published in recent years and focusing on prevention of pneumonia as well as other prospective controlled studies were reviewed systematically. RESULTS: The studies demonstrate neither a clear advantage nor disadvantage of HMEF. No final statement is possible concerning changing intervals and the most appropriate filter materials. However, the data give some evidence for a possible extension of changing intervals to 72 hours without harm to the patients and probably show very little influence of filter materials. CONCLUSION: Because of the economic advantages of HMEF instead of an active humidification, the use of filters--with the exception of contraindications for individual patients--should be preferred.

Pharmacological suppression of corticosterone secretion in response to a physical stressor does not prevent the delayed persistent increase in circulating basal corticosterone concentration.

Elevated basal plasma corticosterone concentrations have been observed for several days after the cessation of severe stress. In the present study, we examined whether or not the acute plasma corticosterone response to stress is necessary to elicit increased basal plasma corticosterone concentrations the following day. Pretreatment with metyrapone (100 m a g , intraperitoneal)1 h before inescapable stress (40 2mA tail shocks delivered over a 1-h period) (IS)blocked the acute plasma corticosterone response to IS. However, elevated basal plasma corticosterone concentrations still emerged the next day. These results suggest that the corticosterone response to stress, and its attendant feedback, are not necessary to produce persistent hypothalamic-pituitary-adrenal axis (HPAA) activation.

Progesterone and cocaine administration affect serotonin in the medial prefrontal cortex of ovariectomized rats.

Due to the hypothetical role of ovarian hormones, estrogen and progesterone, in cocaine-induced behavioral activity and self-administration, this study investigated the effects of cocaine, estrogen, and progesterone administration on monoamine levels in the medial prefrontal cortex of ovariectomized hormone-treated rats. Rats were given either 'binge' cocaine or saline, and one of four hormone treatments: vehicle, estrogen, progesterone, or estrogen+progesterone. The co-administration of progesterone and cocaine resulted in increased levels of serotonin when compared to saline-treated controls and cocaine-treated animals in the other hormone-treatment groups. Further, progesterone-treated rats had higher levels of 5-HIAA than vehicle or estrogen-treated rats. Although levels of dopamine, DOPAC, and homovanillic acid were decreased after cocaine, these alterations failed to reach significance. These results show an interaction between the endocrine environment and cocaine-induced alterations in serotonin system in the medial prefrontal cortex. Thus, these changes may contribute to previously reported gender and estrous cycle differences in behavioral responses to cocaine.

Food deprivation modulates chronic stress effects on object recognition in male rats: role of monoamines and amino acids.

An object recognition task was used to determine if chronic restraint stress (6 h/day for 21 days) impairs non-spatial memory, since chronic restraint is known to impair spatial memory. In addition, food deprivation was tested as a possible modulating factor of any stress effect in this non-reward-dependent task. Following 3 weeks of daily restraint, subjects were tested for open field activity and object recognition (over different delay intervals) during one week in two separate experiments. Experiment 1 involved testing under low demand conditions (small arena) while experiment 2 involved testing under higher-demand conditions (large arena). Basal monoamine and amino acid levels (home cage) were assessed in experiment one and monoamine arousal levels (following a sample trial) were assessed in experiment two. We observed that chronic stress impaired object recognition when the delay was extended beyond 1 h, and that food deprivation could attenuate the degree of impairment. In addition, chronic stress was associated with increased norepinephrine levels in both the amygdala and hippocampus, and dopamine (HVA/DA, DOPAC/DA) in prefrontal cortex. These changes were not observed in stress subjects that were subsequently food deprived. Food deprived subjects had higher basal serotonin activity in prefrontal cortex and hippocampus as well as higher serum CORT levels. Results suggest that food deprivation may act as a novel stress, thereby increasing subjects' arousal and attention toward the objects, which aids stressed subjects, especially in low-demand conditions. Both restraint and food deprivation affected select limbic areas associated with memory functioning.