Although serum vibriocidal activity is used extensively as a marker of immunity to O1 Vibrio cholerae, there are limitations in this assay to detect instances of reexposure. We define the conditions operative in producing secondary vibriocidal responses in North American volunteers primed with either wild-type V. cholerae or CVD 103-HgR live attenuated oral cholera vaccine and then challenged with wild-type V. cholerae 1, 4, or 6 months later. Secondary serum vibriocidal responses occurred under two distinct secondary challenge conditions. The first occurred when secondary challenge produced a breakthrough in clinical protection. Following secondary exposure, 14 of 22 (64%) and 1 of 29 (3%) subjects with and without vibrio stool excretion, respectively, had secondary responses (P < 0.001); 5 of 6 (83%) and 10 of 45 (22%) subjects with or without diarrhea, respectively, mounted a secondary response (P ؍ 0.006). The second condition occurred in the presence of full clinical protection but was dependent on the time interval between exposures. No subject (0 of 17) vaccinated with CVD 103-HgR and given homologous wild-type challenge within 4 months mounted a secondary vibriocidal response compared with 8 of 11 (73%) vaccinated volunteers challenged at 6 months who developed a secondary vibriocidal response (P ؍ 0.0009). The majority of the serum vibriocidal activity was of the immunoglobulin M (IgM) isotype, seen in 96 and 73% of subjects following primary and secondary exposure, respectively. Vibriocidal activity in the IgG fraction following primary and secondary exposures occurred with <50% of volunteers; lipopolysaccharide (LPS)-specific IgG1 and IgG3 subclass responses supported the vibriocidal isotype data. However, following primary exposure, IgG4 LPS responses predominated, occurring in 81% of responding volunteers. These data suggest that, under certain conditions of secondary exposure to V. cholerae O1 antigens, when there is sufficient active local immunity present, there is a block of vibrio antigen resampling at the M cell level. We discuss the implications of and possible explanations for these findings.
We describe a novel approach to assess the excitability of hypoglossal motoneurons in rats during naturally-occurring states of sleep and wakefulness. Adult rats were surgically prepared with permanently-placed electrodes to record the EEG, EOG and neck EMG. A stimulating/recording miniature tripolar cuff electrode was implanted around the intact hypoglossal nerve and a head-restraining device was bonded to the calvarium. After a period of adaptation to head-restraint, the animals did not exhibit any sign of discomfort and readily transitioned between the states of wakefulness, NREM and REM sleep. There was no spontaneous respiratory or tonic activity present in the hypoglossal nerve during sleep or wakefulness. Hypoglossal motoneurons were activated by electrical stimulation of the hypoglossal nerve (antidromically) or by microstimulation directly applied to the hypoglossal nucleus. Microstimulation of hypoglossal motoneurons evoked compound action potentials in the ipsilateral hypoglossal nerve. The magnitude of their integrals tended to be higher during wakefulness (112.6% ± 15; standard deviation) and were strongly depressed during REM sleep (24.7% ± 3.4), compared to the integral magnitude during NREM sleep. Lidocaine, which was delivered using pressure microinjection to the microstimulation site, verified that the responses evoked in hypoglossal nerve can be affected pharmacologically. We conclude that this animal model can be utilized to study the neurotransmitter mechanisms that control the excitability of hypoglossal motoneurons during naturally-occurring states of sleep and wakefulness.
Stimulation of nicotinic and muscarinic cholinoreceptors (nAChR, mAChR) in outbred albino mice with nicotine and aceclidine, respectively, in single equilethal doses 0.5 DL(50)6 h before sepsis induction significantly reduced animal mortality due to a decrease in blood concentrations of proinflammatory cytokines IL-1β, IL-6, and MIP-2. Stimulation of mAChR (injection of aceclidine) stimulated the neutrophilic phagocytic and metabolic activity. Realization of the cholinergic anti-inflammatory pathway (stimulation of the peripheral nicotinic cholinoreceptors (α7nAChR) and central muscarinic cholinoreceptors (mAChR) was modulated by stimulation of the muscarinic cholinoreceptors of the phagocytic monocytic system cells.
Eszopiclone was determined to suppress the apnea-induced hyperexcitability of hippocampal CA1 neurons, thereby reducing/eliminating neurotoxicity. These data lend credence to our hypothesis that eszopiclone, exclusive of its hypnotic actions, has the capacity to function as a potent neuroprotective agent.
The microinjection of nerve growth factor (NGF) into the cat pontine tegmentum rapidly induces rapid eye movement (REM) sleep. To determine if NGF is involved in naturally-occurring REM sleep, we examined whether it is present in mesopontine cholinergic structures that promote the initiation of REM sleep, and whether the blockade of NGF production in these structures suppresses REM sleep. We found that cholinergic neurons in the cat dorsolateral mesopontine tegmentum exhibited NGF-like immunoreactivity. In addition, the microinjection of an oligodeoxyribonucleotide (OD) directed against cat NGF mRNA into this region resulted in a reduction in the time spent in REM sleep in conjunction with an increase in the time spent in wakefulness. Sleep and wakefulness returned to baseline conditions 2 to 5 days after antisense OD administration. The preceding antisense OD-induced effects occurred in conjunction with the suppression of NGF-like immunoreactivity within the site of antisense OD injection. These data support the hypothesis that NGF is involved in the modulation of naturally-occurring sleep and wakefulness.
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