Biomedical subjects
Publications and source records attributed to I de Andrés.
Two patients with chronic motor neuropathy, high antiganglioside antibody (AGA) titers, and a declining response to IV immunoglobulins were treated with rituximab at a standard dose. The drug was well tolerated and effectively eliminated peripheral B cells (CD20+), but AGA titers continued significantly high. No clinical improvement was detected during the 1-year follow-up.
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We report the effects of permanently separating the immature forebrain from the brain stem upon sleeping and waking development. Kittens ranging from postnatal 9 to 27 days of age sustained a mesencephalic transection and were maintained for up to 135 days. Prior to postnatal day 40, the electroencephalogram of the isolated forebrain and behavioral sleep-wakefulness of the decerebrate animal showed the immature patterns of normal young kittens. Thereafter, the isolated forebrain showed alternating sleep-wakefulness electrocortical rhythms similar to the corresponding normal patterns of intact, mature cats. Olfactory stimuli generally changed forebrain sleeping into waking activity, and in cats with the section behind the third nerve nuclei, normal correlates of eye movements-pupillary activity with electrocortical rhythms were present. Behind the transection, decerebrate animals showed wakefulness, and after 20 days of age displayed typical behavioral episodes of rapid eye movements sleep and, during these periods, the pontine recordings showed ponto-geniculo-occipital waves, which are markers for this sleep stage, together with muscle atonia and rapid lateral eye movements. Typically, but with remarkable exceptions suggesting humoral interactions, the sleep-waking patterns of the isolated forebrain were dissociated from those of the decerebrate animal. These results were very similar to our previous findings in midbrain-transected adult cats. However, subtle differences suggested greater functional plasticity in the developing versus the adult isolated forebrain. We conclude that behavioral and electroencephalographic patterns of non-rapid eye movement sleep and of rapid eye movement sleep states mature independently in the forebrain and the brain stem, respectively, after these structures are separated early postnatally. In terms of waking, the findings strengthen our concept that in higher mammals the rostral brain can independently support wakefulness/arousal and, hypothetically, perhaps even awareness. Therefore, these basic sleeping-waking functions are intrinsic properties of the forebrain/brain stem and as such can develop autochthonously. These data help our understanding of some normal/borderline sleep-waking dissociations as well as peculiar states of consciousness in long term patients with brain stem lesions.
The aim of this work was to study which genes upregulated by the IFN-gamma/STAT1 system in human muscle might be involved in the process of muscle fiber atrophy in dermatomyositis (DM). These proteins included proteases (cathepsins B and L, calpain), proteins implicated in apoptosis and cell cycle (Bcl-x(l), Fas, p21), structural proteins (beta-actin, utrophin, desmin), and other proteins whose expression is known to be modified by IFN-gamma (neural cell adhesion molecule (N-CAM), major histocompatibility complex-I (MHC-I)). We performed immunocytochemistry, Western blot, and semiquantitative reverse transcriptase-polymerase chain reaction using human muscle cultures. We found upregulation of cathepsins B and L, bcl-x(l) and p21 while N-CAM, calpain, utrophin, desmin, beta-actin and Fas remained at basal levels. Immunohistochemistry on frozen sections from biopsies of patients with different muscle diseases showed upregulation of cathepsin L and calpain in perifascicular muscle fibers in DM. In view of these results, the increased expression of cathepsins L and B after IFN-gamma stimulation in muscle cultures and its inhibition using fludarabine, a STAT1 blocker, further support our previous studies and suggest that the increased expression of cathepsins detected in perifascicular muscle fibers in DM is mediated by IFN-gamma/STAT1 and contributes to their atrophy.
This study examines the influence of lesions in the centralis superior raphe nucleus (CeSR) and adjacent paramedial pontine tegmentum on the sleep/wakefulness cycle (SWC) in cats. Sixteen cats had electrodes implanted for electro-oculogram (EOG), electromyogram (EMG), electroencephalogram (EEG) and ponto-geniculo-occipital (PGO) recordings. There were 10 experimental animals: seven animals received diathermocoagulation lesions destroying between 7 and 27% of the CeSR; the remaining three cats suffered bilateral lesions in the paramedial portion of the reticularis pontis oralis (RPO) and caudalis (RPC) nuclei. Six sham-operated animals were used as controls. Recordings were taken of all animals in continuous 23-h sessions once a week for 12 weeks. Results indicated that the threshold for SWC state changes (increase of wakefulness (W) and drowsiness (D), and decrease of slow wave sleep (SWS)) after CeSR lesion is approximately 11.3% following volumetric destruction of the nucleus. The amount of CeSR damage (CeSR-D) only correlated significantly with the amount of W (positive correlation) and SWS (negative correlation) during the first week post-lesion. The changes in W over the course of the study were different in the two experimental groups. In both groups, total W was increased with respect to the controls, however, these increases were observed earlier in the CeSR-D group. The return to near control values in SWC state over days 15-28 of the study does not represent a definitive recovery by the CeSR-D cats. All the SWC states returned to control values by the tenth week in the cats with paramedial reticular pontine damage.
Neocortical and hippocampal EEG power spectra obtained during REM-like sleep induced by unilateral carbachol microinjections (0.01 M, 0.02 M and 0.2 M; volume 20 nl) into the ventral part of the nucleus reticularis pontis oralis have been compared with EEG power spectra obtained during spontaneous REM sleep. Our findings indicate that neocortical and hippocampal electrical activities during the REM-like state generated by carbachol delivery in this pontine region mimic those present in spontaneous REM sleep.
The effects on sleep/wakefulness states of morphine, morphiceptin (specific mu agonist), DPDPE (delta agonist) and U-50,488H (kappa agonist) microinjections in the Locus coeruleus area (LC) were studied in cats. Morphine (0.8-1.75 nmols in 50 nl of saline) and morphiceptin (1.75 nmols) in LC significantly increased the total time spent in slow wave sleep (SWS) and the mean duration of SWS episodes. Prior naloxone administration blocked the morphine hypnogenic effects. The total time spent in SWS was unaffected by delivery of equimolar doses of DPDPE or U-50,488H in LC; however, the mean duration of the SWS episodes increased significantly after U-50,488H microinjections in LC. Thus, when acting in the LC, opiates have a SWS-enhancing effect and this effect appears to be mediated by mu receptors, although kappa receptors may have a subsidiary action.
BACKGROUND: Previous studies have shown that the region of the nucleus of the solitary tract (NST) is involved in the control of electrocortical activity and in sleep mechanisms. It also is well known that this region contains the highest concentration of opioid receptors within the medullary brainstem. The involvement of the NST opioid system in sleep-wakefulness states were evaluated. METHODS: Ten cats were implanted with electrodes for chronic polygraphic recordings of their sleep-wakefulness states and provided with an implanted guide cannula stereotaxically aimed at the NST region. Microinjections of saline, morphine sulfate, morphiceptin (specific mu agonist), D-pen-2-D-pen-5-enkephalin (delta agonist), and U-50488H (kappa agonist) were given to the freely moving animals (doses 0.8-2.4 x 10(-9) M, in a volume of 0.05 microliters of saline). After microinjections, sleep-wakefulness recordings were obtained for 8 h. RESULTS: Morphine microinjections in NST provoked a dose-dependent enhancement of all the polygraphic and behavioral manifestations of slow wave sleep. This effect was blocked by the prior intraperitoneal administration of naloxone. The mu and delta agonists also produced a hypnotic effect by enhancing slow wave sleep. By contrast, the kappa agonist caused no changes in sleep-wakefulness states. CONCLUSIONS: These results indicate that endogenous opioids could be involved in controlling electrocortical activity generated by NST and that activation of mu and delta NST opioid receptors enhanced the electroencephalographic synchronization associated with behavioral slow wave sleep in cats.
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In order to examine the prosencephalic mechanisms that might sustain the effects of opiates on EEG and sleep-wakefulness, the actions of morphine sulfate on the EEG and the pupil size were examined in the chronically isolated forebrain of brainstem-transected cats. Single morphine doses (0.5, 2.0 or 3.0 mg/kg, i.p.) administered to these animals produced a long-lasting EEG desynchronization in the isolated forebrain which was associated with pupil mydriasis. The specificity of these morphine effects was shown by the fact that naloxone blocks both the EEG and pupillary effects of the drug. After morphine, spontaneous synchronized EEG with delta waves normally seen in the isolated forebrain preparation was suppressed for 6-18 h, followed by a strong rebound. Both the suppression and rebound in synchronization with delta waves occurred in a dose-dependent manner. The duration of these effects closely paralleled previously reported morphine effects on non-rapid eye movement (NREM) sleep in intact cats. Therefore, in relation to the effects of morphine on EEG and sleep-wakefulness in intact animals, this study suggests that: (1) Morphine suppression of NREM sleep and the subsequent arousal state of the animal are mediated by prosencephalic structures; (2) the generation of the typical neocortical EEG slow burst activity produced by opiates depends on lower brainstem structures.
Previous studies have shown that opiates suppress both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Furthermore, during the induced insomnia period, characteristic species-specific behaviors occur which are associated with high voltage slow waves in the EEG. This paper investigates the lower brainstem mechanisms involved in the generation of these effects, and describes the action of single morphine doses (0.5, 2.0 or 3.0 mg/kg, i.p.) on the behavior and REM sleep of chronic decerebrate cats. The effects of morphine in the decerebrate cat followed a 3-stage time course similar to that seen in intact cats: (1) autonomic manifestations (3-8 min postdrug); (2) a quiet state (10-60 min postdrug) with behavioral signs of NREM; and (3) a state of activated behavior (1-6 h postdrug), including motor activity and variations in muscle tone. The decerebrate cats also showed a dose-dependent suppression of REM sleep. The present results indicate that: (1) the lower brainstem provides the basic mechanisms for the behavioral deactivation-activation and the autonomic effects of the drug; (2) hypnogenic and synchronizing influences arising from the brainstem might induce the high voltage, slow burst EEG produced by opiates; (3) REM sleep suppression originates only partially in the lower brainstem; (4) the subsidiary action of the prosencephalon seems to be required for the full expression of the drug's effect on behavior and the EEG.
The activity of 72 neurons recorded in the reticularis pontis oralis nucleus (RPO) was examined in anesthetized and curarized rats during hippocampal theta (theta) rhythm elicited by either sensory stimulation or carbachol microinjections. During hippocampal theta rhythm evoked by sensory stimulation, 63.9% of RPO neurons increased their discharge rate while the firing rate decreased in 20.8%. In all cases, the RPO neurons maintained a non-rhythmic discharge pattern. In 44% of the neurons the discharges tended to occur on the positive wave of the theta rhythm. Similar firing patterns were seen in 18 RPO neurons recorded during theta rhythm elicited by both, sensory stimulation and a carbachol microinjection; this effect was blocked by atropine. These results indicate that the RPO region contributes to the generation of hippocampal theta rhythm with a tonic and nonrhythmic outflow through a cholinergic system which may be muscarinic.
Some of our personal contributions in the last years on pontine sleep mechanisms are presented. The results after specific pontine lesions and cholinergic microstimulation of brain stem areas are reviewed. These results are discussed in relation to current concepts about the role of the pontine tegmentum in sleep mechanisms.
In order to study the variability of the phases of the sleep-wakefulness cycle (SWC) in the laboratory cat, eight animals were implanted with the standard array of electrodes for EEG, EOG and EMG recordings. Six twenty-four-hour recordings were obtained from each cat at weekly intervals. Three recordings were carried out in the cat colony while the remaining three were obtained with the cat alone in the sound proof chamber. Furthermore, in four cats, other three longitudinal twenty-four-hour recordings were obtained in the sound-proof chamber. In all situations the animals were under a 12:12 light/dark regime and were fed once a day. Sleep recordings were scored according to the polygraphic criteria for wakefulness (W), drowsiness (D), slow sleep (SS) and paradoxical sleep (PS). In each situation a two way analysis of variance (animals and days) was made. Results showed that W, D and SS were the states of the SWC exhibiting the largest variability among animals, while PS was the most stable phase. Variations of the four states among the different days of weekly intervals were not significant. However, a significant increase in PS was observed on the first day in the cases with longitudinal recordings.
Visual evoked potential parameters (latencies, intervals of latencies and amplitudes) obtained by photic stimulation using a light-emitting diode implanted in the frontal sinus of cats were studied by statistical methods (analysis of variance) during the stages of wakefulness, slow sleep and paradoxical sleep. The results show: a) greater intraindividual homogeneity in all cases with special emphasis on the latencies; b) the greatest homogeneity of responses was found during slow sleep and paradoxical sleep stages; c) in relation to the influences exerted by the sleep-wakefulness cycle on the visual evoked potentials, the parameters most affected were those closely related to the secondary complex. We conclude, that latency, due to its great homogeneity, is the most useful parameter in this kind of experiments and secondly, that it is the secondary complex of the visual evoked potentials that is affected by the endogenous conditions of the subject (in our case the sleep-wakefulness cycle stage).
Cats injected with a relatively low single dose of morphine sulfate (0.5-3.0 mg/kg i.p.) exhibit a long-lasting group of behaviors which we quantified via a time-sampling video technique. The dominant events are complex head movements accompanied by discrete paw, ear and body movements with the animal in a quiet posture, all of which appeared to be visually mediated. Cats with extensive lesions of the caudate nuclei do not show this profile; instead they show unspecific locomotor activity proportional to the size of the ablation and to the dose of morphine. These effects are blocked by naloxone in both intact and lesioned animals. The robustness of these results indicate that (i) the striatum is involved in the behavioral effects of morphine, and (ii) that the cat is a useful, sensitive model for the study of the behavioral effects of opiates.
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