Imaging of atherosclerosis, targeting LFA-1 on inflammatory cells with 111In-DANBIRT.

BACKGROUND: 111In-DOTA-butylamino-NorBIRT (DANBIRT) is a novel radioligand which binds to Leukocyte Function-associated Antigen-1 (LFA-1), expressed on inflammatory cells. This study evaluated 111In-DANBIRT for the visualization of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: ApoE-/- mice, fed an atherogenic diet up to 20 weeks (n = 10), were imaged by SPECT/CT 3 hours post injection of 111In-DANBIRT (~ 200 pmol, ~ 40 MBq). Focal spots of 111In-DANBIRT were visible in the aortic arch of all animals, with an average Target-to-Background Ratio (TBR) of 1.7 ± 0.5. In vivo imaging results were validated by ex vivo SPECT/CT imaging, with a TBR up to 11.5 (range 2.6 to 11.5). Plaques, identified by Oil Red O lipid-staining on excised arteries, co-localized with 111In-DANBIRT uptake as determined by ex vivo autoradiography. Subsequent histological processing and in vitro autoradiography confirmed 111In-DANBIRT uptake at plaque areas containing CD68 expressing macrophages and LFA-1 expressing inflammatory cells. Ex vivo incubation of a human carotid endarterectomy specimen with 111In-DANBIRT (~ 950 nmol, ~ 190 MBq) for 2 hours showed heterogeneous plaque uptake on SPECT/CT, after which immunohistochemical analysis demonstrated co-localization of 111In-DANBIRT uptake and CD68 and LFA-1 expressing cells. CONCLUSIONS: Our results indicate the potential of radiolabeled DANBIRT as a relevant imaging radioligand for non-invasive evaluation of atherosclerotic inflammation.

Mania resulting from continuous positive airways pressure in a depressed man with sleep apnea syndrome.

The authors report the case of a 50-year-old man, with no previous history of bipolar illness, hospitalized with a very severe depression and who was resistant to a 7-weeks treatment of venlafaxine and trazodone (the respective daily doses were 300 and 50 mg which were stable during the last 4 weeks). A diagnosis of sleep apnea syndrome led to the use of the continuous positive airways pressure technique (CPAP). A few days after starting CPAP, he presented a mood switch, first hypomanic, then mixed. The authors discuss the contribution of the sleep apnea syndrome to the appearance and the maintenance of the depressive disorder.

The effects of two single doses of tramadol on sleep: a randomized, cross-over trial in healthy volunteers.

BACKGROUND AND AIM: The effects of analgesic drugs on sleep are poorly understood. We investigated short- and medium-term effects of tramadol on sleep structure. METHODS: Eight healthy volunteers received a placebo (predrug placebo-night), then, in a randomized, double-blind, cross-over fashion a single oral dose of tramadol 50 mg or 100 mg (drug-night), and finally, again a placebo (postdrug placebo-night). Standardized polysomnography (electroencephalogram, electro-oculogram, submental electromyogram) was continuously recorded during placebo- and drug-nights. RESULTS: During drug-nights both doses of tramadol significantly increased the duration of stage 2 sleep, and significantly decreased the duration of slow-wave sleep (stage 4). Tramadol 100 mg but not 50 mg significantly decreased the duration of paradoxical (rapid eye movement) sleep. In the placebo-night after tramadol 100 mg (but not after 50 mg) duration of stage 2 sleep was significantly shorter, and duration of stage 4 sleep was significantly longer compared with the predrug placebo-night. CONCLUSION: In healthy volunteers, a single dose of tramadol 50 mg disturbs sleep in the night of drug application. With 100 mg, sleep is disturbed in both the night of drug application and in the subsequent night.

Spectral characteristics of sleep EEG in chronic insomnia.

To determine whether the spectral characteristics of the sleep electroencephalogram (EEG) of insomniacs differ from that of healthy subjects, we compared in each of the first four non-rapid eye movement (NREM) and rapid eye movement (REM) episodes: (a) the time courses of absolute power, averaged over the subjects in each group, for the delta, theta, alpha, sigma and beta frequency bands; (b) the relationship between these time courses; and (c) the overnight trend of integrated power in each frequency band. The results show that NREM power, for all frequencies below the beta range, has slower rise rates and reaches lower levels in the insomniac group, whereas beta power is significantly increased. In REM, insomniacs show lower levels in the delta and theta bands, whereas power in the faster frequency bands is significantly increased. Thus, the pathophysiology of insomnia is characterized not only by the generally acknowledged slow wave deficiency, but also by an excessive hyperarousal of the central nervous system throughout the night, affecting both REM and NREM sleep. This hyperarousal is interpreted in terms of the neuronal group theory of sleep which provides a possible explanation for the discrepancies observed between subjective impressions and objective measures of sleep. Also, it is suggested that the progressive hyperpolarization of the thalamocortical neurons as sleep deepens is slower in the patient population and that this may explain the observed slow wave deficiency. The homeostatic control of slow wave activity, on the other hand, would appear to be intact in the patient population.

Evolution of delta activity within the nonREM sleep episode: a biphasic hypothesis.

The time course of delta activity within nonREM (NREM) episodes is measured for 24 healthy subjects with normal REM latencies. The first two NREM episodes in particular, show two very clearly separated peaks for about 35% of the subjects. Another 25% show two less well separated peaks. These double peak patterns are also prevalent in the literature, but there has been a tendency to dismiss them as a skipped REM effect. They are, however, still evident even when the data are averaged over the 24 subjects, indicating a systematic phenomenon. These averaged data are well fitted by an analytic function given by the sum of two consecutive overlapping Gaussian curves. The well-behaved residuals also, are an indication that a biphasic model of this kind is statistically appropriate. The model proposed is simple, with parameters related to physiological phenomena, and it suggests that there may be an underlying process with delta waves emanating from two separate signal sources. Recent neurophysiological findings suggest that delta oscillations are generated both in the thalamus and in the cortex and show that excessive synchronization of slow oscillations may lead to seizures. Hence the speculation that the biphasic process may emanate from cortical and thalamic sources and be protective in the sense that it permits smaller delta amplitudes at each source while retaining the integral delta energy necessary to satisfy sleep pressure. It is significant that the two peaks are most evident in the first two NREM episodes where delta power is high.

Relationship between the time courses of power in the frequency bands of human sleep EEG.

The time course of the different frequency bands in the human sleep EEG spectrum within separate NREM and REM episodes averaged over 24 healthy subjects is measured and plotted with the aim of studying their inter-relationship and also the particularities of the beta band. In NREM, a negative sigma-delta cross-correlation corresponding to that expected from neurophysiological data, is found only in the central zone of each episode. The overall correlation is found to be negligible. A neurophysiological explanation is proposed to account for some aspects of this sigma-delta relation. Below the beta frequency range in NREM, the sequence of build-up in power for the different frequencies is from fast to slow, suggesting that there may be a smooth progression in the frequency of oscillation of the thalamocortical neurons depending on their degree of polarization. The beta band is the only one showing a reciprocal relationship with delta throughout the NREM episode, and it is the only one not declining in the REM episode. These differences, together with the close similarity of the beta evolution with that of the REM-on neuronal activity, suggest that beta could directly reflect this activity.

Differential effects of an alpha-2 agonist on wakefulness and paradoxical sleep in the rat: A polygraphic and biochemical approach.

The purpose of this experiment was to determine the sensitivity of wakefulness and paradoxical sleep to the α2-agonist, c1onidine. The drug inhibited both wakefulness and paradoxical sleep but the smallest dose necessary to inhibit wakefulness was 64 times larger than the smallest dose inhibiting paradoxical sleep. The effect on paradoxical sleep was inhibitory for all the clonidine doses but wakefulness was enhanced transiently after the four largest doses used. The time between injection and maximum wakefulness enhancement was highly correlated with the dose of c1onidine. The brain level measured after these four different doses at the moment of maximum wakefulness enhancement was the same, suggesting that this effect occurred only when a critical concentration of the drug was attained in the brain and not when the concentration was higher or lower. These data suggest that different α2-adrenoceptors are involved in these two states of vigilance or, alternatively, that their sensitivity is modulated physiologically. In addition, a sensitivity imbalance between different α2-adrenoceptors may exist in wakefulness but not in paradoxical sleep.

[Insomnia]. / Insomnies.

Insomnia is frequently met in everyday medical practice. Half of the population can present this symptom during their life-time. Objective impairment of sleep, as well as complaints of patients, are various and require investigations. Two forms of insomnias, transient and chronic, can be identified. The former is mainly factual and the latter is consecutive to a longstanding organic or psychiatric condition or constitute what is generally referred to primary chronic insomnia. The form, the duration, the severity and the etiology are important clues for the choice of treatment, notably the prescription of hypnotics.

Subjective assessment of sleep: statistical analysis in a population of healthy subjects.

A principal components analysis was carried out on subjective data obtained from the sleep questionnaire systematically used in our laboratory on the morning following a polysomnographic recording. This technique, based on 70 healthy subjects, revealed three principal axes which explore the questionnaire. The first axis reflects the subjective evaluation of the quality of sleep. The second underlines the importance of dreams and of the brief waking periods which immediately follow. Finally, the third axis brings out the subjective assessment of sleep efficiency. The third axis was the most ambiguous and the only one to show a gender difference. Women tend to better estimate general sleep events, while men tend to evaluate better the more circumstantial events. Finally, given the results, it would be interesting to apply a similar analysis to populations presenting sleep disorders in order to establish the presence of an eventual pattern specific to the disorder.

New variables for defining sleep continuity.

One very synthetic way to represent a night's sleep is by way of a hypnogram: a graphical representation of the sleep stages as a function of time. The hypnogram is generally quantified by a series of variables that measure the durations and latencies of the various sleep stages including wake. These variables, however, do not fully account for all the information contained in the hypnogram, in particular information on sleep continuity. A series of variables that measure and localize disruption of this continuity are proposed and their utility validated on three groups of patients presenting sleep disorders. Utility is established if the variable is capable of differentiating between patients and healthy controls. Two sets of variables are examined: those that use the entire sleep period as unit of measurement, and those that are measured within each consecutive NREM-REM sleep cycle. The results show that the variables proposed are able to differentiate between groups and, therefore, are useful measures reflecting the hypnogram more precisely. They also show that fragmentation of REM sleep does not present a systematic trend across the night, but that fragmentation of NREM sleep goes up linearly.

Effect of zolpidem on sleep in healthy subjects: a placebo-controlled trial with polysomnographic recordings.

The aims of this double-blind, placebo-controlled study, conducted in a group of healthy young adults with normal sleep patterns, were to ascertain the effect of various doses of zolpidem on polysomnographic variables and to determine whether zolpidem disrupts sleep architecture. Of the 15 subjects recruited, 8 were included in the final analysis. Subjects underwent four experimental sessions during three nights, of which the first night was used for adaptation, the second for zolpidem (10, 20, and 40 mg) or placebo administration, and the third for placebo administration. Sleep was assessed by conventional sleep parameters (latency, duration, wakefulness) and by subjective questionnaire. Polysomnographic recordings were analyzed for sleep stage, paradoxical sleep, graphic features, and longitudinally with reference to sleep stage. Zolpidem had little effect on polysomnographic variables, except for a trend toward a hypnotic effect and a slight, transient inhibition of paradoxical sleep at the highest dose. In particular, the clearcut reduction of stage 4 sleep and increase in spindle density often observed with benzodiazepine administration was not observed with zolpidem. Adverse effects were restricted to three reports of daytime drowsiness each after zolpidem 10 and 40 mg and placebo, and one amnesic episode after the highest dose (40 mg). There were no signs of ataxic symptomatology.

Effects of moclobemide on sleep in healthy human subjects.

Ten healthy, normal subjects (5 male and 5 female) aged 20-28 years participated in this experimental study of the effect of moclobemide on sleep. The design consisted of 2 sessions of 5 nights each, comprising 1 adaptation night, 2 nights on placebo and 2 inputs of moclobemide 4 mg/kg (session B). The 2 sessions were separated by at least 15 days and their order was balanced and randomized. During the last 4 nights of each session, sleep parameters were recorded throughout the night according to standard procedures. Moclobemide at a dose of 4 mg/kg induced moderate changes in the sleep-wake balance: a significant increase in stage 1 on the second drug night, a slight increase in stage 2 and a significant decrease in paradoxical sleep on the 2 drug nights. There was also a moderate reduction in the number of rapid eye movements (REM) during paradoxical sleep, but the number of cycles and latency to paradoxical sleep were unchanged, as well as all other sleep parameters measured. With 6.5 mg/kg, the changes were more pronounced: total sleep time was diminished, but this was significant only on the second and third nights. Transient awakenings increased significantly on the first drug night, and wakening latency decreased. The only modification of orthodox sleep was an increase in the percentage of stage 2 on the first drug night, whereas slow-wave sleep was unchanged. Paradoxical sleep was reduced on the first 2 drug nights, but tolerance appeared on the third night. The decrease in paradoxical sleep was exacerbated in the last part of the night. REM were decreased during paradoxical sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

The intrasleep relationship between wake and stage 4 examined by transition probability analysis.

The relationship between wake and stage 4 of slow-wave sleep (SWS), in particular the previously observed deficiency in SWS accompanying sleep containing long-wake periods, is examined in this study of 147 health subjects. Stage shift comportment is compared between those NREM/REM cycles with wake periods greater than 3 minutes and those with less, using the method of transition probabilities. It is shown that these long wake interruptions occur preferentially in light sleep, and systematically disrupt the regular normal descent towards SWS, but do not significantly reduce the number of SWS episodes. There is at the same time, however, a reduction in the average duration of stage 4 periods of SWS which accounts for the observed reduction in the total amount of SWS.

Differential effects of flunitrazepam on human sleep in combination with flumazenil.

The experiments reported here were designed to characterize in detail the spectrum of activity of flunitrazepam in human sleep. The direct and residual effects of flunitrazepam, as well as the antagonism by flumazenil, an antagonist of benzodiazepine receptors, were studied in 28 normal subjects recorded in the sleep laboratory. The five categories of variables--sleep-wake balance, sleep organization, orthodox sleep, phasic events in sleep, and sleep waveforms--were all modified by flunitrazepam. Some of these modifications were observed only on the drug night and were antagonized by flumazenil, whereas others persisted in the placebo postdrug night and were not antagonized by flumazenil. A few variables showed changes intermediate between these two types of reactivity. The results do not fit well with the multiple benzodiazepine receptors theory, but instead support the concept of spare receptors. Along these lines, the study of the reactivity of sleep components to ligands of benzodiazepine receptors can contribute to the better understanding of the neuronal systems involved in their control.

Sleep pharmacology of typical and atypical ligands of benzodiazepine receptors.

The effects of several benzodiazepine and non-benzodiazepine ligands of benzodiazepine receptors have been investigated in sleep of normal young adults. The spectrum of activity of each compound has been characterized using a number of sleep variables in addition to the standard sleep stages. These substances affect all the principal components of sleep, that is the sleep-wake balance, paradoxical sleep, orthodox sleep and the EEG waveforms in the different sleep stages. Some, but not all, modifications induced by flunitrazepam are antagonized by flumazenil and they recover with various time constants after a single administration of the drug. The results of these experiments indicate a heterogeneity in the mechanism of action of benzodiazepine and non-benzodiazepine ligands of benzodiazepine receptors, because they affect differently the various components of sleep. It is not necessary to invoke a heterogeneity of the central benzodiazepine receptors (the BZ1-BZ2 theory) in order to account for these differences, but they can be explained by the concept of spare receptors.

[Sleep in Pick disease]. / Le sommeil dans la maladie de Pick.

19 polygraphic sleep recordings from 12 patients with Pick's Disease, including four histologically proved cases, were compared to those of an age-matched control group. Symptoms had been present for a mean 8 years, the patients being aged 59 to 78 (mean 70.5 years). All sleep stages could be identified. Total sleep time was reduced and the number of awakenings was sharply increased. High proportion of stage 1 contrasted with the reduction in the other sleep stages with disappearance of stage 4 in advanced cases. REM Sleep was identified in all recordings, although reduced as a function of the length of the illness; its production as a function of total sleep time was not different from that of the control. REM Sleep appeared often fragmented and with a remarkably short latency, reminiscent of that observed in severely depressed patients.

Effect of the benzodiazepine antagonist Ro 15-1788 on flunitrazepam-induced sleep changes.

1 The modifications of human sleep induced by benzodiazepines, and particularly by flunitrazepam, are complex. Stage 4 and paradoxical sleep are both decreased; however, these two effects have a different evolution during and after single or short-term drug administration. 2 The benzodiazepine antagonist Ro 15-1788 also tends to depress stage 4, but with immediate recovery in the post-drug night, and does not modify paradoxical sleep. 3 In combined administration, this drug totally reverses the hypnogenic effect of flunitrazepam, as well as its effect on paradoxical sleep but not the decrease of slow wave sleep. 4 Some of the benzodiazepine-induced alterations of sleep may be related to receptors different from central benzodiazepine receptors, or to mechanisms not directly connected to this type of receptors.

[The structure of the occurrence of rapid eye movements in paradoxical sleep is similar in homozygotic twins]. / La structure d'occurrence des mouvements oculaires rapides du sommeil paradoxal est similaire chez les jumeaux homozygotes.

Whereas there are considerable interindividual variations in the temporal patterns of rapid eye movement during paradoxical sleep in young adult Males, these patterns are similar in monozygotous twins.

Paradoxical sleep rebound without previous debt: the effect of minute doses of clonidine in man.

This report describes an experimental condition in which clonidine administration does not modify paradoxical sleep (PS) directly, but is followed by a secondary rebound. After oral consumption of minute doses of clonidine (CLN), 12 subjects showed no direct effect of CLN, but showed a significant increase of PS production in the following placebo night. Four other subjects experienced a decrease of PS under CLN and no rebound the next night. In addition, these four subjects had mechanisms of slow wave sleep production significantly weaker than the first 12 subjects.