Immunoassays were investigated for the determination of melatonin in biological samples in the presence of a naphthalenic structural analogue S 20098, which is currently under development as a melatonin agonist. The lack of specificity of commercially available antibodies in the presence of closely related molecules led us to develop an LC-RIA procedure with a quantification limit set at 15 pg ml−1. Because this technique was not sensitive enough and difficult to use on a routine basis, a more sensitive GC-MS technique was developed. This method involved automated solid-phase extraction (plasma) or liquid–liquid extraction (saliva), derivatization of the indolic moiety and GC separation with an automated switching device before MS detection. The method was validated over the range 1–100 pg ml−1, with a quantification limit set at 1 pg ml−1 in human plasma and saliva. Intra-assay and inter-assay precision and accuracy were within 16% for all concentrations investigated and each biological matrix. The stability of melatonin in plasma and saliva under various storage conditions was also determined. The specificity of the assay for the analysis of melatonin in the presence of S 20098 and its metabolises was demonstrated. The method was subsequently applied for the determination of endogenous melatonin concentrations in plasma and saliva samples from clinical studies performed with S 20098 to provide pharmacodynamic data.

Cyamemazine is an anxiolytic antipsychotic, which reduces ethanol withdrawal symptoms. Here, we investigated if cyamemazine can be also effective as substitute drug to facilitate benzodiazepine withdrawal. A total of 168 patients treated with benzodiazepines for at least 3 months and with a < 18 score in the Hamilton Anxiety Rating Scale (HARS) were included in the study. Previous benzodiazepine treatment was withdrawn, and patients were randomized to a 4-week treatment with cyamemazine (25–50 mg q.d.) or bromazepam (3–6 mg q.d.), followed by 2 weeks of placebo. The primary efficacy variable was the maximal anxiety rebound as measured with the HARS during the 42 days of treatment. No statistically significant differences between treatment groups were found for the extent or incidence of rebound anxiety. Considering all dropout patients as withdrawal failures, after 6 months of follow-up, 56/84 patients in the cyamemazine group (66.7%) and 55/84 patients in the bromazepam group (65.5%) were successfully withdrawn. 28 patients in the cyamemazine group and 18 in the bromazepam group had an adverse event, including anxiety, insomnia, dry mouth and somnolence. No extra-pyramidal symptoms were reported. In conclusion, cyamemazine was comparable to bromazepam in ensuring successful benzodiazepine withdrawal and in controlling the acute benzodiazepine withdrawal syndrome. Cyamemazine may be useful to facilitate benzodiazepine withdrawal in those patients where bromazepam substitution is not appropriate.

This paper presents the “caddie paradigm” a new interface for teleoperation of mobile robots. We present a prototype based on the use of a treadmill as a free-locomotion interface. The “caddie paradigm” allows for controlling a real robot by “pushing” its virtual representation displayed on a large projection screen. This system lets the operator walk right behind the robot situated in a remote location. A discussion on the advantages of the interface is presented. The implemented prototype shows the feasibility of using this paradigm of interaction to control robots remotely.

The effects of milnacipran (50 mg bid) on sleep patterns of eight depressed inpatients, treated for 4 weeks, were studied during the initial (days 1-3) and terminal (days 26-28) treatment periods and compared with those obtained from three sleep recordings performed just prior to the initiation of the treatment. The clinical evolution of patients was evaluated weekly using the MADRS depression scale and the Spiegel and Norris sleep scales. Clinical improvement, shown by a mean reduction of 58% in MADRS scale scores, was accompanied by an improvement of disturbed sleep parameters. From the beginning of treatment, there was an increase in the total duration of sleep and stage II sleep, a decrease in sleep latency and an increase in sleep efficiency. Total REM sleep was not modified although, since there was an increase in total sleep time, the percent REM sleep was significantly reduced. REM latency was increased early in the study, an effect classically associated with antidepressant treatment. This study suggests that milnacipran improves disturbed sleep parameters in depressed patients without any additional disturbance at the onset of treatment. Copyright (C) 2004 John Wiley Sons, Ltd.

This paper presents an interface paradigm based on the con- cept of mediators: simple virtual entities that serve as interface to more complex environments. We present a prototype consisting of a Haptic Workstation with force-feedback on both arms and hands and an HMD. The system is used to manipulate virtual objects (mediators) that play the role of a virtual interface for driving a car situated in a remote and more complex virtual environment.

In most vehicle simulators, complete physical mockups equipped with steering wheel, gearshift and pedals are required. These devices are essential in trying to simulate real conditions, but as a drawback the system becomes expensive, huge (non mobile), and limited to reflect changes on the vehicle type, dimensions, or interior design. We have implemented different configurations for an immersive vehicle simulator, ranging from the use of a real mockup equipped with force-feedback steering wheel, gearshift and pedals, to fully virtual control metaphors, which are based only on trackers and datagloves. We propose such fully virtual control metaphors as an alternative to minimize the use of physical devices in simulators.

Serum neuron-specific enolase (NSE) levels were studied by an enzymo-immunoassay method in 2 groups of patients: a group of epileptic patients, and a group of patients with refractory major depression after electroconvulsive therapy (ECT). In patients without organic neurological disease (n = 274) the mean serum NSE level (± S.D.) was 8.4 ± 3.4 μg/l. No correlation with sex or age was observed. No significant difference was observed between epileptic patients without seizure or major electroencephalogram (EEG) abnormality, and a reference group. Significant increases were observed in 32 samples collected from patients with interictal EEG without spikes and waves before the 7th day after a seizure, in whom mean NSE was 21.5 ± 9.4 μg/l, and in 26 samples from 4 patients without seizures but with spikes and waves in the interictal EEG, whose mean NSE was 20.6 ± 11.5 μg/l. The increases of serum NSE levels in epileptic patients seem therefore to be linked to seizures and/or to EEG abnormalities. The consequences of these observations for the survey of epileptic patients, and for the diagnosis of cerebral tumors (mainly neuroblastoma) or for monitoring treatment after surgical resection, are discussed. In only 1 patient out of 6, an increase in serum NSE levels was observed with a peak about 12 h after ECT. No significant correlation with the ECT features (length of seizures, one- or two-sided electrodes) was observed.

In order to determine whether a decrease in the amplitude of heart rate circadian rhythm (HRCR) could represent a chronobiological marker of depression and to answer the question of the possible role of this alteration in the reduction of rapid eye movement sleep latency (REM latency) observed in depression, 22 major depressed patients (DSM III R, Montgomery Asberg Depression Rating Scale) and 11 healthy volunteers entered this study, which included the simultaneous recordings of sleep and heart rate (HR) during two consecutive 24-h periods. After a smoothing procedure, the HR data, obtained from a portable device providing mean HR/min, were computed with the single cosinor method for the classical circadian parameters. We also determined the cosinor fitting index (CFI = percentage to fit). When studied as a single group and compared to the control group, the depressed patients, who had difficulties in sleep initiation and whose REM latencies were within normal limits, were characterized by a dampening of the amplitude HRCR and of the day-night HR difference. This was linked to a lesser increase of HR during the day and a reduced decrease at night. No significant phase modification of HRCR was observed in this group of depressives. In a second step, the depressives were divided into a depressed arrhythmic group (DAG, CFI < 50%, 11 patients) and a depressed rhythmic group (DRG, CFI > 50%, 11 patients) who did not differ on MADRS scores. Even though the amplitude of HRCR was reduced in the DAG only, with HR higher at night and lower during the daytime than for controls, both DAG and DRG significantly differed from controls on those items related to sleep induction and maintenance. In the DAG only was there a tendency toward a reduction of total sleep time and REM sleep time while REM latency was normal. This finding suggests that sleep problems are not responsible for the differences in HRCR parameters between the two depressed groups. These differences in HR and sleep parameters between two groups of similarly depressed patients also suggest that a short REM latency does not systematically imply a disruption of all circadian clocks.

Heart rate (HR) was continuously monitored during successive 24-hr periods in 19 healthy subjects and 26 major depressed patients (DSM III-R). Recordings were performed after a 2-week wash-out period and the morningness or eveningness typology of each subject was determined. The chronobiological parameters and rhythm percentage (RP) were calculated by the single cosinor method from the smoothed HR curves of each subject. In normal subjects, HR follows a circadian rhythm (RP greater than 65%) with the lowest values at night. Morning type subjects have an earlier peak time (13:30) than evening type subjects (17:30). Major depressive patients were split into two groups; in the first one HR circadian rhythm was still present (RP greater than 63%) with a decrease in amplitude (24%) while in the second group, no circadian rhythm of HR could be detected (RP less than 25%, decrease in amplitude greater than 70%). In the group of patients with a persisting HR circadian rhythm, no veritable phase advance was observed. Our results suggest that circadian HR rhythm, which can be easily studied with non-invasive methods, might represent a chronobiological marker of some depressions. Given the lag that exists between the rhythms of morning type and evening type subjects, our study also stresses the importance of taking into account this behavioural trait in chronobiological studies.

Preliminary results are presented from an ongoing study in hospitalised depressed patients. Changes in sleep parameters were assessed on days 1 to 3 and 12 to 14 of a 4-week study in which patients received trimipramine 150 mg on day 1 and 100 mg thereafter. On days 1 to 3 and 12 to 14, 7 depressed patients had a significantly increased total sleep time and sleep efficiency index and a significantly decreased total wake time and number of intrasleep wake episodes per hour of sleep. Trimipramine treatment had no significant effect on REM sleep, percentage of REM sleep, REM duration and REM sleep stability index. However, a significant increase in REM latency was noted on days 1 to 3 but not on days 12 to 14. These polygraphic data suggest that trimipramine effects a very rapid and maintained sleep improvement in these depressed patients without significant alterations to the parameters of REM sleep.

8 patients with narcolepsy were treated with oral tyrosine. Within six months all were free from daytime sleep attacks and cataplexy.

Twelve patients with clinical, polysomnographic and oxymetric features of Sleep Apnoea Syndrome (S.A.S.) were recorded, after a 2-week wash-out period, during 2 nights without treatment and 2 nights after receiving 50 mg naltrexone at bed-time. Clinical symptoms improved immediately in four patients, within one month in three patients and after 3 months of treatment in the remaining five ones. Sleep Apnoea index as well as the number, duration and intensity of hypoxic events were dramatically improved by this treatment that has now been prescribed to 25 patients, for more than 2 years in 14 of them.