Search

An understanding of the consequences of sustained operations involving prolonged sleep deprivation is important to the military. Losses in cognitive performance of the order of 30% after one night and 60% after two nights of sleep loss have been shown to occur in several studies. Napping strategies have been proposed as one coping strategy for these performance decrements. An alternate solution is the use of stimulants. Modafinil may offer a safer alternative to more commonly used psychostimulants. It has been shown to counteract the effects of sleep deprivation with fewer side effects than amphetamine. Recent studies on the effects of modafinil during sleep deprivation are reviewed and compared with those of other stimulants such as amphetamine and caffeine, and to prophylactic naps. Recommendations are proposed for the use of modafinil in sustained military missions. For missions of about 24 h, modafinil is preferable to naps. For longer missions, naps should be considered, along with the concomitant use of modafinil to help maintain performance levels. The authors discuss apparent 'overconfidence' and hyperthermia-inducing effects of modafinil, and advise that these effects be taken into account if modafinil is to be used in any mission conducted in the field or in hot environments. It is also recommended that individual sensitivity to the drug should be tested before any mission of a sustained nature, especially if it involves small operational groups or combat aircrew, where the impact of such effects on individuals would be more critical.

Patients with human African trypanosomiasis, sleeping sickness, show a major disturbance in the circadian distribution of sleeping and waking, with sleep and wake episodes equally distributed throughout the nycthemeron. In order to develop an animal model, polysomnography was taken continuously in 8 male OFA rats in a 12:12 h light-dark cycle, during 1 baseline week and for 2 weeks after infection with Trypanosoma brucei brucei. Considerable sleep fragmentation was observed in the infected rats, with numerous sleep-wake stage changes and an increased number of wakefulness and slow-wave sleep phases. Although the infection produced a progressive disruption of the sleep-wake cycle, the extensive disturbances of the circadian rhythm of the sleep-wake cycle observed in humans with sleeping sickness was not attained in the rats.

Previous studies have revealed that modafinil elevates resting core temperature during periods of sustained wakefulness. The purpose of this study was to examine the effects of modafinil on core temperature during rest and exercise throughout 40 h of sustained wakefulness in a warm environment.Ten males performed a drug session (three 100 mg doses per day) and a placebo session that involved a control day, 40 h of sustained wakefulness, and a recovery sleep. For 38 h of the sustained wakefulness, subjects were exposed to 30 degrees C with 50% relative humidity. During the afternoon of both days of wakefulness and during the early morning of the second day, subjects performed 2 h of exercise at 60% VO2max while exposed to the warm environment.The data revealed that rectal temperature (Tre) was elevated at rest 0.15-0.2 degrees C following modafinil ingestion throughout the period of sustained wakefulness. This increase in body temperature at rest was due to an increase in heat production during the first day of wakefulness followed by a lower evaporative heat loss during the second day. During exercise, an inconsistent effect of the drug on Tre was observed throughout the 38-h period. On the first afternoon, the impact of modafinil on Tre was no longer evident after 20 min of exercise. In contrast, during the early morning and afternoon of the second day, the effects of the drug on Tre at rest remained during exercise. For seven subjects who had Tre data for 80 min during all exercise periods, Tre during the placebo session was 38.9, 38.4, and 38.7 degrees C after 80 min of exercise for periods one, two and three, respectively, whereas the corresponding values during the modafinil session were 38.8, 38.7, and 38.9 degrees C.With a greater cumulative dose of the drug, Tre remained elevated throughout the exercise period to an extent similar to the increase observed under resting conditions when compared with the placebo condition.

Cardiotoxicity has become a major concern during treatment with antimalarial drugs. Lengthening of the QTc and severe cardiac arrhythmia have been observed, particularly after treatment with halofantrine for chloroquine-resistant Plasmodium falciparum malaria. The purpose of this prospective study was to evaluate whether antimalarial agents alter dispersion of the QTc and ventricular repolarization dynamicity. Sixty patients with uncomplicated falciparum malaria were randomly allocated in four groups of 15 patients and treated with quinine, mefloquine, artemether, or halofantrine at recommended doses. Patients in treatment groups were compared with a group including 15 healthy controls with no history of malaria and/or febrile illness within the last month. QTc dispersion was measured on surface electrocardiograms. Repolarization dynamicity was analyzed from Holter recordings, which allow automatic beat-to-beat measurement of QT and RR intervals. Plasma drug concentration was determined by reversed-phase high-performance liquid chromatography. No change in QTc dispersion was observed after treatment with quinine, mefloquine, or artemether. Treatment with halofantrine was followed by a significant increase in QTc dispersion at 9 hours (P < 0.0001) and 24 hours (P < 0.01). Assessment of QT heart rate variability by QT/RR nychtohemeral regression slope demonstrated no significant difference between the artemether (mean +/- SEM = 0.170 +/- 0.048), mefloquine (0.145 +/- 0.044), and the control groups (0.172 +/- 0.039). A significant decrease in the Q-eT/RR slope was observed in the quinine group compared with the control and artemether groups (0.135 +/- 0.057; P < 0.04). With halofantrine, a significant increase in the QT/RR regression slope (0.289 +/- 0.118) was observed (P < 0.0002). QTc interval, QT dispersion, and QT regression slope were significantly correlated with halofantrine and quinine plasma concentration. Mefloquine and artemether did not alter ventricular repolarization. Quinine induced a significant decrease in QT/RR slope of the same order of magnitude as those previously observed with quinidine. Both QTc dispersion and QT/RR slope were significantly modified by halofantrine. These repolarization changes were related to a class-III antiarrhythmic drug effect and may explain the occurrence of ventricular arrhythmia and/or sudden deaths reported after halofantrine intake.

Modafinil is a wake-promoting agent that affects hypothalamic structures involved in the homeostatic and circadian regulation of vigilance. Administered during sleep deprivation, it reduces the need for prolonged recovery sleep and decreases the rebound in EEG slow-wave activity. These diachronic effects suggest an action of modafinil on a homeostatic sleep regulatory process.The aim of this study was to determine whether modafinil, in comparison to the d-amphetamine reference psychostimulant and to placebo, interferes with the vigilance regulatory processes reflected in the EEG during waking.Thirty-three healthy subjects were investigated during 60 h of sustained wakefulness in a double-blind placebo-controlled parallel-design study. A 4-min maintenance-of-wakefulness test administered hourly allowed the concomitant assessment of alertness and waking EEG activity. The effects of equipotent psychostimulant dosages (modafinil 300 mg and d-amphetamine 20 mg) were evaluated at the beginning of the first sleep deprivation night, at the end of the second sleep deprivation night and in the afternoon preceding the first recovery night.One hour following ingestion, both psychostimulants increased alertness during 10-12 h, independently of the time of administration. At the level of the waking EEG, d-amphetamine attenuated the natural circadian rhythm of the different frequency bands and suppressed the sleep deprivation-related increase in low frequency (0.5-7 Hz) powers. In contrast, modafinil, which exhibited a transient amphetamine-like effect, had slight effect on circadian rhythms. Its selective action was characterized by maintenance of the alpha(1) (8.5-11.5 Hz) EEG power, which under placebo exhibited a homeostatic decrease paralleling that of alertness with a circadian trough at night.These findings demonstrate that the alertness-promoting effects of modafinil and d-amphetamine involve distinct EEG activities and do not reside on the same vigilance regulatory processes. While d-amphetamine inhibits the expression of a sleep-related process, probably through a direct cortical activation masking EEG circadian rhythms, modafinil, through a synchronic effect, preferentially disrupts the homeostatic down-regulation of a waking drive.

At the meningoencephalitis stage, human African trypanosomiasis (HAT), sleeping sickness, causes dysregulation of the circadian rhythm of the sleep/wake cycle, rather than hypersomnia. In bedridden patients, total sleep time does not exceed 9 hours. The change in the 24-hour distribution of sleep and wakefulness is proportional to severity of clinical symptoms and laboratory abnormalities. The internal structure of sleep is also altered. All patients present sleep onset rapid eye movement periods (SOREMP), i.e., several sleep episodes beginning with rapid eye movement (REM) sleep. In mild cases, treatment with melarsoprol reverses circadian dysregulation, and SOREMP either decrease in number or disappear. Other circadian disturbances may be observed in HAT. These may include circadian dysrhythmia of hormonal secretions, but the relationship between hormonal pulses and sleep/wake states is preserved. The circadian rhythm of secretion of prolactin, renin, growth hormone and cortisol disappears in severe cases, but persists in mild ones. The amplitude and mean 24-hour value of plasma melatonin are normal with nocturnal peaks and no diurnal secretion. However, peak melatonin secretion occurs 2 hours earlier than in healthy African controls. In conclusion, HAT-induced dysregulation of circadian rhythm is proportional to disease severity. Presence of SOREMP and precocity of peak melatonin secretion support disturbance of the serotoninergic network rather than direct action on the biological clock.

Ultrasound guidance is useful for venipuncture and placement of central venous access catheters; however, anatomical variants may complicate catheter insertion. A 52-yr-old female patient was admitted to the intensive care unit with acute respiratory distress due to bilateral pneumonia. Her respiratory status worsened rapidly and she required mechanical ventilation. For cardiovascular monitoring, an ultrasound-guided cannulation of her left subclavian vein was performed uneventfully using an Acuson CV70 cardiovascular ultrasound system (Siemens , Erlangen, Germany), and a central venous catheter (CVC) was inserted. A chest x-ray revealed a left-sided paramediastinal course of the CVC (Figure, Panel A), at which point, we considered the potential for arterial placement, accidental venous placement in normal structures (superior intercostal vein or internal thoracic vein), or a malformed left superior vena cava. Subsequently, the diagnosis of persistent left superior vena cava (PLSVC) was confirmed by thoracic computed tomography with contrast injection. Reconstructed computer tomography scan imaging (Figure, Panel B) showed the left subclavian vein give rise to the PLSVC, which drains into in the left atrium, and the brachiocephalic vein that forms the right superior vena cava. The CVC was then removed, and another was inserted uneventfully into the right internal jugular vein using ultrasound guidance. The patient’s respiratory status improved progressively, and her trachea was extubated 21 days later. Persistent left superior vena cava is the most common major anomaly of the systemic venous system. This anatomic variant, which is asymptomatic, results from persistence of an embryological vessel that normally involutes into the coronary sinus. Persistent left superior vena cava is not an absolute contraindication for subclavian vein cannulation if adequate drainage into the right atrium exists. Nevertheless, difficulties can arise during CVC insertion, transjugular intrahepatic portosystemic shunt insertion, and pulmonary artery catheter and pacemaker insertion. The etiology of the CVC false tracking in patients with PLSVC is usually established by chest x-ray and can be confirmed by echocardiography. This case illustrates that thoracic computed tomography is an important diagnostic imaging modality to delineate variant central venous anatomy.

In response to mission imperatives, transport aircrews must often sleep at inappropriate circadian times resulting in inadequate sleep. This study was undertaken to determine whether either melatonin or zopiclone could facilitate early circadian sleep, and to assess whether either of these medications would result in a psychomotor performance decrement which would preclude their use in aircrew.Thirteen subjects from DCIEM completed a double-blind cross-over protocol. All subjects were assessed for psychomotor performance during 3 drug conditions (placebo, 10 mg melatonin, and 7.5 mg zopiclone), which were separated by one week. Each of these conditions involved 2 nights of sleep, back-to-back, with the first night being a normal circadian control sleep (23:00 h bedtime, arising at 06:45 h), and the second night being an early circadian drug sleep (drugs at 16:45 h, 17:00 h bedtime, arising at 23:45 h). All subjects were tested for psychomotor performance, on both nights of each of the 3 drug conditions, pre- and post-sleep. Further, during the early circadian drug night, all subjects were tested every hour after arising at 23:45 h (24:00 h until 07:00 h. At the beginning of each psychomotor test session, subjects were asked for their subjective levels of sleepiness and fatigue.Relative to placebo (339.5 min) the subjects slept more on melatonin (370.2 min, p0.01), and zopiclone (373.3 min, p0.01). Performance in serial reaction time (SRT) task (p0.001), logical reasoning task (LRT) (p0.001), serial subtraction task (SST) (p0.02), and Multitask (MT) (p0.03) were impaired for all 3 drug conditions immediately on awakening, compared with pre-sleep performance, as a result of a sleep-inertia effect. With respect to the subjective data, sleep inertia effects were evident for sleepiness (p0.001), mental fatigue (p0.002), and physical fatigue (p0.05). For SRT, LRT, and SST, performance recovered to pre-sleep levels within 1.25 h of awakening, and for MT recovery occurred 2.25 h after awakening. There were no differences in performance or subjective measures between placebo, melatonin and zopiclone.Both zopiclone and melatonin improved sleep relative to placebo. After sleep inertia, performance recovered to pre-sleep levels for all tasks and was sustained at that level throughout the balance of the testing period. There was no impact of melatonin or zopiclone on performance measures compared with placebo.

Femtosecond time-resolved experiments in neat water under terawatt ultraviolet laser pump power density are reported. For the first time, the formation of a decimolar concentration of hydrated electron is demonstrated. The contribution of non-geminate recombination is discussed.

Background and objectives Chronic pain often has negative social and professional repercussions. The care of patients who suffer from chronic pain causing problems at work is long overdue, complex, and fragmented. The objective of our network is to propose customised care covering medical, psychological, social and occupational aspects for patients with chronic pain. Our first priority was to set up multidisciplinary case review meetings. Programme The network is managed by the Pain Department of the palliative care unit of Nice university hospital. The multidisciplinary meetings follow the model given in the French national Cancer Plan (2003–2007) and have been validated through professional practice appraisal. From October 2007 to September 2009, the department held 20 multidisciplinary meetings attended by 35 health professionals. They included 21 workplace doctors (non-hospital and hospital sectors), a health officer from French national health insurance, a doctor from the county9s office for the disabled, two doctors from the Regional Assembly, a rheumatologist/algologist, a neurosurgeon, a psychiatrist, three psychologists, two nurses and two social workers. The files of 112 patients, including 59 cases of lumbo-radicular pain and 33 cases of cervico-brachial pain, were reviewed. Fifty-two patients had been away from work for an average of 20.2 months (2–85) because of workplace accidents: 17 cases of permanent partial incapacity, 20 cases of sick leave, seven cases of leave for an occupational disease, seven cases of being laid off work because of incapacity, and 25 ‘active solidarity income’ beneficiaries. A review of each case led to a customised programme of medical-psychological-social-occupational care being handed to each patient, with a copy sent to the general practitioner (GP). The proposals included 20 neurosurgical assessments, 48 offers of psychological or psychiatric follow-up, 22 social assessments, 52 requests for visits with the workplace doctor for job redesign or adaptation of the workplace, and 14 applications lodged with the county office for the disabled. Results in terms of clinical impact Our programme has improved patient access to professionals with expertise in chronic pain management. Waiting times have decreased to under 15 days. The multidisciplinary approach has led to faster solutions to social-occupational problems; 34 patients still hold their job after 6 months. Discussion and conclusion Including the patient9s GP into the programme and the continued presence of the national health insurance officer are two programme priorities. We are currently looking into a health economics assessment of the programme. In conclusion, multidisciplinary review meetings provide a global approach (medical, psychological, social and occupational) to the care of patients with chronic pain who have difficulties at work and offer a concerted, proactive treatment proposal for each patient. Objectif La douleur chronique a frequemment des repercussions socio-professionnelles. La prise en charge des patients douloureux chroniques en difficulte avec le monde du travail est tardive, complexe et cloisonnee. L9objectif du reseau est de definir de maniere pluridisciplinaire une proposition de prise en charge individualisee medico-psycho-socio- professionnelle. Pour y repondre, la priorite a ete la creation de Reunions de Concertation Pluridisciplinaires (RCP). Programme Ces reunions ont ete crees sur le modele des RCP de cancerologie, defini par la mesure 31 du Plan Cancer 2003-2007 et ont fait l9objet d9une validation de l9 evaluation des pratiques professionnelles. D9octobre 2007 a Septembre 2009, le Departement d9Evaluation et Traitement de la Douleur - Medecine Palliative du CHU de Nice a coordonne 20 RCP reunissant 35 professionnels de sante soit 21 medecins du travail (ville-hopital), un medecin conseil, un medecin de la Maison Depatemental des Personne Handicapees (MDPH), deux medecins du Conseil General, un rhumato-algologue, un neuro-chirurgien, un psychiatre, trois psychologues, deux infirmiers, deux assistantes sociales. Les dossiers de 112 patients ont ete discutes dont 59 lombo-radiculalgies, 33 cervico-brachialgies. Cinquante-deux patients sont en accident de travail depuis en moyenne 20.2 mois (2-85) avec 17 consolidations, 20 en arret maladie, 7 en maladie professionnelle, 7 sujets licencies pour inaptitude au poste, 25 sujets allocataires du revenu de solidarite active. Apres discussion un programme personnalise de soins medico-psycho-socio professionnel a ete remis au patient, le double adresse au medecin traitant. Les propositions ont concerne: 20 evaluations neuro-chirurgicales, 48 evaluations avec suivi psychologique ou psychiatrique, 22 evaluations sociales, 52 demandes de visite de pre reprise aupres du medecin du travail pour reclassement professionnel ou amenagement de poste, 14 depots de dossier MDPH. Resultats en terme d9impact clinique Ce programme a permis d9ameliorer l9accessibilite a une expertise “douleur chronique” avec des delais de prise en charge raccourcis (inferieurs a 15 jours). Il a egalement permis l9elaboration pluridisciplinaire d9une solution socio-professionnelle plus rapide: a 6 mois le maintien dans l9emploi concernait 34 sujets. Discussion-perspectives Sur le plan organisationnel, l9integration du medecin traitant au dispositif et la perennisation de la presence du medecin conseil constituent deux axes prioritaires. Une reflexion est egalement engagee afin de mettre en place une eventuelle evaluation medico-economique d9un tel programme. Conclusion La mise en place de ces RCP permet, en decloisonnant la prise en charge des patients douloureux chroniques en difficulte avec le monde du travail, une approche globale bio-psycho-sociale et l9elaboration d9une proposition therapeutique concertee et anticipative.

Keita, M., Vincendeau, P., Buguet, A., Cespuglio, R., Vallat, J.-M., Dumas, M., and Bouteille, B. 2000. Inducible nitric oxide synthase and nitrotyrosine in the central nervous system of mice chronically infected with Trypanosoma brucei brucei. Experimental Parasitology 95, 19–27. Human African trypanosomiasis, or sleeping sickness, evolves toward a meningoencephalitic stage, with a breakage in the blood–brain barrier, perivascular infiltrates, and astrocytosis. The involvement of nitric oxide (NO) has been evoked in the pathogenic development of the illness, since NO was found to be increased in the brain of animals infected with Trypanosoma brucei (T. b.) brucei . An excessive NO production can lead to alterations of neuronal signaling and to cell damage through the cytotoxicity of NO and its derivatives, especially peroxynitrites. In African trypanosomiasis, the sites of NO production and its role in the pathogenicity of lesions in the central nervous system (CNS) are unknown. In a chronic model of African trypanosomiasis (mice infected with T. b. brucei surviving with episodic suramin administration), NADPH–diaphorase staining of brain slides revealed that NO synthase (NOS) activity is located not only in endothelial cells, choroid plexus ependymal cells, and neurons as in control mice but also in mononuclear inflammatory cells located in perivascular and parenchyma infiltrates. An immunohistochemical study showed that the mononuclear inflammatory cells expressed an inducible NOS activity. Furthermore, the presence of nitrotyrosine in inflammatory lesions demonstrated an increased NO production and the intermediate formation of peroxynitrites. The detection of extensive formation of nitrotyrosine in the CNS parenchyma was observed in mice having shown neurological disorders, suggesting the role of peroxynitrites in the appearance of neurological troubles. In conclusion, this study confirmed the increased NO synthesis in the CNS of mice infected with T. b. brucei and suggests a deleterious role for NO, through the formation of peroxynitrites, in the pathogenesis of African CNS trypanosomiasis.

To determine whether the circadian disruption of the sleep/wake cycle observed in sleeping sickness, human African trypanosomiasis (HAT), can be reversed after trypanosomicide treatment, 10 Congolese patients infected by Trypanosoma brucei gambiense underwent 24-h polysomnographic recordings before treatment with melarsoprol and after each of three weekly treatment sessions. Polysomnography consisted of a continuous recording of the electroencephalogram, electromyogram and electro-oculogram on a Minidix Alvar polygraph. Sleep traces were analysed in 20-sec epochs for wakefulness, REM sleep, and NREM sleep [stages 1, 2, 3, 4; stages 3 and 4 representing slow-wave sleep (SWS)]. As previously described (Buguet et al. 1993), the 24-h distribution of the sleep/wake cycle was disturbed proportionally to the severity of the illness. The overall amounts of each sleep/wake stage did not change after treatment. However, the patterns of occurrence of sleep episodes, REM sleep and SWS phases were determinant in the evaluation of treatment efficacy. The trypanosomicide action of melarsoprol led to a reduction in the number of sleep episodes, except in one patient whose health condition worsened during the third treatment session: sleep onset REM sleep phases (SOREMPs) decreased and the number of SWS episodes during a sleep episode increased. We conclude that in HAT, the reversibility of the sleep/wake cycle alteration and that of sleep structure constitute the basis for an evaluation of the healing process.

Patients with human African trypanosomiasis (HAT, sleeping sickness), due to the inoculation of Trypanosoma brucei gambiense or rhodesiense by the tsetse fly, are "sleepy by day and restless by night." The first 24 h polysomnographic recording (electroencephalogram [EEG], electromyogram [EMG], electrooculogram [EOG]), showing a disappearance of the 24 h rhythmicity of sleep and wakefulness, was performed in 1988. Thereafter, our team recorded 18 patients and 6 control volunteers at bed rest during 24 h sessions. Blood samples were taken hourly from 8 of the patients through a venous catheter and every 10 minutes from the remaining 10 patients. Plasma cortisol, prolactin, growth hormone (GH), melatonin, and plasma renin activity were analyzed. No disruptions of the circadian rhythms of sleep and wakefulness were described in the 6 healthy African subjects, and there also were no disturbances of 24 h hormone profiles. The patients experienced a dysregulation of the circadian rhythmicity of sleep and wakefulness that was proportional to the severity of the disease. Sleep onset rapid eye movement (REM) episodes were more frequent in the most severely sick patients, who also showed major disruptions in the 24 h plasma hormonal profiles, with intermediate profiles being observed at earlier stages of the sickness. However, the relationship between hormonal secretions and the states of vigilance persisted. Contrary to the other hormones, melatonin secretion remained undisturbed. These findings indicate that, at the stage of meningoencephalitis, HAT represents a dysregulation of the sleep-wake cycle and sleep structure, rather than a hypersomnia; this dysregulation is proportional to the degree of severity of the clinical and biological symptoms. It is accompanied by a circadian dysrhythmia of hormonal secretions, although the relationship between hormone pulses and sleep states is preserved. We therefore favor the involvement of the serotonergic raphe nuclei-suprachiasmatic nuclei liaison in the reversible disturbance of the circadian rhythms of the sleep-wake cycle and of hormonal secretions.

PURPOSE. To investigate the effect of blood nitric oxide (NO) as a mediator of the neurovascular syndrome in rats following gamma-irradiation.Using a voltametric method together with a carbon fibre based sensor, NO measurements were carried out in sham-irradiated and irradiated animals either in blood from the abdominal aorta or in blood samples from the heart.In in vitro conditions, properties of the probe were not altered by the ionizing radiation. Significant increases of +17% and +25.6% were observed in the voltametric signal height at 90 min and 24 h respectively after a 15 Gy gamma-ray exposure. These effects were followed on days 3 and 4 by a progressive decrease in the signal height of 7% and 18% respectively. Dose-effect relationships were observed at 90 min and 24 h after exposure to gamma-rays in the range of 3-15 Gy. Finally, the NO dependence on the measured voltametric signal was controlled by using inhibitors of the NO synthase (NOS) and by performing nitrate assays.Specific blood NO voltametric measurements are possible. Functional changes associated with NO after gamma-ray exposure are discussed.

Although it was practically eradicated by the 1960s, sleeping sickness or human African trypanosomiasis (HAT) is now spreading rapidly and affecting more than 10% of the population in certain endemic areas [1]. This disease, described more than a century ago, was thought to be specific of Melanoids [2]. It is anchored by the geographical distribution of the tse-tse fly, which infects humans with a protozoa, Trypanosoma brucei gambiense (Western and Central Africa) or T. b. rhodesiense (Eastern Africa). The hemolymphatic phase (stage I) represents the invasion of the blood and lymphatic tissues and is followed by a meningoencephalitis (stage II), with the presence of trypanosomes in the cerebrospinal fluid (CSF) and perivascular infiltrates of lymphoplasmocytic cells [3].

Anesthetized rats exposed to a high ambient temperature develop heatstroke with brain ischemia. Since nitric oxide (NO) plays an important role during normothermic ischemia, its cortical and cerebellar production were continuously assessed in pentobarbital anesthetized rats exposed to heat by using differential pulsed voltammetry. After 60 min at thermoneutrality, the rats were submitted to an ambient temperature of 40 degrees C until death. After 60 min in the heat, the rats were injected intraperitoneally with saline, MK801 (1 mg.kg(-1)), an antagonist of N-methyl-D-aspartate (NMDA) receptors, or L-arginine p-nitroanilide (L-ANA; 100 mg.kg(-1)), an inhibitor of NO synthase. Just before death, a 70% increase in NO production was observed in both the cerebellum and the cortex of saline-treated rats. The cortical increase in NO was not modified by MK801 while the NO signal was suppressed by L-ANA.

The kinetic profile for free radical photopolymerization of a low viscous acrylate resin was found to exhibit an unusual behaviour under atmospheric conditions: two successive waves of polymerization were observed and characterized by RT-FTIR and confocal Raman microscopy. The first wave is merely attributed to the conventional photoinitiation process with a good depth curing but a surface layer which is strongly inhibited by molecular oxygen. During this inhibition process, hydroperoxides are generated at a relatively high concentration. After full consumption of the photoinitiator, these hydroperoxides are further responsible for the second polymerization wave. Depth profiling experiments and determination of the variation of hydroperoxide concentration with time confirm this assumption.

Patients with human African trypanosomiasis present a major dysruption of the circadian rhythmicity of the sleep-wake cycle, which was also found in rats infected with Trypanosoma brucei brucei (T.b.b.). The alterations in the immune function and nervous system in African trypsanosomiasis led us to investigate the involvement of nitric oxide (NO), a key molecule in immune and neurophysiological mechanisms, in experimental trypanosomiasis. NO was measured in 35 Sprague Dawley rats using differential impulsional voltammetry with a carbon fiber coated with porphyrin-nickel and nafion, ex vivo in the blood and in vivo in the brain. The rats were anaesthetized with sodium chlorate. Infection was performed intraperitoneally (i.p.) with 0.2 ml of a T.b.b. cryostabilate (clone AnTat 1.1E). Blood was collected by an intracardiac puncture with immediate replacement of blood volume (1 ml) in 7 control rats and 8 rats infected since 15 days, before and after i.p. administration of L-ANA (L-arginine-p-nitro-anilide, 100 mg.kg-1, an inhibitor of NO synthase). Brain measures were done in 20 rats (8 controls, and 12 rats infected since 15 or 21 days), in the cortex (H, -0.5 mm; AP, -0.8 mm; L, 1.2 mm) and the lateral ventricle (H,-3.2 mm). In infected rats, blood NO was at 70% of control values (p0.001), and L-ANA suppressed the NO signal in all animals (p0.0001), demonstrating that the signal originated from NO. Cortical NO was higher than in the ventricle in both control (p0.0001) and infected rats (p0.001). NO was more elevated in both structures in 15-day-infected rats than in control rats (p0.0001), the difference being enhanced in 21-day-infected rats (p0.001). L-ANA suppressed the NO signal in 30 to 60 min. These data suggest that NO intervenes in the development of trypanosomiasis in different manners. It is increased in the brain, which remains unexplained, where it may be involved in blood-brain barrier permeation. Conversely, it is decreased in the blood, may be because of macrophage function impairment, which would explain why trypanosomes can multiply in the host.

An exonic BalI polymorphism and an intronic MspI polymorphism of the dopamine D3 gene were genotyped in 101 Caucasians from the Alsace and in 56 people from the Congo. This is the first study of the BalI polymorphism in sub-Saharan Africa and the first population study of the MspI site. BalI allele 1 was rare in the Congo (0.12) whereas it is the most frequent allele in all studies in Europe and Asia. MspI allele 1 was also significantly less frequent in the Congolese (0.24) than in Caucasians (0.52). D3 gene alleles show different frequencies in sub-Saharan Africa and may be useful for population studies.

SUMMARY Polysomnograms were obtained from 37 volunteers, before (baseline) and after (two consecutive recovery nights) a 64-h sleep deprivation, with (d-amphetamine or modafinil) or without (placebo) alerting substances. The drugs were administered at 23.00 hours during the first sleep deprivation night (after 17.5 h of wakefulness), to determine whether decrements in cognitive performance would be prevented; at 05.30 hours during the second night of sleep deprivation (after 47.5 h of wakefulness), to see whether performance would be restored; and at 15.30 hours during the third day of continuous work, to study effects on recovery sleep. The second recovery night served to verify whether drug-induced sleep disturbances on the first recovery night would carry over to a second night of sleep. Recovery sleep for the placebo group was as expected: the debt in slow-wave sleep (SWS) and REM sleep was paid back during the first recovery night, the rebound in SWS occurring mainly during the first half of the night, and that of REM sleep being distributed evenly across REM sleep episodes. Recovery sleep for the amphetamine group was also consistent with previously published work: increased sleep latency and intrasleep wakefulness, decreased total sleep time and sleep efficiency, alterations in stage shifts, Stage 1, Stage 2 and SWS, and decreased REM sleep with a longer REM sleep latency. For this group, REM sleep rebound was observed only during the second recovery night. Results for the modafinil group exhibited decreased time in bed and sleep period time, suggesting a reduced requirement for recovery sleep than for the other two groups. This group showed fewer disturbances during the first recovery night than the amphetamine group. In particular, there was no REM sleep deficit, with longer REM sleep episodes and a shorter REM latency, and the REM sleep rebound was limited to the first REM sleep episode. The difference with the amphetamine group was also marked by less NREM sleep and Stage 2 and more SWS episodes. No REM sleep rebound occurred during the second recovery night, which barely differed from placebo. Hence, modafinil allowed for sleep to occur, displayed sleep patterns close to that of the placebo group, and decreased the need for a long recovery sleep usually taken to compensate for the lost sleep due to total sleep deprivation.

Modafinil is an alerting substance that is considered safer than amphetamine with fewer side effects. Although modafinil has been used successfully to treat narcolepsy, relatively little is known about its ability to ameliorate fatigue and declines in mental performance due to sleep deprivation (SD) in a normal population. Forty-one military subjects received either 300 mg of modafinil, 20 mg of d-amphetamine, or placebo on 3 separate occasions during 64 hours of continuous cognitive work and sleep loss. Three drug treatments were given: at 23.30 hours and 05.30 hours during the first and second SD nights, respectively, and once at 15.30 hours during the third day of continuous work. Subjective estimates of mood, fatigue and sleepiness, as well as objective measures of reaction time, logical reasoning and short-term memory clearly showed better performance with both modafinil and amphetamine relative to placebo. Both modafinil and amphetamine maintained or increased body temperature compared to the natural circadian cycle observed in the placebo group. Also, from subject debriefs at the end of the study, modafinil elicited fewer side-effects than amphetamine, although more than the placebo group. Modafinil appears to be a good alternative to amphetamine for counteracting the debilitating mood and cognitive effects of sleep loss during sustained operations.

This study was designed to examine the impact of exhaustive endurance exercise on a number of immune parameters of physically fit male subjects (VO2max 66.5 +/- 5.3 ml/min/kg) who performed treadmill exercise at 65% of their VO2max for 120 min. Serial blood samples were taken before, during and after exercise and changes in leukocyte and lymphocyte subset concentrations; immunoglobulin production in vitro; and natural killer (NK) cell response were measured. The exercise regimen was found to induce the well-known phenomenon of leukocytosis which consisted primarily of a granulocytosis and lymphocytosis. Among the lymphocyte subsets, peripheral pan T cells (CD3+) as well as helper (CD4+) and suppressor (CD8+) T cells were found to be elevated. A relatively smaller increase in CD4+ than CD8+ cells resulted in depressed CD4/CD8 ratios throughout the exercise period. After exercise, T cells declined progressively and, 2 h post-exercise, were less than 60% of their pre-exercise level. In contrast, the CD4/CD8 ratio demonstrated a progressive increase, thus representing a reversal in the pattern observed during exercise and a trend towards an elevated ratio during recovery. B cells (CD19+) were relatively unaffected by exercise, although IgM production by pokeweed mitogen-stimulated lymphocytes obtained from blood samples after 120 min of exercise was significantly depressed. NK cells were affected dramatically by exercise. Both CD16+ cell numbers and NK cytotoxicity were increased during exercise, followed by a persistent depression in the post-exercise period. The strenuous exercise induced profound effect on NK cells as evidenced by a 40% depression of the NK cell count for as long as 7 days after the cessation of exercise. Our results provide direct kinetic evidence demonstrating that exhaustive exertion alters both lymphocyte distribution pattern and effector function, suggestive of possible exercise-induced immune compromise, particularly in the post-exercise recovery period.

Biological/physiological data sampled over a period of 24 h can be subjected to a mathematical analysis to determine the presence of circadian rhythmicity. Several procedures have been proposed, most being complex. To render such an analysis simpler and easy to use by non-mathematicians, we developed and tested the cosinor technique using a commonly available commercial spreadsheet (Excel). It can be used to analyze equally or unequally time-spaced data over 24 h with missing data, as well as to calculate the significance and the main limit of the resultant circadian rhythm (mesor, amplitude, acrophase and their confidence limits). Examples of its application to hourly samples of plasma cortisol and minute-by-minute rectal temperatures are shown.

We have previously demonstrated that human African trypanosomiasis (sleeping sickness) at the stage of meningoencephalitis results in a major disruption of the circadian rhythmicity of sleep and wakefulness that is proportional to the severity of the disease. This paper examines the corresponding 24-hourly secretion in cortisol and prolactin and compares it with the hourly distribution of sleep composition in infected patients and healthy African subjects. The secretion of cortisol in humans follows a circadian rhythm relatively independent of the sleep-wake cycle, whereas that of prolactin exhibits fluctuations over the 24-hr day that are strongly related to the sleep-wake cycle. After the clinical classification of the patients according to the severity of the disease, hourly blood samples were taken over 24 hr via an indwelling catheter. Plasma cortisol and prolactin were analyzed by radioimmunoassay, and the variations in the hourly concentrations were analyzed for the presence of a potential 24-hr rhythm (circadian). All of the healthy African subjects showed significant circadian rhythms in both cortisol and prolactin secretion, similar to data on humans from temperate regions, and a sleep-related anamnestic afternoon peak of prolactin. Major disruptions in the circadian rhythms of plasma cortisol and prolactin were found in the three patients with the most severe illness, in contrast to the four who were less severely ill and the healthy controls. Thus, it appears that as the disease progresses in severity, major disruptions begin to occur in body circadian rhythms, not only in the sleep-wake cycle as reported elsewhere, but also in cortisol and prolactin secretion, suggesting that sleeping sickness affects the circadian timing system.

To test the somnogenic properties of the automassage of point 7 heart of acupuncture, polygraphic night sleep was studied in six healthy volunteers (age: 27.8 +/- 1.6 years) from 23:00 h to 07:00 h. After one night of adaptation, two PEBA cones (Polyether Block Amides; Isocones) were fixed bilaterally at both points 7 heart (active application, AA) or on the back of hand (placebo application, AP). The alternate application was used 2 weeks later, using a randomized, double-blind, and cross-over protocol. Cyclic alternating patterns (CAP) were also analysed on the electroencephalogram during non-REM sleep. Sleep efficiency increased in AA, due to a decrease in wakefulness, and an increase in total sleep time due to an increase in non-REM sleep. The number of CAP decreased in AA, as did the number of CAP sequences and the ratio of CAP duration to total sleep time (CAP rate) and to the duration of slow-wave sleep. In conclusion, the application of Isocones at point 7 heart during the night induced a decrease in wakefulness and an increase in non-REM sleep during night sleep in healthy subjects.

The 24-h hormone profiles have been well documented in caucasians living in a temperate climate, but they have never been examined in melanoid subjects under equatorial conditions, with a 12-h light-dark cycle in a hot climate. To establish normal data for this population, blood samples were taken at 10-min intervals over 24 h in five healthy young melanoids living in Abidjan (Ivory Coast). Cortisol and thyroid stimulating hormone (TSH) concentrations and plasma renin activity (PRA) were determined by radio-immunoassay and sleep was registered using polysomnography. Data were compared with results obtained in Strasbourg (France) from six healthy aged-matched caucasians. The 24-h profile of cortisol concentration was similar in both groups, with a 2-h phase advance in the melanoids. Nocturnal fluctuations of PRA, strongly linked to the rapid eye movement-non rapid eye movement (REM-NREM) sleep cycles, occurred in both groups, with higher levels in the caucasians in the last 2 h of sleep along with greater amounts of NREM sleep. After an evening increase in TSH, the sleep onset-related decrease seen in the caucasians was not observed in the melanoids. In both groups, increasing concentrations of TSH and cortisol occurred with awakening, decreasing concentrations being observed during slow-wave sleep. As in the caucasians studied in the temperate climates, the melanoid subjects living at the equator showed the same temporal organization of hormone rhythms within the 24-h period and the same relationships between the pulses and specific sleep stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraocular pressure was measured hourly during 24 hours in 12 young (20.6 +/- 0.3 years, mean +/- SEM) and 12 older (59.5 +/- 1.6 years) healthy white adults to determine whether intraocular pressure followed a circadian rhythm and whether its nocturnal variations were related to the stages of sleep in the subjects. An electronic tonometer (Tono-Pen), working on the applanation principle, which was shown to give accurate intraocular pressure measurements in any posture, was used to measure intraocular pressure. Nocturnal polysomnography was measured. Wakefulness, light sleep (stages 1 and 2), slow-wave sleep (stages 3 and 4), and rapid eye movement sleep were scored. Intraocular pressure followed a circadian rhythm with a nocturnal peak value (acrophase). The variations in intraocular pressure were related to the stage of sleep, being lowest during rapid eye movement sleep, and highest during slow-wave sleep.

During both the cool and hot periods of the dry season of the Sahelian climate, sleep patterns of four African sportsmen from Niger (23 +/- 0.8 years old) were studied after square-wave cycle ergometer exercise. The sleep patterns were studied in the sedentary (Baseline) condition and under two exercise conditions, with and without rehydration. All conditions were randomly assigned. The exercise programme consisted of 3 sequences of cycling, beginning with 10 min at 30% of maximal aerobic power (MAP), followed by an exhaustive supramaximal effort (130% of MAP), and ending with a 10 min recovery at 30% of MAP. Polysomnography was recorded for 2 consecutive nights in each condition. One adaptation night, to familiarize the subjects to the polysomnography protocol, preceded the first session. Baseline slow-wave sleep (SWS) and REM sleep were high. In the hot season, there was an overall increase in SWS (p0.02), due primarily to an increase in Stage 4 (p0.01). Stage 2 sleep decreased (p0.01). This effect was also observed after exercise with rehydration, but was absent in the non-hydration condition. This distinction between the rehydrated and non-rehydrated condition is thought to be due to the greater stress which may accompany an exercise-induced relative dehydration. REM sleep decreased after exercise in the cool season (p0.001), but equalled baseline levels during the hot season. The results suggest a combined action of hyperthermia, water balance and stress, and are further supportive of an underlying hypothalamic control of human sleep.

Polysomnography was performed in two military personnel who contracted human African trypanosomiasis (HAT) in Rwanda. They were evacuated to France and gramined during the fourth, sixth and eleventh months of evolution. Patient A presented a meningoencephalitis with Trypanosoma brucei rhodesiense (T. b. r.) in the cerebrospinal fluid. Between the second and third treatments with melarsoprol, the patient presented an acute encephalitic attack with pyramidal and cerebellar symptoms, which were improved by corticotherapy and disappeared progressively in 6 months. Patient B presented a major inflammatory syndrome with T. b. r. in the blood and the medulla. Cerebrospinal fluid and serology remained normal. The patient received only one session of melarsoprol treatment. Polysomnography recordings were continuously taken on an ambulatory Oxford Medilog system during 48 hours. The different stages of vigilance were scored according to the classical Rechtschaffen and Kales criteria. During the fourth month, both subjects presented several long diurnal naps, with the presence of rapid-eye-movement sleep at the end of the sleep episodes. These abnormalities disappeared progressively during the following recordings. Electroencephalographic abnormalities were observed in patient A, particularly during the eleventh month. They consisted in transitory arousal phases concomitant with myoclonic jerks and with the persistence of slow waves during slow-wave sleep. The various anomalies noted in the two patients allow us to recommend the supervision of the evolution of HAT by polysomnographic recording in a sleep laboratory.

Prolonged latency in the appearance of REM sleep as a marker of depression has been demonstrated in patients with the sickle-cell disease. To detect the possible existence of depressive disturbances in patients with sickle-cell disease, the Hamilton rating scale for depression (17 items) was used in 30 patients with homozygote sickle-cell disease and 31 carriers of the sickle-cell trait, treated or not with vasodilator drugs. None of the 61 subjects studied presented a score of 18 or more on the Hamilton rating scale, this being the threshold value for confirming the existence of moderate depression. However, analysis of variance showed an increase in mental dullness, agitation and somatization disorder. Dullness was related to the extent of anemia and the number of sickle-cell crises per year. Treatment had an effect on agitation in patients, with pentoxyfylline having a soothing effect unlike cinepazide maleate. Women complained of insomnia in the middle of the night and somatic anxiety and presented higher total scores than men. Men exhibited a higher degree of mental dullness. The findings of this preliminary study indicate that while not associated with frank depression, the sickle-cell gene has psychological repercussions on various depressive parameters and that these patients can benefit from treatment with pentoxyfylline.

We studied plasma melatonin profiles by radioimmunoassay in nine patients suffering from human african trypanosomiasis and six healthy controls matched according to the age and the photoperiodic conditions. The circadian periodicity of the sleep-wake cycle was disturbed proportionally to the degree of severity of the disease. On the contrary, the patients' plasma melatonin profile was similar to the controls' one. These results suggest that, beside the master clock generating the main circadian rhythms (sleep-wake, melatonin and core temperature rhythms), an additional regulating system of the melatonin rhythm could be involved.

It has been shown previously that sleeping sickness at the stage of meningoencephalitis manifests itself as a significant disturbance in the circadian rhythm of sleep-wakefulness. The objective of the current study was to examine the extent of circadian disruption in infected patients by measuring 24 hours patterns of plasma cortisol, an example of a classical circadian rhythm relatively independent of sleep, and prolactin, a primarily sleep-related rhythm. Plasma levels of certain cytokines were also measured to examine the immunopathogenesis of human African trypanosomiasis. An attempt was made to relate any circadian disruptions to the severity of the disease. The three most advanced patients demonstrated circadian disruptions in cortisol, prolactin and sleep-wake rhythms. The prime cytokine factor that correlated with the progression of the disease in humans was interferon-gamma, levels being 7- to 12-fold higher in the patients without any circadian rhythms. Our findings support the hypothesis that human African trypanosomiasis induces selective changes in the suprachiasmatic nucleus, important as a pacemaker for biological rhythms, resulting in disruptions of circadian rhythmicity in advanced stages of the disease.

In order to determine whether sleep disturbances would affect the hormonal patterns and the normal relationships between hormone pulses and sleep stages, the 24-hour profiles of cortisol, prolactin and plasma renin activity (PRA) were analysed in 6 sleeping sickness patients studied at Brazzaville and in 5 healthy African controls studied in Abidjan. Polysomnographic recordings were done continuously and blood was taken every 10 minutes throughout the 24-hour period. Plasma was analyzed for cortisol, prolactin and PRA. The circadian rhythm of cortisol, considered as an example of an endogenous rhythm was attenuated in all the patients but one, but as in normal subjects, slow wave sleep (SWS) remained associated with the declining phases of the secretory episodes. Prolactin and PRA profiles, which are strongly influenced by the sleep-wake cycle did not show the increase normally associated with long sleep periods and reflected the spreading of sleep and wakefulness throughout the 24-hour period. However, rapid-eye movement (REM) sleep began in sleeping sickness patients, as in normal subjects, during the descending phases of prolactin pulses. In both groups, PRA reflected the sleep stage distribution with non rapid-eye movement (NREM) sleep occurring during the ascending phases and REM sleep during the descending phases of the oscillations. However, in sleeping sickness patients, the marked sleep fragmentation often did not allow sufficient time for PRA to increase significantly, as observed with regular NREM-REM sleep cycles. These results demonstrate that, together with the disruption of the sleep-wake cycle, there are profound differences in the temporal organization of the 24 hour hormone profiles in human African trypanosomiasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Last century, patients with human African trypanosomiasis were described as sleepy by day and restless by night, and physicians referred to this condition as sleeping sickness. Such a description could have evoked a disturbance of circadian rhythms. However, it is only in 1989 that the first 24-hour recording was performed by our team in Niamey (Niger) in a patient with sleeping sickness. The patient was a Niger-born farm worker who had contracted the disease near Gagnoa (Côte d'Ivoire). Polysomnographic recordings (electroencephalogram, EEG, electrooculogram, electromyogram, electrocardiogram, buccal and nasal airflow, and chest respiratory movements) showed a disappearance of the circadian distribution of sleep and wakefulness, which tended to occur evenly throughout day and night, with a sleep-wake alternation of approximately 80 minutes. Two investigations were conducted thereafter. The first one was done at Daloa (Côte d'Ivoire) in 8 patients who were recorded during two 24-hour periods, with and without hourly blood samples; the second at Brazzaville (Congo) in 10 patients recorded for 24 hours before and after treatment with melarsoprol. All patients were at the stage of early meningoencephalitis. At Daloa, polysomnographic recordings were taken on two 8-channel EEG machines (Alvar Minihuit, and T3-ECEM), as well as on a portable Oxford Medilog 9000 system from the same electrodes. Sleep and wake structure was altered in the most severely sick patient, the EEG trace being loaded with slow waves. Stages 1 and 2, and stages 3 and 4 could not be distinguished from one another. In the other patients, all sleep stages were easily scored. No difference was seen between recordings, regarding blood collection.(ABSTRACT TRUNCATED AT 250 WORDS)