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COVID-19, the human primarily respiratory disease caused by the coronavirus SARS-CoV-2, commonly involves the nervous system, the effects of which may persist for many months. Post-acute sequelae of COVID-19 include relapsing and remitting neurological and neuropsychiatric symptoms that can affect children and adults, including those who had mild acute illness. Since longer-term adverse effects on the central and peripheral nervous system of COVID-19 cannot be excluded, patient and societal health trends should be monitored going forward. Urgent present needs include not only global immunization against SARS-CoV-2 but also the reestablishment of lapsed mass vaccination programs to prevent resurgence of other viral diseases (e.g., measles, polio) that can impact the nervous system. © Spencer P.S., Roman G., Buguet A., Guekht A., Reis J., 2021

We address the impact of the tropical environment on the human nervous system using the multifaceted approach characteristic of environmental neurology. First, environmental factors are examined according to their nature (physical, chemical and biological) and in relation to human activity and behavior. Some factors are specific to the tropics (climate and infections), while others are non-specific (chemicals, human communities and their way of life). Second, we examine the major role of human adaptation to the success of Homo sapiens, with emphasis on the linkage between thermoregulation and sleep-wake regulation. Third, we examine the performance of environmental neurology as a clinical discipline in tropical climates, with focus on the diagnostic and therapeutic challenges posed by human African trypanosomiasis. Finally, the prevention, early detection and monitoring of environmental neurological diseases is examined, as well as links with political and economic factors. In conclusion, practitioners of environmental neurology seek a global, multidisciplinary and holistic approach to understanding, preventing and treating neurological disorders within their purview. Environmental neurology integrates an expanded One Health concept by linking health and wellness to the interaction of plants, animals, humans and the ecosystem. Recent epidemics and the current COVID-19 pandemic exemplify the need for worldwide action to protect human health and biodiversity.

IMPORTANCE: The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations. OBJECTIVE: To study the neurologic manifestations of patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, observational case series. Data were collected from January 16, 2020, to February 19, 2020, at 3 designated special care centers for COVID-19 (Main District, West Branch, and Tumor Center) of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. The study included 214 consecutive hospitalized patients with laboratory-confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 infection. MAIN OUTCOMES AND MEASURES: Clinical data were extracted from electronic medical records, and data of all neurologic symptoms were checked by 2 trained neurologists. Neurologic manifestations fell into 3 categories: central nervous system manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations. RESULTS: Of 214 patients (mean [SD] age, 52.7 [15.5] years; 87 men [40.7%]) with COVID-19, 126 patients (58.9%) had nonsevere infection and 88 patients (41.1%) had severe infection according to their respiratory status. Overall, 78 patients (36.4%) had neurologic manifestations. Compared with patients with nonsevere infection, patients with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19, such as fever and cough. Patients with more severe infection had neurologic manifestations, such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]). CONCLUSIONS AND RELEVANCE: Patients with COVID-19 commonly have neurologic manifestations. During the epidemic period of COVID-19, when seeing patients with neurologic manifestations, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.

Michel Jouvet directed my medical thesis on paradoxical sleep in cats obtained in 1969, and my research on sleep in extreme environments (Antarctica, Arctic winter cold, physical exercise), which was the subject of my Ph.D. dissertation in 1984. As a military MD and scientist, I was posted in “exotic” (far away) places (Antarctica, Canada, Niger) and participated in several remote field trials (Canada, Cote d’Ivoire, Congo, Angola). Michel Jouvet supervised my research activity, allowing me the use of his laboratory facilities. He co-authored the work on sleep in Antarctica in 1987. In 1988, he was invited to Niamey (Niger) to preside on the international jury of medical doctorate dissertations. He then examined one of my patients with narcolepsy-like sleep attacks, suspect of sleeping sickness. Jouvet also co-authored our work on nitric oxide in the rat model of sleeping sickness. His scientific curiosity led him to study REM sleep eye movements in Bassari people, an isolated ethnic group in Senegal. With Monique Gessain, he co-authored a book on the Bassari oneiric activity. He was convinced that research in electricity-free villages was capital for understanding past mankind story. The present contribution recognizes the tremendous work capacity and scientific curiosity of Michel Jouvet.

Sleeping habits and morningness-eveningness questionnaires (chronotype), and polysomnography (internal sleep organization) were proposed to healthy volunteers living under natural climates from different locations in West Africa (Niger, Cote d'Ivoire) and Central Africa (Angola, Congo). Under the Sahelian dry climate, 138 Niger medical students (130 had afternoon naps) completed 1792 sleep questionnaires during 7-day sessions in the cool-dry and hot-dry seasons. As everywhere else on Earth, daily sleep lasted 7 to 8hours. In Abidjan (hot-humid climate), 78 medical students reported shorter sleep time, because of course schedules. Also in Abidjan, 23 African sportsmen and Expatriate soldiers slept at night and in afternoon naps. They reported similar sleep amounts than Niger students. In Congo villages, during a 5-year human African trypanosomiasis (HAT) research campaign, 45 healthy volunteers expressed morning chronotypes. The 71 HAT patients shifted from the indifferent chronotype towards morningness type. Chronotyping such patients may help evaluating treatment efficacy on brain function alterations. French soldiers executing missions in Africa were typed for morningness-eveningness. Regarding malaria prophylaxis and mosquito control, morning chronotype was more compliant than evening type. Polysomnography demonstrated internal sleep organization differences in different geoclimatic zones. The Sahelian climate promoted N3 slow-wave sleep in Africans and Expatriates during both the cool-dry and hot-dry seasons, with higher amounts in the hot-dry season. Increasing heat load by physical exercise further augmented N3. Rapid-eye-movement R sleep was high compared with values from temperate and hot-humid climates. Supramaximal exercise triggered a surprising R stage increase in the hot-dry season. In Cote d'Ivoire, Caucasian and African volunteers fragmented their sleep, although internal sleep organization approached that of temperate climates. Sleep patterns were also similar in Angola high hills and on Congo River shores. Therefore, Africans and Caucasians living in Niger hot-dry Sahelian climate exhibited major differences with those exposed to hot-humid or temperate climates.

To study the anatomo-biochemical substrates of brain inflammatory processes, Wistar male rats were infected with Trypanosoma brucei brucei. With this reproducible animal model of human African trypanosomiasis, brain cells (astrocytes, microglial cells, neurons) expressing the inducible nitric oxide synthase (iNOS) enzyme were revealed. Immunohistochemistry was achieved for each control and infected animal through eight coronal brain sections taken along the caudorostral axis of the brain (brainstem, cerebellum, diencephalon and telencephalon). Specific markers of astrocytes (anti-glial fibrillary acidic protein), microglial cells (anti-integrin alpha M) or neurons (anti-Neuronal Nuclei) were employed. The iNOS staining was present in neurons, astrocytes and microglial cells, but not in oligodendrocytes. Stained astrocytes and microglial cells resided mainly near the third cavity in the rostral part of brainstem (periaqueductal gray), diencephalon (thalamus and hypothalamus) and basal telencephalon. Stained neurons were scarce in basal telencephalon, contrasting with numerous iNOS-positive neuroglial cells. Contrarily, in dorsal telencephalon (neocortex and hippocampus), iNOS-positive neurons were plentiful, contrasting with the marked paucity of labelled neuroglial (astrocytes and microglial) cells. The dual distribution between iNOS-labelled neuroglial cells and iNOS-labelled neurons is a feature that has never been described before. Functionalities attached to such a divergent distribution are discussed.

A comprehensive review of the neurological disorders reported during the current COVID-19 pandemic demonstrates that infection with SARS-CoV-2 affects the central nervous system (CNS), the peripheral nervous system (PNS) and the muscle. CNS manifestations include: headache and decreased responsiveness considered initial indicators of potential neurological involvement; anosmia, hyposmia, hypogeusia, and dysgeusia are frequent early symptoms of coronavirus infection. Respiratory failure, the lethal manifestation of COVID-19, responsible for 264,679 deaths worldwide, is probably neurogenic in origin and may result from the viral invasion of cranial nerve I, progressing into rhinencephalon and brainstem respiratory centers. Cerebrovascular disease, in particular large-vessel ischemic strokes, and less frequently cerebral venous thrombosis, intracerebral hemorrhage and subarachnoid hemorrhage, usually occur as part of a thrombotic state induced by viral attachment to ACE2 receptors in endothelium causing widespread endotheliitis, coagulopathy, arterial and venous thromboses. Acute hemorrhagic necrotizing encephalopathy is associated to the cytokine storm. A frontal hypoperfusion syndrome has been identified. There are isolated reports of seizures, encephalopathy, meningitis, encephalitis, and myelitis. The neurological diseases affecting the PNS and muscle in COVID-19 are less frequent and include Guillain-Barré syndrome; Miller Fisher syndrome; polyneuritis cranialis; and rare instances of viral myopathy with rhabdomyolysis. The main conclusion of this review is the pressing need to define the neurology of COVID-19, its frequency, manifestations, neuropathology and pathogenesis. On behalf of the World Federation of Neurology we invite national and regional neurological associations to create local databases to report cases with neurological manifestations observed during the on-going pandemic. International neuroepidemiological collaboration may help define the natural history of this worldwide problem., Highlights • SARS-CoV-2 has definitive neurogenic capacity. • After binding to ACE2 receptors in nasal epithelium it invades the olfactory nerve and bulb progressing to invade the brainstem respiratory centers. • Irreversible respiratory failure may be the reason for the dismal prognosis of COVID-19 respirator-dependent patients. • SARS-CoV-2 binds to ACE2 receptors in endothelial cells causing endotheliitis. • Stroke occurs as a result of the pro-thrombotic state caused by endotheliitis. • Multi-organ failure occurs secondary to virus invasion of ACE2 receptors in lung, kidney, intestines, and brain.

Neuronal Per-Arnt-Sim (PAS) domain protein 4 (Npas4) is a key protein that intervenes in GABA synapse scaling and neurotrophicity enhancing. Since GABA and neurotrophicity are implicated in stress response and Npas4-deficient rodents exhibit behavioral alterations, an investigation was designed in rats to verify whether stress-induced spontaneous hippocampus Npas4 mRNA expression would be associated with specific patterns of stress response. The rats were exposed to one of three stressor levels: no stress (CTL, n = 15), exposure to a footshock apparatus (Sham, S, n = 40) and footshock (F, n = 80). After stress exposure the S and F rats were tested in an activity cage, and subsequently in an elevated plus maze (EPM), just prior to the sacrifice. Using cluster analysis, the animals already assigned to a stress level were also distributed into 2 subgroups depending on their Npas4 mRNA levels. The low (L) and high (H) Npas4 expression subgroups were identified in the S and F groups, the CTL group being independent of the Npas4 levels. The Npas4 effect was studied through the interaction between stress (S and F) and Npas4 level (L and H). The biological stress response was similar in H and L rats, except blood corticosterone that was slightly lower in the H rats. The H rats were more active in the actimetry cage and presented higher levels of exploration in the EPM. They also exhibited higher hippocampus activation, as assessed by the c-fos, Egr1 and Arc mRNA levels. Therefore high Npas4 expression favors stress management.

Recent publications focusing on sleep-wake alternation, using actigraphic recordings in hunter-gatherers, stressed the existence of a potential effect of electricity availability on sleep habits. These reports prompted us to achieve a new analysis of the polysomnographic data already obtained in healthy African volunteers in equatorial Africa during two different investigations. Comparison of the 24-h polysomnographic sleep patterns were done between 9 volunteers sleeping in a laboratory in Abidjan (Abidjan cohort) and 11 villagers living in electricity-free bush villages (Sinfra cohort). Sleep was lighter in the villagers, with more stage 1 and less slow wave sleep (SWS). Latency to SWS was also shorter. Total sleep time, however, was not different between the two groups. There were no indications as to whether the observed differences were attributable to the availability of electrical power. Reactivity of human sleep structure to the environment was discussed in terms of multifactorial influences such as daylight length, temperature, humidity, electromagnetic field, time of sleep onset, thermoregulatory mechanisms, stress or anxiety.

Human African trypanosomiasis staging follows human African trypanosomiasis diagnosis (trypanosomes in blood and/or lymph glands, trypanosome-positive). Staging determines treatment, as stage 2 medications are toxic and/or difficult to administer. It relies on cerebrospinal fluid examination: stage 1 (no cerebrospinal fluid trypanosome, trypanosome-negative; white blood cell count ≤5/µl); stage 2 (trypanosome-positive and/or white blood cell count ≥20/µl); intermediate stage (6–19 white blood cell/µl; trypanosome-negative). Lumbar puncture is repeated biannually during the 24-month post-treatment follow-up to confirm cure or detect relapse. Sleep disorders are major at stage 2, with a two-symptom polysomnographic syndrome: sleep–wake circadian disruptions; and sleep-onset rapid eye movement sleep periods. Polysomnography (PSG) was proposed as a noninvasive diagnostic tool, and 24-h PSG recordings were performed throughout a 5-year survey in Congo. Before treatment, 76 patients were included and recorded. Normal sleep–wake patterns occurred in 45 out of 47 stage 1 patients and in 16 out of 19 intermediate-stage patients. PSG syndrome was observed in seven out of ten stage 2 patients. During post-treatment follow-up, PSG syndrome occurrence indicated relapse at stage 2. Thus, noninvasive PSG may represent a valuable alternative for human African trypanosomiasis staging, especially in the post-therapeutic follow-up. The detection of a PSG syndrome would then provoke examination of the patient’s cerebrospinal fluid.

Nitric oxide (NO) production involves four different NO-synthases (NOSs) that are either constitutive (neuronal, nNOS; endothelial, eNOS; mitochondrial, mNOS) or inducible (iNOS) in nature. Three main processes regulate NO/NOSs output, i.e., the L-arginine/arginase substrate-competing system, the L-citrulline/arginosuccinate-recycling system and the asymmetric dimethyl-/monomethyl-L-arginine-inhibiting system. In adult animals, nNOS exhibits a dense innervation intermingled with pontine sleep structures. It is well established that the NO/nNOS production makes a key contribution to daily homeostatic sleep (slow-wave sleep, SWS; rapid eye movement sleep, REM sleep). In the basal hypothalamus, the NO/nNOS production further contributes to the REM sleep rebound that takes place after a sleep deprivation (SD). This production may also contribute to the sleep rebound that is associated with an immobilization stress (IS). In adult animals, throughout the SD time-course, an additional NO/iNOS production takes place in neurons. Such production mediates a transitory SD-related SWS rebound. A transitory NO/iNOS production is also part of the immune system. Such a production contributes to the SWS increase that accompanies inflammatory events and is ensured by microglial cells and astrocytes. Finally, with aging, the iNOS expression becomes permanent and the corresponding NO/iNOS production is important to ensure an adequate maintenance of REM sleep and, to a lesser extent, SWS. Despite such maintenance, aged animals, however, are not able to elicit a sleep rebound to deal with the challenge of SD or IS. Sleep regulatory processes in adult animals thus become impaired with age. Reduced iNOS expression during aging may contribute to accelerated senescence, as observed in senescence-accelerated mice (SAMP-8 mice).

Resume Objectifs Verifier l’adequation entre les posologies de vancomycine recommandees par les societes savantes et les objectifs pharmacologiques a atteindre chez des patients de reanimation : concentration a l’equilibre (CE) et rapport CE/CMI (concentration minimale inhibitrice). Des facteurs de variabilite des CE de vancomycine ont egalement ete recherches. Patients et methode Etude monocentrique observationnelle retrospective portant sur 66 patients de reanimation sous antibiotherapie incluant la vancomycine, seule ou en association, en traitement d’une infection severe a cocci Gram positif. Les posologies utilisees etaient de 15 mg/kg sur une heure (avec pour vitesse maximale 1 g/h) pour la dose de charge, puis de 40 a 60 mg/kg chaque 24 heures en injection veineuse continue. Les CE de vancomycine et les CMI des germes impliques ont ete recueillies. Le rapport CE/CMI etait considere comme efficace si superieur a 8. Resultats Quarante-deux pour cent des CE de vancomycine etaient efficaces. Vingt-trois pour cent des rapports CE/CMI etaient superieurs a 8. Le taux de guerison clinique etait de 71 % des patients. La duree de l’antibiotherapie a ete identifiee comme interagissant de facon positive avec l’efficacite biologique de la vancomycine, et le sepsis severe comme un facteur d’interaction negative. Conclusion Moins de la moitie des CE et moins du quart des rapports CE/CMI sont efficaces dans notre etude. Vingt-neuf pour cent des patients sont en echec therapeutique, malgre l’utilisation des posologies recommandees, posant la question de la revision des posologies, de l’administration et du dosage de la vancomycine.

International audience; Metyrapone, a cytochrome P(450) inhibitor used to inhibit corticosterone synthesis, triggers biological markers of stress and also reduces stress-induced anxiety-like behaviors. To address these controversial effects, 6 separate investigations were carried out. In a first set of investigations, abdominal temperature (T(abd)), spontaneous locomotor activity (A(S)) and electroencephalogram (EEG) were recorded in freely moving rats treated with either saline or 150 mg kg(-1) metyrapone. An increase in T(abd) and A(S) occurred in saline rats, while, metyrapone rats exhibited an immediate decrease, both variables returning to basal values 5h later. Concomitantly, the EEG spectral power increased in the gamma and beta 2 bands and decreased in the alpha frequency band, and the EMG spectral power increased. This finding suggests that metyrapone depressed stress-induced physiological response while arousing the animal. In a second step, restraint stress was applied 5h after injection. Metyrapone significantly blunted the stress-induced T(abd) and A(S) rise, without affecting the brain c-fos mRNA increase. Corticosterone (5 and 40 mg kg(-1)) injected concomitantly to metyrapone failed to reverse the observed metyrapone-induced effects in T(abd) and A(S). Finasteride (50 mg kg(-1)), which blocks neurosteroid production, was also unable to block these effects. In conclusion, metyrapone acutely reduced stress-induced physiological response in freely behaving rats independently from glucocorticoids and neurosteroids.

Resume Objectifs Verifier l’adequation entre les posologies d’aminosides recommandees et les objectifs de quotient inhibiteur (QI) a atteindre chez des patients de reanimation. Patients et methode Etude monocentrique observationnelle retrospective de 87 patients de reanimation places sous double antibiotherapie incluant obligatoirement un aminoside (amikacine ou gentamicine), en traitement d’une infection severe. Les posologies utilisees etaient de 15 mg/kg pour l’amikacine et de 5 mg/kg pour la gentamicine. Les concentrations maximales (Cmax) d’aminosides et les concentrations minimales inhibitrices (CMI) des germes impliques ont ete recueillies. Le rapport Cmax/CMI (ou QI) a ete calcule. Un QI est considere comme efficace s’il est superieur a 10. Les Cmax du premier pic d’aminosides ont ete comparees aux Cmax theoriques a atteindre. Des facteurs de variabilite des concentrations plasmatiques au pic d’aminosides (Cmax) ont ete recherches : index de gravite standardise 2 (IGS2), âge, sexe, poids, gravite du sepsis. Resultats Parmi les Cmax, 50,3 % etaient efficaces, soit 59,6 % pour l’amikacine et 38,9 % pour la gentamicine. Quarante-six pour cent des premiers QI etaient efficients ; 12,6 % des premieres Cmax atteignaient les valeurs theoriques. Une efficacite clinique etait observee a 72 heures chez 67,8 % des patients. Les facteurs interagissant negativement avec l’efficacite biologique des aminosides etaient les infections a cocci Gram positif et a anaerobies, et les patients de chirurgie programmee. Conclusion Parmi les QI de notre etude, 49,7 % etaient inefficaces et 32,2 % des patients etaient en echec therapeutique, malgre l’utilisation des posologies d’aminosides recommandees, posant la question de la revision des modalites d’administration des aminosides et surtout des doses recommandees.

This paper focuses on the development of an automatic system for sleep analysis. The system proposed in this paper combines two phases needed in sleep analysis. In a first step, an artefact detection system selects the polysomnographic signals (EEG, EOG, EMG) that are not corrupted by artefacts. In a second step, relevant features are extracted from the selected signals and classified using a neural network chosen among a bank of four neural networks. The four classifiers differ one from the others by the signals used for the classification. They were learnt using information provided by different combination of signals (EEG, EEG+EOG, EEG+EMG, EEG+EOG+EMG). Thus, the complete system enables the classification to be performed using relevant features computed from artefact-free signals, without losing too many data. The performance reached by the two-steps system is 85% of accuracy, calculated on 47 night sleep recordings.

Glossina, the tsetse fly, provokes human African trypanosomiasis (HAT) by injecting Trypanosoma brucei (T. b.) gambiense or rhodesiense. All aspects of HAT are exposed, emphasizing historical milestones and scientific background. Breaking-up with the unique clinical approach of the past centuries, the turn of the nineteenth century was a fecund period. A dramatic epidemic ravaged Central Africa and the colonial powers launched medical research teams. In 15 years, the agents, the trypanosomes, and their vectors were discovered. The two previously separated entities, recurrent Trypanosoma fever and sleeping sickness, merged in the clinical and biological continuum of HAT, becoming hemolymphatic stage 1 and meningoencephalitic stage 2. Even treatments were proposed. During World War I, specific services and mobile teams were created to track trypanosomes and treat patients, initiating modern epidemiology. In 1960, HAT was virtually eliminated from intertropical Africa. However, political and military unrest impeached surveillance and, in the 1990s, a new epidemic wave burst out. In recent years, new biological tests were designed to elaborate field-adapted diagnosis and staging tools. Nevertheless, diagnosis still relies on direct microscopic trypanosome detection or after concentration techniques. Staging is based on trypanosome detection in the cerebrospinal fluid (CSF) or CSF white blood cell (WBC) counts (stage 1, no trypanosome, WBC counts ≤ 5/µL; stage 2, trypanosomes, WBC counts ≥ 20/µL; T. b. gambiense HAT intermediate stage, between these thresholds and no trypanosome). Staging is vital: stage 1 treatment with pentamidine (T. b. gambiense) or suramine (T. b. rhodesiense) is well tolerated, but stage 2 requires toxic drugs (melarsoprol, especially for rhodesiense HAT; eflornithine or nifurtimox–eflornithine combination therapy, NECT, for gambiense HAT).

Cerebral involvement during malaria is a complication that leads to seizure, coma, and death. The effect of new neuroprotective therapies has not yet been investigated, although cerebral malaria shares some features with neurological stroke. Erythropoietin (EPO) is one of the more promising drugs in this area. We measured the effect of EPO on the survival of mice infected with Plasmodium berghei ANKA and demonstrated that inoculations of recombinant human EPO at the beginning of the clinical manifestations of cerebral malaria protect >90% of mice from death. This drug has no effect on the course of parasitemia. The effect of EPO was not related to either the inhibition of apoptosis in the brain or the regulation of the increase and decrease of nitric oxide production in the brain and blood, respectively. Tumor necrosis factor-alpha and interferon-gamma mRNA overexpression was inhibited by EPO, and treated mice had fewer brain hemorrhages. EPO has been used in patients with chronic diseases for years, and more recently it has been used to treat acute ischemic stroke. The data presented here provide the first evidence indicating that this cytokine could be useful for the symptomatic prevention of mortality during the acute stage of cerebral malaria.

This paper describes the process of sleep/wake stage classification. It mainly focuses on the problem of selection of relevant features extracted from the polysomnographic recordings. Iterative features selection methods were applied on a large database composed of several night recordings from different healthy adults. The results showed that the use of relative power of EEG in five frequency bands enables to correctly classify 71% of the whole data base. The addition of features extracted from EOG enables to reach 75% of agreement with the expert classification, but no significant improvement was obtained when adding features extracted from EMG.

Human African trypanosomiasis, caused by Trypanosoma brucei ( T.b. ) gambiense or rhodesiense , evolves in two stages: haemolymphatic stage and meningo-encephalitic stages, the latter featuring numerous neurological disorders. In experimental models infected with diverse T.b. sub-species, body weight (BW) loss, drop in food intake (FI), and hypo-activity after an asymptomatic period suggest the occurrence of a similar two-stage organization. In addition to daily measurement of BW and FI, body core temperature ( T co ) and spontaneous activity (SA) were recorded by telemetry in T.b. brucei -infected rats. After a 10–12-day symptom-free period, a complex clinical syndrome occurred suddenly. If the animal survived the access, the syndrome re-occurred at approximately 5-day intervals until death. The syndrome was made of a drop in FI and BW, a sharp decrease in T co and a loss of SA, suggesting a brisk alteration of the central nervous system functioning. Such events confirm the existence of a two-stage disease development in experimental trypanosomiasis. The entry into the second stage is marked by the occurrence of the first access, BW follow-up being essential and often sufficient its determination.

Periodogram techniques on detrended data were used to determine the incidence of Trypanosoma brucei brucei infection on the distribution of the core temperature of rats and the expression of temperature rhythms. In such an animal model, sudden episodic hypothermic bouts were described. These episodes of hypothermia are used here as temporal marks for the purpose of performing punctual comparisons on temperature organization. The experiment was conducted on 10 infected and 3 control Sprague-Dawley rats reared under a 24 h light-dark cycle. Core temperature was recorded continuously throughout the experiment, until the animals' death. Temperature distributions, analyzed longitudinally across the full duration of the experiment, exhibited a progressive shift from a bimodal to unimodal pattern, suggesting a weakening of the day/night core temperature differences. After hypothermic events, the robustness of the circadian rhythm substantially weakened, also affecting the ultradian components. The ultradian periods were reduced, suggesting fragmentation of temperature generation. Moreover, differences between daytime and nighttime ultradian patterns decreased during illness, confirming the weakening of the circadian component. The results of the experiments show that both core temperature distribution and temperature rhythm were disrupted during the infection. These disruptions worsened after each episode of hypothermia, suggesting an alteration of the temperature regulatory system.

Arginase serum levels were increased in human African trypanosomiasis patients and returned to control values after treatment. Arginase hydrolyzes l -arginine to l -ornithine, which is essential for parasite growth. Moreover, l -arginine depletion impairs immune functions. Arginase may be considered as a biomarker for treatment efficacy.

Arousal (AR) from sleep is associated with an autonomic reflex activation raising blood pressure and heart rate (HR). Recent studies indicate that sleep deprivation may affect the autonomic system, contributing to high vascular risk. Since in sleep disorders a sleep fragmentation and a partial sleep deprivation occurs, it could be suggested that the cardiovascular effects observed at AR from sleep might be physiologically affected when associated with sleep deprivation. The aim of the study was to examine the effect of sleep deprivation on cardiac arousal response in healthy subjects.Seven healthy male subjects participated in a 64 h sleep deprivation protocol. Arousals were classified into four groups, i.e.36 s,610 s,1015 s and15 s, according to their duration. Pre-AR HR values were measured during 10 beats preceding the AR onset, and the event-related HR fluctuations were calculated during the 20 beats following AR onset. As an index of cardiac activation, the ratio of highest HR in the post-AR period over the lowest recorded before AR (HR ratio) was calculated.For AR lasting less than 10 s, the occurrence of AR induces typical HR oscillations in a bimodal pattern, tachycardia followed by bradycardia. For AR lasting more than 10 s, i.e. awakenings, the pattern was unimodal with a more marked and sustained HR rise. The HR response was consistently similar across nights, during NREM and REM sleep, without difference between conditions.Overall, total sleep deprivation appeared to have no substantial effect on cardiac response to spontaneous arousals and awakenings from sleep in healthy subjects. Further studies are needed to clarify the role of chronic sleep deprivation on cardiovascular risk in patients with sleep disorders.In healthy subjects acute prolonged sleep deprivation does not affect the cardiac response to arousal.

Study objectives The hierarchical definition of arousals from sleep includes a range of physiologic responses including microarousals, delta and K-complex bursts, and variations in autonomic system. Whether patterns in slow-wave electroencephalographic activity and autonomic activation are primary forms of arousal response can be addressed by studying effects of total sleep deprivation. We therefore examined changes in arousal density during recovery sleep in healthy subjects. Design Participants spent 6 consecutive 24-hour periods in the laboratory. Nights 1 and 2 were baseline nights followed by 64-hour total sleep deprivation, then 2 consecutive recovery nights. Setting Sleep-deprivation protocol was conducted under laboratory conditions with continuous behavioral and electrophysiologic monitoring. Participants Twelve drug-free men aged 27.4 +/- 7.9 years were studied. None reported sleepiness or altered sleep-wake cycle, and none had neurologic, psychiatric or sleep disorders. Intervention N/A. Measurements and results Arousals were classified into 4 levels: microarousals, phases of transitory activation, and delta and K-complex bursts. Sleep deprivation induced changes in the density of considered arousals except phases of transitory activation, with a distinct pattern among the different types. The greatest change was found for microarousals, which showed a significant decrease in the first recovery night (P = .01), with return to baseline thereafter. A fall in K-complex and delta-burst density was noted in the first recovery night, not, however, reaching statistical significance. The phases of transitory activation rate were virtually unaffected throughout the experimental nights. Conclusions We conclude that homeostatic sleep processes exert an inhibitory effect on arousal response from sleep with a significant effect only on the microarousal density. Decreased delta and K-complex burst rates, though not significant, support the hypothesis that they may be activating processes, probably modulated by factors independent from those implicated in cortical arousal.

Study Objectives: Patients with human African trypanosomiasis (sleeping sickness) due to the inoculation of Trypanosoma brucei gambiense or rhodesiense show a major disruption of the 24-hour sleep-wake distribution, accompanied by the occurrence of sleep-onset rapid-eye-movement (REM) sleep episodes, proportional to the severity of the illness. Although animal models of human African trypanosomiasis have been developed to understand the pathogenic mechanisms leading to immune alterations, the development of an animal model featuring the alterations of endogenous biologic rhythms remains a necessity. Animals: Sprague-Dawley rats (N = 10) entrained to a 12:12-hour dark-light regimen. Interventions: Rats were infected with Trypanosoma brucei brucei AnTat 1.1E and instrumented with electrocorticographic and electromyographic electrodes. Polysomnography was recorded continuously from 2 days before infection until the animal's death. Measurements and Results: The analysis of the spontaneous sleep-wake architecture revealed an increased proportion of slow-wave sleep (SWS) and a decreased amount of wakefulness 2 days before death. Considerable sleep fragmentation was observed in the infected rats, with numerous changes in sleep-wake stages and an increased number of episodes of wakefulness and SWS. Infected rats presented a fragmented pattern of SWS and a marked reduction in the mean paradoxical-sleep (PS) latency, resulting in a considerable disruption of the PS-SWS sequences. Abnormal transitions, particularly the appearance of sleep-onset REM episodes, marked the disruption of the internal sleep structure. The electrocorticogram traces were modified during SWS, with the occurrence of abnormal hypersynchronic slow waves and a disappearance of spindles. Conclusion: The Trypanosoma brucei brucei-infected rat is a good model of the syndrome seen in human African trypanosomiasis, ie, the 24-hour disruption of the sleep-wake cycle and the occurrence of sleep-onset REM-like sleep episodes.

Animal models of Human African Trypanosomiasis (HAT) have been developed to understand the pathogenic mechanisms leading to the passage into the neurological phase, most of them referring to histological aspects but not clinical or behavioral data. Our study aimed at defining simple clinical and/or behavioral markers of the passage between the hemolymphatic phase and the meningo-encephalitic stage of the disease. Sprague-Dawley rats (n=24) were infected with Trypanosoma brucei brucei AnTat 1.1E. Food intake and body weight were measured daily from the day of infection until death. Hematocrit was measured twice a week. Behavioral disturbances were evaluated through an Open-field test. A sudden weight loss occurred on the twelfth day after infection, due to a significant drop of food intake starting two days before. The rats developed an anemic state shown by the hematocrit measurements. The Open-field test showed them to be less active and reactive as soon as the second week after infestation. A complementary histological study observed trypanosomes and inflammatory cells in the choroid plexus at the same period. These results are in favor of central nervous system functional disturbances. The observed weight loss is discussed as being a parameter of the entry in the meningo-encephalitic phase. The rat model reproduces neurological symptoms observed in the human disease and may prove to be useful for further neurohistological and therapeutic studies.

During the lunar month of Ramadan, Muslims abstain from eating, drinking and smoking from sunrise to sunset. We reported previously that Ramadan provokes a shortening in nocturnal total sleep time by 40 min, an increase in sleep latency, and a decrease in slow-wave sleep (SWS) and rapid eye movement (REM) sleep duration during Ramadan. During the same study, the effects of Ramadan intermittent fasting on daytime sleepiness were also investigated in eight healthy young male subjects using a quantitative waking electroencephalograph (EEG) analysis following the multiple sleep latency test (MSLT) procedure. This procedure was combined with subjective alertness and mood ratings and was conducted during four successive experimental sessions: (1) baseline (BL) 15 days before Ramadan, (2) beginning of Ramadan (R11) on the 11th day of Ramadan, (3) end of Ramadan (R25) on the 25th day of Ramadan, (4) recovery 2 weeks after Ramadan (AR). During each session, four 20-min nap opportunities (MSLTs) were given at 10:00, 12:00, 14:00 and 16:00 h and were preceded by rectal temperature readings. Nocturnal sleep was recorded before each daytime session. Subjective daytime alertness did not change in R25 but decreased in R11 at 12:00 h, and subjective mood decreased at 16:00 h, both in R11 and R25. During the MSLT, mean sleep latency decreased by an average of 2 min in R11 (especially at 10:00 and 16:00 h) and 6 min in R25 (especially at 10:00 and 12:00 h) compared with BL. There was an increase in the daily mean of waking EEG absolute power in the theta (5.5-8.5 Hz) frequency band. Significant correlations were found between sleep latency during the MSLT and the waking EEG absolute power of the fast alpha (10.5-12.5 Hz), sigma (11.5-15.5 Hz) and beta (12.5-30 Hz) frequency bands. Sleep latency was also related to rectal temperature. In conclusion, Ramadan diurnal fasting induced an increase in subjective and objective daytime sleepiness associated with changes in diurnal rectal temperature.

Human African trypanosomiasis (HAT) or sleeping sickness is a severe vector-borne disease, with marked involvement of the peripheral and central nervous system. Still endemic in sub-Saharan Africa, HAT is caused by transmission of subspecies of the protozoan parasites Trypanosoma brucei (T. b.) through bites of tsetse flies (genus Glossina). Foci of HAT are reported mostly in remote, resource-poor settings, and areas of political instability. The disease has a chronic form caused by T. b. gambiense in Western and Central Africa, and an acute form caused by T. b. rhodesiense in Eastern and Southern Africa. Both forms, almost invariably fatal without treatment, evolve from a first, hemolymphatic stage to a second, meningoencephalitic stage due to T. b. brain invasion. Clinical features involve a constellation of sensory, motor and neuropsychiatric signs and symptoms, with a characteristic sleep disorder leading to sleep-wake cycle disorganization and sleep structure alterations. Therapy currently available to cure the second stage of both HAT forms is toxic. Stage biomarkers and safer therapy are urgently needed. Clinical objective evaluation is essential for diagnostic purposes, treatment assessment and patients’ follow-up. The recent decline in the number of reported new HAT cases should not foster further neglect of this highly neglected nervous system infection.

During the month of Ramadan intermittent fasting, Muslims eat exclusively between sunset and sunrise, which may affect nocturnal sleep. The effects of Ramadan on sleep and rectal temperature (Tre) were examined in eight healthy young male subjects who reported at the laboratory on four occasions: (i) baseline 15 days before Ramadan (BL); (ii) on the eleventh day of Ramadan (beginning of Ramadan, BR); (iii) on the twenty-fifth day of Ramadan (end of Ramadan, ER); and (iv) 2 weeks after Ramadan (AR). Although each session was preceded by an adaptation night, data from the first night were discarded. Polysomnography was taken on ambulatory 8-channel Oxford Medilog MR-9000 II recorders. Standard electroencephalogram (EEG), electro-oculogram (EOG) and electromyogram (EMG) recordings were scored visually with the PhiTools ERA. The main finding of the study was that during Ramadan sleep latency is increased and sleep architecture modified. Sleep period time and total sleep time decreased in BR and ER. The proportion of non-rapid eye movement (NREM) sleep increased during Ramadan and its structure changed, with an increase in stage 2 proportion and a decrease in slow wave sleep (SWS) duration. Rapid eye movement (REM) sleep duration and proportion decreased during Ramadan. These changes in sleep parameters were associated with a delay in the occurrence of the acrophase of Tre and an increase in nocturnal Tre during Ramadan. However, the 24-h mean value (mesor) of Tre did not vary. The nocturnal elevation of Tre was related to a 2-3-h delay in the acrophase of the circadian rhythm. The amplitude of the circadian rhythm of Tre was decreased during Ramadan. The effects of Ramadan fasting on nocturnal sleep, with an increase in sleep latency and a decrease in SWS and REM sleep, and changes in Tre, were attributed to the inversion of drinking and meal schedule, rather than to an altered energy intake which was preserved in this study.

Vascular and immunological mechanisms are both likely to be involved in heatstroke, this condition being preceded by a decrease in cerebral blood flow and an increase in brain cytokine concentrations. As the two mechanisms involve a nitridergic step, we analysed their respective role in heat tolerance by exposing vigil rats to heat after treatment with nitric oxide synthases (NOS) antagonists: non-specific inhibitors Nω-nitro- l -arginine (LNA) and N-nitro- l -arginine-methyl-ester (L-NAME); 7-nitroindazol (neuronal NOS inhibitor) and aminoguanidine (AG) (inducible NOS inhibitor). Heat exposure was interrupted when clinical signs occurred or when colonic temperature reached 43°C. LNA and L-NAME dramatically reduced heat tolerance, while AG did not modify it. These results suggest the involvement of constitutive NOS in heat tolerance. Inducible NOS does not seem to be involved in the occurrence of heatstroke.

Sleeping sickness, once under control, is a re-emergent endemic parasitic disease in intertropical Africa. Its originality resides in its duality. Two trypanosome groups ( Trypanososma brucei gambiense vs. rhodesiense ) are transmitted to humans by tsetse flies from two geographical areas (Western and Central Africa humid forest vs. Eastern Africa arboreous savannah), provoking a slowly or a rapidly evolutive disease. The two stage (haemolymphatic vs. neurological invasion) pathogenic evolution leads to the duality of the immune response, depending on the host-parasite inter-relation differences in the blood and the brain. In the blood, the immune processes involved are both specific (anti-variant surface glycoprotein (VSG) antibodies) and non-specific (complement-mediated lysis, opsonification-facilitated phagocytosis and antibody dependent cell-mediated cytotoxicity). Although macrophages are activated in the blood and infiltrate the brain, nitric oxide decreases in the blood and increases in the brain, with a breakage in the blood–brain barrier, leading to brain lesions through the production of deleterious molecules. Prophylactic means are affected by the duality of pathogenic processes. This finally leads to a two stage disease (haemolymphatic vs. neurological) with two different therapeutic strategies. The sleep–wake cycle and other biological rhythms are also marked by the disappearance of circadian rhythmicity demasking basic ultradian activities and relationships, such as the interdependence of endocrine profiles and the sleep–wake alternation. 2001 Harcourt Publishers Ltd

Trypanosoma brucei gambiense, a causative agent of sleeping sickness, induced a dose-de- pendent production of tumor necrosis factor (TNF)-a by human macrophages in vitro. TNF- a! was also induced in the Mono Mac 6 cell line, which indicates a direct effect of parasite components on macrophages. Parasite-soluble factors were also potent inducers of TNF-a. The addition of anti-TNF-a to cocultures of macrophages and parasites increased the number of trypanosomes and their life span, whereas irrelevant antibodies had no effect. TNF-o( may have a direct role (i.e., direct trypanolytic activity) andlor an indirect one, such as TNF- a-mediated induction of cytotoxic molecules. A direct dose-dependent lytic effect of TNF-a on purified parasites was observed. This lytic effect was inhibited by anti-TNF-a. These data suggest that, as in experimental trypanosomiasis, TNF-o( is involved in parasite growth control in human African trypanosomiasis. Trypanosoma brucei gainbiense and Trypanosoma brucei rliodesiense, the causative agepts of human African trypano- somiasis (HAT), also called sleeping sickness, are tse-tse fly- transmitted protozoa that multiply extracellularly in the blood- &em, lymph, and interstitial fluids of their hosts (l). There is currently a huge resurgence of HAT because of the deterioration of health facilities, war, and civil disturbances. Blood monocytes and tissue macrophages play a key role in the control of protozoan parasites. Increases in the number of macrophages and the presence of macrophage activation mark- ers are noted in trypanosomiasis (2). Macrophages synthesize effector molecules with antitumoral and antimicrobial prop- erties, including tumor necrosis factor (TNF)-a!. TNF-a! fulfills important functions in host-parasite interactions and plays an important role in controlling infections by various pathogens. TNF-a! is also involved in the pathogenesis of septic shock and systemic inflammatory reactions (3). Trypanosomiasis was one of the first diseases in which the involvement of TNF-a! was observed (3). Trypanosome-derived

Objective The study was performed in early middle-aged African natives with primary open-angle glaucoma to compare the 24-hour intraocular pressure (IOP) variations in healthy versus young glaucoma patients, because IOP follows a circadian (24-hour) oscillation in healthy Caucasians. Design Case-control study. Participants Sixteen healthy African volunteers (age 24.5 ± 1 years, mean ± standard error of the mean) and 11 open-angle glaucoma African patients (age 36.2 ± 3.3 years). Methods IOP was measured hourly during 24 hours with a Modular One pneumatonometer (Modular One, Digilab, Cambridge, MA), which allows measures in supine subjects. To allow the IOP measurement at night, subjects were awakened under polysomnography (electroencephalogram, electromyogram, electro-oculogram) recorded at night and during a 90-minute afternoon nap. Main outcome measures Hourly IOP values were analyzed for circadian rhythmicity with the Cosinor technique and in relation to the state of wakefulness, light sleep (stages 1 and 2), slow-wave sleep (stages 3 and 4), and rapid eye movement (REM) sleep upon awakening. Results Sleep patterns did not differ between patients and healthy volunteers. As expected, in the healthy subjects, IOP followed a 24-hour rhythm with a nocturnal peak value (acrophase), and the variations in IOP during sleep were related to sleep structure, being lowest during REM sleep and highest during slow-wave sleep. In the glaucoma patients, however, the 24-hour rhythm of IOP was reversed, with an afternoon acrophase and an early morning trough. Conclusions These data suggest a circadian phase shift in IOP in glaucoma patients, with maintained relation to sleep structure.

The temporal and quantitative interrelationships between the hypothalamo-pituitary-adrenal (HPA) axis activity and the level of central arousal were studied in 10 healthy young men during daytime wakefulness. Two experimental sessions were conducted randomly between 09.00 and 18.00 h, once after nocturnal sleep and once after a night of total sleep deprivation. Spectral analysis of serial waking electroencephalography (EEG) from a short target fixation task repeated every 10 min was undertaken, along with an estimation of cortisol secretory profiles by deconvolution of plasma radioimmunoassay measures obtained from continuous blood withdrawal with regular sampling at a 10-min interval. Following nocturnal sleep, a temporal association between the HPA axis activity and the waking EEG activity was found, cortisol secretory rate following changes in frontal gamma (20–45 Hz) band power by 10 min (average R = 0.458, p < 0.001). Although it remained significant (average R = 0.276, p < 0.05), the association strength decreased significantly following total sleep deprivation (p < 0.05, Wilcoxon test). Cortisol plasma level, secretory rate and pulse amplitude were increased as well as waking EEG power in the delta (0.5–5.5 Hz), theta (5.5–8.5 Hz) and gamma frequency bands (all p values

The ultradian dynamics of the human waking EEG was studied using a short visual fixation task repeated every 10 min throughout the daytime. The EEG spectra obtained from the tasks were assessed for time effect and ultradian periodicity. Fronto-central EEG high frequency powers (22.5‐44.5 Hz) decreased at the time of the midafternoon vigilance dip (14.00‐17.00 h) along with slight concomitant increases in parietal alpha (7.5‐13.5 Hz) and delta (1‐3 Hz) powers. A slow ultradian rhythm with a 3‐4 h periodicity strongly modulated EEG power in all frequency bands between 1 and 44.5 Hz. The high frequency waking EEG may well reflect the activity of a brain arousal process underlying maintenance of the waking state probably throughout the 24 h cycle. NeuroReport 11:1‐5 & 2000 Lippincott Williams & Wilkins.

The effects of zopiclone on the rest/activity rhythm were investigated after a westward flight with a 5-h phase delay (Grenoble-Martinique). The rest/activity rhythm was recorded continuously with an actigraph monitor during a 6-day baseline episode in Grenoble and a 6-day sojourn in Martinique. Rectal temperature was recorded before the flight on day 2 and after the flight on days 2 and 5. Subjective jet-lag score was assessed before the flight on days 1 and 2 and in Martinique on days 1, 2, 5 and 6. Zopiclone (7.5 mg) or placebo were administered double blind 30 min prior to bedtime during the first 4 post-flight days (D1-D4). Under zopiclone treatment, sleep was less fragmented on the first post-flight night and the curtailment of sleep duration observed on D2 and D3 under placebo was prevented. During day-time, subjects tended to be more active than with placebo. By contrast, subjective jet-lag scores did not differ between both groups. Zopiclone seemed to accelerate the readjustment of the rest/activity rhythm and the normalisation of the phase relationship between sleep and the temperature rhythm. Zopiclone probably exerts its "resetting" effects on jet-lag desynchronosis by facilitating sleep induction rather than via a chronobiotic action.

The contribution of hyperthermia to the differential leukocytosis of exercise remains obscure. This study examined changes in circulating sympathoadrenal hormone concentrations and patterns of leukocyte and lymphocyte subset (CD3+, CD4+, CD8+, CD19+, CD3−16+/56+) redistribution during exercise, with and without a significant rise of rectal temperature (Tre). Ten healthy men [age 26.9 ± 5.7 (SD) yr, body mass 76.0 ± 10.9 kg, body fat 13.9 ± 4.6%, peak O2consumption: 48.0 ± 12.4 ml ⋅ kg−1⋅ min−1] exercised for 40 min (65% peak O2consumption) during water immersion at 39 or 18°C. Treincreased from 37.2 to 39.3°C ( P < 0.0001) after 40 min of exercise in 39°C water but was held constant to an increment of 0.5°C during exercise in 18°C water. Application of this thermal clamp reduced exercise-associated increments of plasma epinephrine (Epi) and norepinephrine (NE) by >50% ( P < 0.05) and abolished the postexercise increase in cortisol. Thermal clamping also reduced the exercise-induced leukocytosis and lymphocytosis. Multiple regression demonstrated that Trehad no direct association with lymphocyte subset mobilization but was significantly ( P < 0.0001) correlated with hormone levels. Epi was an important determinant of total leukocytes, lymphocytes, and CD3+, CD4+, CD8+, and CD3−CD16+/56+subset redistribution. The relationship between NE and lymphocyte subsets was weaker than that with Epi, with the exception of CD3−CD16+/56+counts, which were positively ( P < 0.0001) related to NE. Cortisol was negatively associated with leukocytes, CD14+monocytes, and CD19+B- and CD4+T-cell subsets but was positively related to granulocytes. We conclude that hyperthermia mediates exercise-induced immune cell redistribution to the extent that it causes sympathoadrenal activation, with alterations in circulating Epi, NE, and cortisol.

The pathogenesis of human African trypanosomiasis (HAT) has been the object of considerable research interest but has remained incompletely understood. The importance of cytokines in the pathophysiology of this protozoan infection is now widely recognized, but the full spectrum of cytokines involved has yet to be determined. In the present investigation we compared the plasma concentrations of TNF-α and IL-10 in normal African controls and patients suffering from advanced meningocephalic (late-stage) Trypanosomiasis brucei (T. b.) gambiense infections, before and after treatment with the arsenical trypanocide melarsoprol. We found that patients with late-stage T. b. gambiense exhibit chronically elevated circulating levels of both of these cytokines, and that these levels quickly decline following melarsoprol treatment. These findings confirm that TNF-α is involved in the immunopathogenesis of late-stage African trypanosomiasis and suggest that IL-10 may also play an important regulatory role in this disease.

In patients suffering from stress-related pathologies and depression, frontal cortex GABA and glutamate contents are reported to decrease and increase, respectively. This suggests that the GABA and/or glutamate content may participate in pathological phenotype expression. Whether differences in frontal cortex GABA and glutamate contents would be associated with specific behavioral and neurobiological patterns remains unclear, especially in the event of exposure to moderate stress. We hypothesized that an increase in prefrontal cortex GABA/glutamate ratio would be associated with a blunted prefrontal cortex activation, an enhanced hypothalamo-pituitary–adrenocortical (HPA) axis activation and changes in behavior. Rats being restrained for 1-h were then tested in an open-field test in order to assess their behavior while under stress, and were sacrificed immediately afterward. The GABA/glutamate ratio was assessed by 1 H high-resolution magic angle spinning magnetic resonance spectroscopy ( 1 H-HRMAS-MRS). The neurobiological response was evaluated through prefrontal cortex mRNA expression and plasma corticosterone levels. The stressed rats were distributed into two subgroups according to their high (H-G/g) or low (L-G/g) GABA/glutamate ratio. Compared to the L-G/g rats, the H-G/g rats exhibited a decrease in c-fos, Arc, Npas4, Nr4a2 mRNA expression suggesting blunted prefrontal cortex activation. They also showed a more pronounced stress with an enhanced rise in corticosterone, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), creatine kinase (CK) and lactate dehydrogenase (LDH) levels, as well as behavioral disturbances with decreased locomotion speed. These changes were independent from prefrontal cortex energetic status as mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathway activities were similar in both subpopulations. The differences in GABA/glutamate ratio in the frontal cortex observed in the stressed animals may participate in shaping individual differences in psychophysiological reactions.

In human African trypanosomiasis (sleeping sickness), sleep and wake episodes are sporadically distributed throughout the day and the night. To determine whether these sleep disturbances affect the 24-h hormone profiles and the normal relationships between hormone pulsatility and sleep stages, poly-graphic sleep recordings and concomitant hormone profiles were obtained in 6 African patients with sleeping sickness and in 5 healthy African subjects selected from Abidjan on the Ivory Coast. Polysomnographic recordings were continuous, and blood was taken every 10 min throughout the 24-h period. Plasma was analyzed for cortisol, prolactin, and plasma renin activity (PRA). The 24-h rhythm of cortisol, considered to be an endogenous circadian rhythm, was attenuated in all of the patients except one. However, as in normal subjects, slow wave sleep (SWS) remained associated with the declining phases of the cortisol secretory episodes. Prolactin and PRA profiles, which are strongly influenced by the sleep-wake cycle, did not manifest the nocturnal increase normally associated with the sleep period; instead, they reflected a sporadic distribution of the sleep and wake episodes throughout the 24-h period. In patients with sleeping sickness as in normal subjects, rapid eye movement (REM) sleep began during the descending phases of prolactin pulses. In both groups, PRA reflected the sleep stage distribution with non REM (NREM) sleep occurring during the ascending phases and REM sleep during the descending phases of the PRA oscillations. However, in sleeping sickness patients, the marked sleep fragmentation often did not allow sufficient time for PRA to increase significantly, as is normally the case in subjects 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-h hormone profiles in humans with African trypanosomiasis. However, the relationship between hormonal pulses and specific sleep stages persists, indicating the existence of a robust link between hormonal release and the internal sleep structure.

Electroencephalographic (EEG) and polygraphic features were analysed in six healthy control subjects and eight patients suffering from sleeping sickness meningoencephalitis in order to determine possible functional relationships. One patient was disqualified because of intermittent metabolic disease. Twenty-four h polygraphic recordings-EEG, electrooculography (EOG), electromyography (EMG), nasal and buccal air flow, chest respiratory movements-were performed continuously both on paper and on cassette tapes. Tapes were played back on paper (paper speed: 15 mm/s). Traces were analyzed for normal and pathologic features, and transient activation phases and paroxysmal hypnopompic hypersynchrony events were counted. During wakefulness, slow theta and delta waves occurred in four patients, but alpha reactivity was present. During sleep, normal features were seen. However, transient activation phases were decreased in the patients. During slow-wave sleep, four patients presented predominantly monophasic frontal delta bursts along with paroxysmal hypnopompic hypersynchrony events. In conclusion, in sleeping sickness patients, although dampened, the waking process remains responsive and slows down only during the late stage of meningoencephalitis.