Search

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.

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.

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.

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).

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.

Introduction Le prix Nobel de physiologie et medecine a ete attribue a Hall, Rosbach et Young pour leurs travaux sur les mecanismes moleculaires du controle des rythmes circadiens par l’horloge biologique interne, chez la drosophile. Objectifs L’horloge principale de l’homme, portee par les noyaux suprachiasmatiques, regle les rythmes circadiens corporels. Ils sont alteres par certaines situations comme le decalage horaire, que nous abordons ici. Methodes Apres un vol transmeridien vers l’ouest (Paris-Martinique, decalage horaire 5 h) le cycle veille-sommeil (sommeil autorise de 22 h 30–06 h 30) a ete analyse par actimetrie de poignet (Actigraph monitor, Cambridge, Royaume-Uni) chez 24 volontaires (10 hommes, 14 femmes, 51,2 ± 2,2 ans) pendant 3 nycthemeres en Metropole et 2 × 3 nycthemeres en Martinique (M1 : J1–J3 ; M2 : J4–J6). L’ajustement au nouveau lieu de sejour a ete etudie sous placebo vs zopiclone (7,5 mg les deux premiers soirs, 12 sujets). Resultats Sous placebo, la duree du sommeil est plus courte apres le decalage horaire au cours de J1–J3. La zopiclone augmente la duree du sommeil au cours de J1–J3 sans effets residuels negatifs sur le niveau de vigilance. L’acrophase du rythme activite-repos et du rythme de la temperature rectale (Tre) se resynchronisent plus vite (en M1) que sous placebo (en M2). Les relations de phase entre ces deux rythmes se normalisent aussi plus rapidement. Discussion La desynchronisation entre l’horloge interne et les indicateurs temporels du nouvel environnement est responsable des troubles du sommeil pendant les 3 premiers jours qui suivent un decalage horaire. La prise de zopiclone permet de contrecarrer ces effets et accelere l’ajustement des rythmes biologiques au nouvel environnement. Conclusion La desynchronisation de l’horloge interne induit des troubles des rythmes circadiens (du sommeil, de Tre, de l’activite) qui sont longs a se normaliser. L’induction du sommeil peut accelerer leur reajustement. Informations complementaires Presentation dans le cadre de la session du Club de neurologie de l’environnement.

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.

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.

Behavioural consequences of different acute stressors (30 min of restraint, 20 min of forced swim stress, 15 min of inescapable footshocks) applied at the beginning of the active period were assessed in using two behavioural tests: a 20 min light extinction test 24 h after the stressor exposure in order to explore the psychomotor ability and a 10 min open field session within the dark period 48 h after the stressor exposure to estimate the emotional status and the locomotor activity of the rat. Different behavioural responses were observed depending on the nature of the applied stressor. In the light extinction test, the footshock-stressed rats developed a very low activity independent on light conditions whereas the rats submitted to forced swim and restraint exhibited an activity level depending on the strain. Moreover, restrained rats had a higher transient activity than forced swim rats under light condition. In the open field test, none of the stressed rats did develop differences in behaviour. The efficacy of a 24 h recovery period on the behavioural response to an acute stressor exposure depends on the intensity of the applied stressor and the behavioural demands.

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).

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

Nitric oxide (NO) is an important effector molecule of the immune system in eliminating numerous pathogens. Peritoneal macrophages fromTrypanosoma brucei brucei-infected mice express type II NO synthase (NOS-II), produce NO, and kill parasites in the presence ofl-arginine in vitro. Nevertheless, parasites proliferate in the vicinity of these macrophages in vivo. The present study shows thatl-arginine availability modulates NO production. Trypanosomes usel-arginine for polyamine synthesis, required for DNA and trypanothione synthesis. Moreover, arginase activity is up-regulated in macrophages from infected mice from the first days of infection. Arginase competes with NOS-II for their common substrate,l-arginine. In vitro, arginase inhibitors decreased urea production, increased macrophage nitrite production, and restored trypanosome killing. In vivo, a dramatic decrease inl-arginine concentration was observed in plasma from infected mice. In situ restoration of NO production and trypanosome killing were observed when excessl-arginine, but notd-arginine orl-arginine plusNω-nitro-l-arginine (a NOS inhibitor), was injected into the peritoneum of infected mice. These data indicate the role ofl-arginine depletion, induced by arginase and parasites, in modulating thel-arginine–NO pathway under pathophysiological conditions.

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 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.