Chronic Toxoplasma gondii infection and sleep-wake alterations in mice.

AIM: Toxoplasma gondii (Tg) is an intracellular parasite infecting more than a third of the human population. Yet, the impact of Tg infection on sleep, a highly sensitive index of brain functions, remains unknown. We designed an experimental mouse model of chronic Tg infection to assess the effects on sleep-wake states. METHODS: Mice were infected using cysts of the type II Prugniaud strain. We performed chronic sleep-wake recordings and monitoring as well as EEG power spectral density analysis in order to assess the quantitative and qualitative changes of sleep-wake states. Pharmacological approach was combined to evaluate the direct impact of the infection and inflammation caused by Tg. RESULTS: Infected mouse exhibited chronic sleep-wake alterations over months, characterized by a marked increase (>20%) in time spent awake and in cortical EEG θ power density of all sleep-wake states. Meanwhile, slow-wave sleep decreased significantly. These effects were alleviated by an anti-inflammatory treatment using corticosteroid dexamethasone. CONCLUSION: We demonstrated for the first time the direct consequences of Tg infection on sleep-wake states. The persistently increased wakefulness and reduced sleep fit with the parasite's strategy to enhance dissemination through host predation and are of significance in understanding the neurodegenerative and neuropsychiatric disorders reported in infected patients.

Paradoxical anesthesia: Sleep-like EEG during anesthesia induced by mesopontine microinjection of GABAergic agents.

General anesthetic agents are thought to induce loss-of-consciousness (LOC) and enable pain-free surgery by acting on the endogenous brain circuitry responsible for sleep-wake cycling. In clinical use, the entire CNS is exposed to anesthetic molecules with LOC and amnesia usually attributed to synaptic suppression in the cerebral cortex and immobility and analgesia to agent action in the spinal cord and brainstem. This model of patch-wise suppression has been challenged, however, by the observation that all functional components of anesthesia can be induced by focal delivery of minute quantities of GABAergic agonists to the brainstem mesopontine tegmental anesthesia area (MPTA). We compared spectral features of the cortical electroencephalogram (EEG) in rats during systemic anesthesia and anesthesia induced by MPTA microinjection. Systemic administration of (GABAergic) pentobarbital yielded the sustained, δ-band dominant EEG signature familiar in clinical anesthesia. In contrast, anesthesia induced by MPTA microinjection (pentobarbital or muscimol) featured epochs of δ-band EEG alternating with the wake-like EEG, the pattern typical of natural non-rapid-eye-movement (NREM) and REM sleep. The rats were not sleeping, however, as they remained immobile, atonic and unresponsive to noxious pinch. Recalling the paradoxical wake-like quality the EEG during REM sleep, we refer to this state as "paradoxical anesthesia". GABAergic anesthetics appear to co-opt both cortical and spinal components of the sleep network via dedicated axonal pathways driven by MPTA neurons. Direct drug exposure of cortical and spinal neurons is not necessary, and is probably responsible for off-target side-effects of systemic administration including monotonous δ-band EEG, hypothermia and respiratory depression. SIGNIFICANCE STATEMENT: The concept that GABAergic general anesthetic agents induce loss-of-consciousness by substituting for an endogenous neurotransmitter, thereby co-opting neural circuitry responsible for sleep-wake transitions, has gained considerable traction. However, the electroencephalographic (EEG) signatures of sleep and anesthesia differ fundamentally. We show that when the anesthetic state is generated by focal delivery of GABAergics into the mesopontine tegmental anesthesia area (MPTA) the resulting EEG repeatedly transitions between delta-wave-dominant and wake-like patterns much as in REM-NREM sleep. This suggests that systemic (clinical) anesthetic delivery, which indiscriminately floods the entire cerebrum with powerful inhibitory agents, obscures the sleep-like EEG signature associated with the less adulterated form of anesthesia obtained when the drugs are applied selectively to loci where the effective neurotransmitter substitution actually occurs.

Melatonin ameliorates the sleep disorder induced by surgery under sevoflurane anaesthesia in aged mice.

Post-operative sleep disorders induce adverse effects on patients, especially the elderly, which may be associated with surgery and inhalational anaesthetics. Melatonin is a neuroendocrine regulator of the sleep-wake cycle. In this study, we analysed the alterations of post-operative sleep in aged melatonin-deficient (C57BL/6J) mice, and investigated if exogenous melatonin could facilitate entrainment of circadian rhythm after laparotomy under sevoflurane anaesthesia. The results showed that laparotomy under sevoflurane anaesthesia had a greater influence on post-operative sleep than sevoflurane alone. Laparotomy under anaesthesia led to circadian rhythm shifting forward, altered EEG power density and delta power of NREM sleep, and lengthened REM and NREM sleep latencies. In the light phase, the number of waking episodes tended to decline, and wake episode duration elevated. However, these indicators presented the opposite tendency during the dark phase. Melatonin showed significant efficacy for ameliorating the sleep disorder and restoring physiological sleep, and most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist.

The retinoid X receptor: a nuclear receptor that modulates the sleep-wake cycle in rats.

RATIONALE: The nuclear receptor retinoid X receptor (RXR) belongs to a nuclear receptor superfamily that modulates diverse functions via homodimerization with itself or several other nuclear receptors, including PPARα. While the activation of PPARα by natural or synthetic agonists regulates the sleep-wake cycle, the role of RXR in the sleep modulation is unknown. OBJECTIVES: We investigated the effects of bexarotene (Bexa, a RXR agonist) or UVI 3003 (UVI, a RXR antagonist) on sleep, sleep homeostasis, levels of neurochemical related to sleep modulation, and c-Fos and NeuN expression. METHODS: The sleep-wake cycle and sleep homeostasis were analyzed after application of Bexa or UVI. Moreover, we also evaluated whether Bexa or UVI could induce effects on dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine contents, collected from either the nucleus accumbens or basal forebrain. In addition, c-Fos and NeuN expression in the hypothalamus was determined after Bexa or UVI treatments. RESULTS: Systemic application of Bexa (1 mM, i.p.) attenuated slow-wave sleep and rapid eye movement sleep. In addition, Bexa increased the levels of dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine sampled from either the nucleus accumbens or basal forebrain. Moreover, Bexa blocked the sleep rebound period after total sleep deprivation, increased in the hypothalamus the expression of c-Fos, and decreased NeuN activity. Remarkably, UVI 3003 (1 mM, i.p.) induced opposite effects in sleep, sleep homeostasis, neurochemicals levels, and c-Fos and NeuN activity. CONCLUSIONS: The administration of RXR agonist or antagonist significantly impaired the sleep-wake cycle and exerted effects on the levels of neurochemicals related to sleep modulation. Moreover, Bexa or UVI administration significantly affected c-Fos and NeuN expression in the hypothalamus. Our findings highlight the neurobiological role of RXR on sleep modulation.

Inactivation of the Ventral Pallidum by GABAA Receptor Agonist Promotes Non-rapid Eye Movement Sleep in Rats.

GABA, the most abundant inhibitory neurotransmitter in the brain, is closely linked with sleep and wakefulness. As the largest area input to the ventral pallidum (VP), the nucleus accumbens (NAc) has been confirmed to play a pivotal role in promoting non-rapid eye movement (NREM) sleep through inhibitory projections from NAc adenosine A2A receptor-expressing neurons to VP GABAergic neurons which mostly express GABAA receptors. Although these studies demonstrate the possible role of VP GABAergic neurons in sleep-wake regulation, whether and how its modulate sleep-wake cycle is not completely clear. In our study, pharmacological manipulations were implemented in freely moving rats and then the EEG and the EMG were recorded to monitor the sleep-wake states. We found that microinjection of muscimol, a GABAA receptor agonist, into the VP increased NREM sleep in both light and dark period. Microinjection of bicuculline, a GABAA receptor antagonist, into the VP increased wakefulness in the light period. Collectively, our data identify the important role of VP GABAA receptor-expressing neurons in NREM sleep of rats which may help improve the understanding of the pathological sleep disorders.

Opioid use, pain intensity, age, and sleep architecture in patients with fibromyalgia and insomnia.

Opioid use and sleep disruption are prevalent in fibromyalgia. Yet, the effects of opioids on physiological sleep in fibromyalgia are unclear. This study assessed associations between opioid use/dosage and polysomnographically assessed sleep in patients with fibromyalgia and insomnia (FMI) and examined moderating effects of age and pain. Participants (N = 193, Mage = 51.7, SD = 11.8, range = 18-77) with FMI completed ambulatory polysomnography and 14 daily diaries. Multiple regression determined whether commonly prescribed oral opioid use or dosage (among users) independently predicted or interacted with age/pain intensity to predict sleep, controlling for sleep medication use and apnea hypopnea index. Opioid use predicted greater %stage 2 and lower %slow-wave sleep (%SWS). Opioid use interacted with age to predict greater sleep onset latency (SOL) in middle-aged/older adults. Among opioid users (n = 65, ∼3 years usage), opioid dose (measured in lowest recommended dosage) interacted with age to predict SOL and sleep efficiency; specifically, higher dosage predicted longer SOL and lower sleep efficiency for older, but not middle-aged/younger adults. Opioid dose interacted with pain to predict %SWS and arousal index. Specifically, higher dosage predicted reduced %SWS and higher arousal index for individuals with lower pain, increased %SWS for individuals with higher pain, and did not predict %SWS for patients with average pain. Opioid use/dosage did not predict wake after sleep onset, total sleep time, %stage 1 or %rapid eye movement sleep. Opioid use prompts changes in sleep architecture among individuals with FMI, increasing lighter sleep and reducing SWS. Sleep disruption is exacerbated at higher opioid doses in older adults and patients with low pain.

Disruption of sleep, sleep-wake activity rhythm, and nocturnal melatonin production in breast cancer patients undergoing adjuvant chemotherapy: prospective cohort study.

OBJECTIVE: This prospective cohort study captured the patterns of sleep, sleep-wake activity rhythm, and first-morning urinary melatonin in breast cancer patients undergoing adjuvant chemotherapy. METHODS: Breast cancer patients undergoing adjuvant chemotherapy wore wrist actigraph for 168 h and collected first-morning void urine samples before treatment, during the first, and at the last cycle of chemotherapy. We converted actigraphy data into sleep duration, sleep efficiency, nighttime total wake time, percent rhythm, F-statistic, amplitude, mesor, and acrophase. We then assessed urinary 6-sulfatoxymelatonin (aMT6s) levels. RESULTS: This cohort contained 180 participants. Compared with the baseline, sleep efficiency during the first and last cycle decreased by 10.16% [95% confidence interval (95% CI): 5.85%, 14.47%] and 5.01% (95% CI: 0.50%, 9.53%), respectively. Similarly, percent rhythm decreased by 27.20% (95% CI: 19.95%, 34.45%) during the first cycle and 21.20% (95% CI: 13.52, 28.89) during the last cycle. Taking the baseline as the reference, aMT6s levels during the first and last cycle decreased by 11.27% (95% CI: 0.37%, 22.16%) and 14.74% (95% CI: 2.34, 27.11), respectively. CONCLUSION: The first administration of adjuvant chemotherapy is associated with sleep disturbance and sleep-wake activity rhythm disruption among breast cancer patients, while the disturbance and disruption during the last cycle are less severe; nevertheless, repeated administration of chemotherapy results in progressive impairment of nocturnal melatonin production.

Sleep architecture is altered in the reserpine-induced fibromyalgia model in ovariectomized rats.

Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome with various concomitant symptoms like sleep disorders. FM patients are mainly women and menopause might play an important role in the altered processing of somatosensory information. Adverse effects and moderated efficacy of drugs promote treatment discontinuation by patients. Animal models of FM report pain and depression-like behaviors, but none of them have explored sleep disturbance as possible marker in the preclinic diagnostic. The aim of this study was to investigate alterations of the sleep architecture in the reserpine (RES)-induced FM model in ovarectomized (OVX) rats. The behavioral thresholds of nociceptive response in the experimental FM were analyzed in a first block using muscle pressure, tactile response and allodynia to cold stimulus. In a second block, the sleep-wake cycle was examined in a polysomnographic study. Groups (n = 8) consisted in: (a) no treatment, (b) RES vehicle, (c) RES alone, (d) RES + vehicle of fluoxetine (FLX, antidepressant reference drug), and (e) RES + FLX. Our results demonstrated that RES induced pain-related behavior (50-70%) in OVX rats and altered sleep architecture by the increase of total wake time (38%), diminution of the no-REM stage (SWS-I 33% and SWS-II 76%), and abolition of the REM sleep, effects that were partially reverted in the presence of FLX. In conclusion, our results support the face validity of the RES-induced pain-related behavior as FM model showing nociceptive behavioral responses associated to sleep alterations observed as symptoms in FM patients; thus, these evidences substantiate its usefulness to look for alternatives of treatment for FM symptoms.

Nicotine increases sleep spindle activity.

Studies have shown that both nicotine and sleep spindles are associated with enhanced memorisation. Further, a few recent studies have shown how cholinergic input through nicotinic and muscarinic receptors can trigger or modulate sleep processes in general, and sleep spindles in particular. To better understand the interaction between nicotine and sleep spindles, we compared in a single blind randomised study the characteristics of sleep spindles in 10 healthy participants recorded for 2 nights, one with a nicotine patch and one with a sham patch. We investigated differences in sleep spindle duration, amplitude, intra-spindle oscillation frequency and density (i.e. spindles per min). We found that under nicotine, spindles are more numerous (average increase: 0.057 spindles per min; 95% confidence interval: [0.025-0.089]; p = .0004), have higher amplitude (average amplification: 0.260 µV; confidence interval: [0.119-0.402]; p = .0032) and last longer (average lengthening: 0.025 s; confidence interval: [0.017-0.032]; p = 2.7e-11). These results suggest that nicotine can increase spindle activity by acting on nicotinic acetylcholine receptors, and offer an attractive hypothesis for common mechanisms that may support memorisation improvements previously reported to be associated with nicotine and sleep spindles.

Effect of remifentanil during drug-induced sleep endoscopy in patients with obstructive sleep apnea.

PURPOSE: During drug-induced sleep endoscopy (DISE) in patients with obstructive sleep apnea, the increased depth of propofol anesthesia is related to the increased collapsibility of the upper airway with dose-dependent. We examined the effect of remifentanil on propofol concentration during DISE. METHODS: In a prospective randomized trial, 56 adult patients were divided into remifentanil-propofol (n = 28) and propofol alone (n = 28) groups. Anesthesia was administered using a target-controlled infusion system. In the remifentanil-propofol group, 0.5 ng/ml remifentanil was administered prior to propofol infusion and its concentration maintained; thereafter, in the propofol alone group, normal saline was injected instead of remifentanil. Propofol was infused at a concentration of 1.5 µg/ml after the target concentration of remifentanil was reached. In both groups, the concentration of propofol was increased by 0.5 µg/ml if the degree of sedation was not sufficient. The sedation level was targeted at observer's assessment of alertness/sedation (OAA/S) scale 3. RESULTS: The mean propofol concentration was 2.87 ± 0.60 µg/ml in the remifentanil-propofol group, which was lower than that in the propofol alone group (3.38 ± 0.72 µg/ml, P < 0.001). The time until sufficient sedation to perform DISE was shorter in the remifentanil-propofol group (P < 0.001). Apnea-hypopnea index and the lowest peripheral capillary oxygen saturation (SpO2) during polysomnography showed no statistical difference between groups (P > 0.05). The lowest SpO2 and VOTE classification during DISE were also not statistically different (P > 0.05). CONCLUSIONS: Use of remifentanil during DISE reduces the target concentration of propofol required for patient sedation to perform DISE without respiratory depression.

Triphlorethol A, a Dietary Polyphenol from Seaweed, Decreases Sleep Latency and Increases Non-Rapid Eye Movement Sleep in Mice.

In our previous studies, we have demonstrated that marine polyphenol phlorotannins promote sleep through the benzodiazepine site of the gamma-aminobutyric acid type A (GABAA) receptors. In this follow-up study, the sleep-promoting effects of triphlorethol A, one of the major phlorotannin constituents, were investigated. The effect of triphlorethol A on sleep-wake architecture and profiles was evaluated based on electroencephalogram and electromyogram data from C57BL/6N mice and compared with the well-known hypnotic drug zolpidem. Oral administration of triphlorethol A (5, 10, 25, and 50 mg/kg) dose-dependently decreased sleep latency and increased sleep duration during pentobarbital-induced sleep in imprinting control region mice. Triphlorethol A (50 mg/kg) significantly decreased sleep latency and increased the amount of non-rapid eye movement sleep (NREMS) in C57BL/6N mice, without affecting rapid eye movement sleep (REMS). There was no significant difference between the effects of triphlorethol A at 50 mg/kg and zolpidem at 10 mg/kg. Triphlorethol A had no effect on delta activity (0.5⁻4 Hz) of NREMS, whereas zolpidem significantly decreased it. These results not only support the sleep-promoting effects of marine polyphenol phlorotannins, but also suggest that the marine polyphenol compound triphlorethol A is a promising structure for developing novel sedative hypnotics.

Limited Efficacy of Caffeine and Recovery Costs During and Following 5 Days of Chronic Sleep Restriction.

Objectives: To investigate the effects of caffeine on psychomotor vigilance and sleepiness during sleep restriction and following subsequent recovery sleep. Methods: Participants were N = 48 healthy good sleepers. All participants underwent five nights of sleep satiation (time-in-bed [TIB]: 10 hours), followed by five nights of sleep restriction (TIB: 5 hours), and three nights of recovery sleep (TIB: 8 hours) in a sleep laboratory. Caffeine (200 mg) or placebo was administered in the form of chewing gum at 08:00 am and 12:00 pm each day during the sleep restriction phase. Participants completed hourly 10-minute psychomotor vigilance tests and a modified Maintenance of Wakefulness Test approximately every 4 hours during the sleep restriction and recovery phases. Results: Caffeine maintained objective alertness compared to placebo across the first 3 days of sleep restriction, but this effect was no longer evident by the fourth day. A similar pattern of results was found for Maintenance of Wakefulness Test sleep latencies, such that those in the caffeine group (compared to placebo) did not show maintenance of wakefulness relative to baseline after the second night of restriction. Compared to placebo, participants in the caffeine condition displayed slower return to baseline in alertness and wakefulness across the recovery sleep period. Finally, the caffeine group showed greater N3 sleep duration during recovery. Conclusions: Caffeine appears to have limited efficacy for maintaining alertness and wakefulness across 5 days of sleep restriction. Perhaps more importantly, there may be recovery costs associated with caffeine use following conditions of prolonged sleep loss.

Theacrine: A purine alkaloid from Camellia assamica var. kucha with a hypnotic property via the adenosine system.

Theacrine (l,3,7,9-tetramethyluric acid), a purine alkaloid from Camellia assamica var. kucha, has diverse pharmacological properties, including sedative and hypnotic activities, anti-inflammatory and analgesic activities, antidepressant effects, and a protective effect against stress-provoked liver damage. The present study aims to investigate the possible mechanism of the hypnotic activity of theacrine. The results revealed that theacrine significantly enhanced pentobarbital-induced sleep at a dose of 3.0mg/kg (i.g.) in mice. Sleep parameter analysis by EEG and EMG showed that theacrine obviously shortened wake time and increased NREM sleep time and that theacrine almost had no effect on REM sleep. Meanwhile, theacrine markedly attenuated caffeine (a nonselective antagonist of adenosine receptor)-induced insomnia. In pretreatment with the adenosine A1 receptor antagonist DPCPX and the A2A receptor antagonist SCH 58261, theacrine significantly reversed the decrease in sleeping time in pentobarbital-treated mice. In addition, theacrine also markedly increased the adenosine content in the hippocampus of rats. These results suggested that theacrine might mediate the adenosine system to augment pentobarbital-induced sleep.

Lesion of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption.

Alcohol has a profound effect on sleep. However, neuronal substrates mediating sleep-promoting effects of alcohol are unknown. Since the basal forebrain (BF) cholinergic neurons are implicated in the homeostatic regulation of sleep, we hypothesized that the BF cholinergic neurons may have an important role in sleepiness observed after alcohol consumption. 192-IgG-saporin (bilateral BF infusions) was used to selectively lesion BF cholinergic neurons in adult male Sprague-Dawley rats. Standard surgical procedures were used to implant sleep recording electrodes or microdialysis guide cannulas. The first experiment used between-group design [lesion and sham (controls)] and examined effects of BF cholinergic neuronal lesions on alcohol (3 g/Kg; ig) induced sleep promotion. The second experiment used within-group design [lesion (ipsilateral BF) and sham (controls; contralateral BF) in same animal] and local reverse microdialysis infusion of alcohol (300 mM) to examine the effects of cholinergic neuronal lesions on extracellular adenosine in the BF. Alcohol had a robust sleep promoting effect in controls as evidenced by a significant reduction in sleep onset latency and wakefulness; non-rapid eye movement sleep was significantly increased. No such alcohol-induced sleep promotion was observed in lesioned rats with significantly fewer BF cholinergic neurons. Rapid eye movement sleep was minimally affected. Adenosine release was significantly reduced following local infusion of alcohol on the lesion side, with significantly fewer cholinergic neurons as compared with the control side. Based on these results, we suggest that alcohol promotes sleep by increasing extracellular adenosine via its action on cholinergic neurons of the BF. Read the Editorial Highlight for this article on page 620.

Coffee, caffeine, and sleep: A systematic review of epidemiological studies and randomized controlled trials.

Caffeine is the most widely consumed psychoactive substance in the world. It is readily available in coffee and other foods and beverages, and is used to mitigate sleepiness, enhance performance, and treat apnea in premature infants. This review systematically explores evidence from epidemiological studies and randomized controlled trials as to whether coffee and caffeine have deleterious effects on sleep. Caffeine typically prolonged sleep latency, reduced total sleep time and sleep efficiency, and worsened perceived sleep quality. Slow-wave sleep and electroencephalographic (EEG) slow-wave activity were typically reduced, whereas stage-1, wakefulness, and arousals were increased. Dose- and timing-response relationships were established. The sleep of older adults may be more sensitive to caffeine compared to younger adults. Pronounced individual differences are also present in young people, and genetic studies isolated functional polymorphisms of genes implicated in adenosine neurotransmission and metabolism contributing to individual sensitivity to sleep disruption by caffeine. Most studies were conducted in male adults of Western countries, which limits the generalizability of the findings. Given the importance of good sleep for general health and functioning, longitudinal investigations aimed at establishing possible causal relationships among coffee- and caffeine-induced changes in sleep quality and health development are warranted.

Dexamethasone for Dyspnea in Cancer Patients: A Pilot Double-Blind, Randomized, Controlled Trial.

CONTEXT: Dexamethasone is often used to treat dyspnea in cancer patients, but evidence is lacking. OBJECTIVES: We determined the feasibility of conducting a randomized trial of dexamethasone in cancer patients and estimated the efficacy of dexamethasone in the treatment of dyspnea. METHODS: In this double-blind, randomized, controlled trial, patients with dyspnea ≥4 were randomized to receive either dexamethasone 8 mg twice daily × four days then 4 mg twice daily × three days or placebo for seven days, followed by an open-label phase for seven days. We documented the changes in dyspnea (0-10 numeric rating scale), spirometry measures, quality of life, and toxicities. RESULTS: A total of 41 patients were randomized and 35 (85%) completed the blinded phase. Dexamethasone was associated with a significant reduction in dyspnea numeric rating scale of -1.9 (95% CI -3.3 to -0.5, P = 0.01) by Day 4 and -1.8 (95% CI -3.2 to -0.3, P = 0.02) by Day 7. In contrast, placebo was associated with a reduction of -0.7 (95% CI -2.1 to 0.6, P = 0.38) by Day 4 and -1.3 (95% CI -2.4 to -0.2, P = 0.03) by Day 7. The between-arm difference was not statistically significant. Drowsiness improved with dexamethasone. Dexamethasone was well tolerated with no significant toxicities. CONCLUSION: A double-blind, randomized, controlled trial of dexamethasone was feasible with a low attrition rate. Our preliminary data suggest that dexamethasone may be associated with rapid improvement in dyspnea and was well tolerated. Further studies are needed to confirm our findings. TRIAL REGISTRATION: ClinicalTrials.govNCT01670097.

Thalidomide treatment in cutaneous lesions of systemic lupus erythematosus: a multicenter study in China.

Thalidomide is effective for treating severe cutaneous lupus patients. The aim of this study was to observe the optimum effective and maintenance doses of thalidomide to maximize clinical benefit and minimize side effects for patients with cutaneous lupus in China. Sixty-nine patients with lupus rash from eight hospitals in China were enrolled and treated with different doses of thalidomide. We started the dose of thalidomide at 25 mg daily and gradually increased administration dose once a week until erythema was markedly improved. The effective and maintenance doses were documented. The size of skin lesions was noted once a week. Systemic lupus erythematosus disease activity index (SLEDAI) score, levels of erythrocyte sedimentation rate (ESR), and serum TNF-α were measured before and after treatment. The remission rates were evaluated weekly until 8 weeks. Sixty-eight percent of patients showed an effective dose of 50 mg daily; another 13, 10, and 9 % of patients had an effective dose of 100, 75, and 25 mg daily, respectively. The maintenance dose was 50 mg daily for 71 % of the patients, and 100, 75, and 25 mg daily for 9, 14, and 6 % of the patients. SLEDAI score and serum ESR levels significantly decreased 4 weeks after thalidomide treatment. At the end of the fourth week, the rates of complete remission, partial remission, and no response were 56 % (n = 39), 41 % (n = 28), and 3 % (n = 2). At the eighth week, the rate of total remission rose up to 100 %. The most common side effects were drowsiness and constipation. No peripheral neuropathy was observed in these patients. Thalidomide at a dose of 50 mg daily may offer a better benefit to risk ratio in the treatment of Chinese cutaneous lupus patients.

Ketamine and propofol have opposite effects on postanesthetic sleep architecture in rats: relevance to the endogenous sleep-wakefulness substances orexin and melanin-concentrating hormone.

BACKGROUND: Anesthesia and surgery disturb sleep. Disturbed sleep adversely affects postoperative complications involving the cardiovascular system, diabetes, and infection. General anesthetics share neuronal mechanisms involving endogenous sleep-wakefulness-related substances, such as orexin (OX) and melanin-concentrating hormone (MCH). We evaluated changes in sleep architecture and the concentration of OX and MCH during the peri-anesthetic period. METHODS: To examine sleep architecture, male Sprague-Dawley rats weighing 350-450 g received ketamine 100 mg/kg (n = 9) or propofol 80 mg/kg (n = 6) by intraperitoneal injection. Electroencephalography was recorded from 2 days pre- to 5 days postanesthesia. To quantify levels of OX and MCH, 144 similar rats received the same doses of ketamine (n = 80) or propofol (n = 64). Brain concentrations of these substances were determined at 0, 20, 60, and 120 min after anesthetic administration. RESULTS: Ketamine decreased OX content in the hypothalamus during the anesthesia period. OX content was restored to pre-anesthesia levels in the hypothalamus and pons. Both anesthetics increased brain MCH content in the postanesthetic period, with the degree of increase being greater with propofol. Ketamine enhanced wakefulness and inhibited non-rapid eye movement sleep (NREMS) immediately after anesthesia. Conversely, propofol inhibited wakefulness and enhanced NREMS in that period. Ketamine inhibited wakefulness and enhanced NREMS during the dark phase on the first postanesthesia day. CONCLUSIONS: Anesthetics affect various endogenous sleep-wakefulness-related substances; however, the modulation pattern may depend on the type of anesthetic. The process of postanesthetic sleep disturbance was agent specific. Our results provide fundamental evidence to treat anesthetic-related sleep disturbance.

Effects of Dexamethasone and Placebo on Symptom Clusters in Advanced Cancer Patients: A Preliminary Report.

OBJECTIVE: Advanced cancer patients frequently experience debilitating symptoms that occur in clusters, but few pharmacological studies have targeted symptom clusters. Our objective was to examine the effects of dexamethasone on symptom clusters in patients with advanced cancer. METHODS: We reviewed the data from a previous randomized clinical trial to determine the effects of dexamethasone on cancer symptoms. Symptom clusters were identified according to baseline symptoms by using principal component analysis. Correlations and change in the severity of symptom clusters were analyzed after study treatment. RESULTS: A total of 114 participants were included in this study. Three clusters were identified: fatigue/anorexia-cachexia/depression (FAD), sleep/anxiety/drowsiness (SAD), and pain/dyspnea (PD). Changes in severity of FAD and PD significantly correlated over time (at baseline, day 8, and day 15). The FAD cluster was associated with significant improvement in severity at day 8 and day 15, whereas no significant change was observed with the SAD cluster or PD cluster after dexamethasone treatment. CONCLUSION: The results of this preliminary study suggest significant correlation over time and improvement in the FAD cluster at day 8 and day 15 after treatment with dexamethasone. These findings suggest that fatigue, anorexia-cachexia, and depression may share a common pathophysiologic basis. Further studies are needed to investigate this cluster and target anti-inflammatory therapies.

Protective effect of blue-light shield eyewear for adults against light pollution from self-luminous devices used at night.

We investigated sleep quality and melatonin in 12 adults who wore blue-light shield or control eyewear 2 hours before sleep while using a self-luminous portable device, and assessed visual quality for the two eyewear types. Overnight melatonin secretion was significantly higher after using the blue-light shield (P < 0.05) than with the control eyewear. Sleep efficacy and sleep latency were significantly superior for wearers of the blue-light shield (P < 0.05 for both), and this group reported greater sleepiness during portable device use compared to those using the control eyewear. Participants rated the blue-light shield as providing acceptable visual quality.