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Introduction: Kleine-Levin syndrome (KLS) is a rare and debilitating disorder presenting with periodic hypersomnolence, cognitive, psychiatric and behavioral disturbances. In the absence of biomarkers it can be difficult to diagnose. Rare LMOD3 variants in a family and in seven sporadic cases with KLS have been described. Here we report a patient and her family with an unclassified, familial, periodic central disorder of hypersomnolence (CDH) in whom the presence of a LMOD3 gene variant was assessed.Case Description: The female patient presented since early adulthood with recurrent episodes of hypersomnolence. Over more than 20 years of follow-up the diagnoses of idiopathic hypersomnia, KLS and hypersomnia associated with a psychiatric condition were made. The family history is positive for periodic hypersomnolence and psychiatric conditions. The patient, her symptomatic mother and her asymptomatic sister carried a Proline for Histidine substitution at codon 552 of the LMOD3-gene. This variant was previously reported in two sporadic KLS patients and its frequency in the general population is below 0.02%.Discussion: We report the association of periodic hypersomnia with a polymorphism of the LMOD3-gene in a patient with atypical KLS and a positive family history. Further research is needed to assess the pathological and predictive value of LMOD3 variants in KLS. [ABSTRACT FROM AUTHOR]

Low-temperature fracture toughness and fracture energy are two important measures that could be used to investigate the impacts of using asphalt modifiers on the performance of asphalt pavements in cold regions. The aim of this research was to identify the impacts of using various proportions of five different asphalt modifiers on the fracture toughness and the fracture energy of Hot Mix Asphalts (HMA) under mode I loading and at low environmental temperatures. The asphalt modifiers used for this purpose were: Elastoplastomer Polymer Strings (EPS), Parafiber, Sulfur Polymer, Polyolefin-Aramid Compound Structural Fibers (PACSF) and Sasobit. These modifiers were individually used at three different proportions to produce Semi-circular Bend Specimens containing vertical edge crack. Each specimen was then tested under symmetric monotonic three-point bend loading at - 15°C. The results indicated that, except for the EPS, both fracture toughness and fracture energy were increased with an increase in the modifier proportion. The highest increase in both measures was observed in the specimens modified with the PACSF, closely followed by specimens modified with the Parafibers. The least increase in these two measures was observed in the specimens modified with the Sulfur Polymer. The results indicated the applicability of examined modifiers to improve the resistance of HMA to crack initiation and crack growth at low temperatures. [ABSTRACT FROM AUTHOR]

The merits for development and application of crash frequency prediction models for safety promotion on any road type, with a focus on urban collector streets, are presented in this article. The city of Yazd, a medium-sized city in the middle of Iran, was selected as a case study and the data required for modelling crash frequencies along five collector streets comprising 31 street sections were collected. Six models including Poisson and negative binomial models and their deviations along with a hybrid artificial neural networks (ANN) model were developed to predict crash frequency along each street section. The overfitting problem was addressed using appropriate sensitivity analysis methods which were also used to identify the input variables with significant impact on the model performance. The results indicated that the developed hybrid ANN model provided the best performance in terms of accuracy and the number of input variables. The application of hybrid ANN model to evaluate the safety impacts of four different strategies, each resembled by one of the input variables of this model, indicated that these models can successfully be used for this purpose. [ABSTRACT FROM AUTHOR]

Sleep disorders are very prevalent and represent an emerging worldwide epidemic. However, research into the molecular genetics of sleep disorders remains surprisingly one of the least active fields. Nevertheless, rapid progress is being made in several prototypical disorders, leading recently to the identification of the molecular pathways underlying narcolepsy and familial advanced sleep-phase syndrome. Since the first reports of spontaneous and induced loss-of-function mutations leading to hypocretin deficiency in human and animal models of narcolepsy, the role of this novel neurotransmission pathway in sleep and several other behaviors has gained extensive interest. Also, very recent studies using an animal model of familial advanced sleep-phase syndrome shed new light on the regulation of circadian rhythms. [Copyright &y& Elsevier]

Abstract: Background and purpose: Investigation of Chinese–Taiwanese patients with excessive sleepiness, but no association with other sleep disorders, and with the presence or absence of cataplexy. Patients and methods: Thirty-five patients, successively referred between 2002 and 2004, underwent polysomnography (PSG), repeat multiple sleep latency test (MSLT), and human leukocyte antigen (HLA) typing. Three patients without cataplexy also had cerebrospinal fluid (CSF) hypocretin measurements. Results: DQB1*0602 was associated with cataplexy in over 90% of Chinese–Taiwanese cases. Absence of cataplexy and <2 sleep-onset REM periods (SOREMPs) was seen in only two subjects, but presence of two SOREMPs did not dissociate DQB1*0602 positive and negative or cataplexy positive and negative subjects. As a group, narcoleptics with cataplexy had a higher number of SOREMPs, and the mean sleep latency was much shorter in narcoleptics with cataplexy than in the non-cataplectic patients, independent of the number of SOREMPs. Conclusions: Chinese–Taiwanese patients with cataplexy present with similar HLA findings as Black and Caucasian patients, but the presence of two or more SOREMPs in Chinese–Taiwanese patients is not a sufficient diagnostic tool to identify narcolepsy. When cataplexy is not present, description of PSG nd HLA findings may be a better approach than using a label with little scientific significance, allowing for better collection of patients’ phenotype. [Copyright &y& Elsevier]

In rodents, the electroencephalogram (EEG) during paradoxical sleep and exploratory behavior is characterized by theta oscillations. Here we show that a deficiency in short-chain acyl-coenzyme A dehydrogenase (encoded by Acads) in mice causes a marked slowing in theta frequency during paradoxical sleep only. We found Acads expression in brain regions involved in theta generation, notably the hippocampus. Microarray analysis of gene expression in mice with mutations in Acads indicates overexpression of Glo1 (encoding glyoxylase 1), a gene involved in the detoxification of metabolic by-products. Administration of acetyl-L-carnitine (ALCAR) to mutant mice significantly recovers slow theta andGlo1 overexpression. Thus, an underappreciated metabolic pathway involving fatty acid β-oxidation also regulates theta oscillations during sleep. [ABSTRACT FROM AUTHOR]

Despite the very important role of primary arteries and transportation network in providing relief for regions affected by an earthquake and black spots, they have received less attention. Therefore, in the current study, at first, the status quo of the traffic black spots and safe regions was identified to predict the movement direction, evacuation of residents from their habitat and temporary residence using the region zoning. The trips were assigned to the network based on the trip distribution matrix and their relevant travel times both related to the crisis state. The results indicated that out of 94 traffic regions, located in the area under investigation, 7 regions were put in the very low risk or safe regions group and 10 traffic regions were put in a very high-risk group. Additionally, the results indicated that out of 794 links, located in the area under investigation, about 32 links will have a very undesirable status following an earthquake. [ABSTRACT FROM AUTHOR]

The article examines how much sleep is needed by individuals for optimal daytime performance and well-being. The amount of time people sleep, with no noticeable difference in health and waking performance, ranges from 6-9 hours. Topics include the genetic basis for long and short sleepers, an overview of research by He and colleagues providing evidence that a mutation in the transcription factor DEC2 is associated with short sleep in humans and mice, and the processes that control sleep and wakefulness, which are thought to be independent of each other. Also discussed is how He's team sequenced candidate genes in a family with members that slept for short durations, the physiological aspects of the mutation of DEC2, and physiological differences between long and short sleepers.

A letter to the editor in response to the article "Promotion of sleep by targeting the orexin system in rats, dogs and humans," by Francois Jenck, Catherine Brisbane-Roch, Michael Scherz, Susan Flores, Ralf Koberstein, Oliver Nayler, Jasper Dingermanse and Martine Clozel in a previous issue of "Nature Medicine" is presented.

Background: By identifying the geographical location for the crucial relief stations, it is possible to facilitate the accessibility of the medical services to the injured individuals in crisis situations. The main objective of this research is to study the possibility of combined application of the Analytical Hierarchy Process (AHP), ArcGIS and Transcad software to identify the factors which affect the vulnerability of infrastructure in a study region, to determine the relative importance of these factors in relation to each other, to identify the high risk regions, to identify appropriate health-care centers for relief purposes and to examine the capability of these centers for providing the services required in crisis conditions. Materials and Methods: This is a case study type of research, conducted in the central region of Isfahan, a large city located in the middle of Iran. The required data and information have been collected from the results of the "Population and Housing Census" comprising maps presenting the current status of Isfahan. They were then analyzed using Arc GIS and Transcad software and an AHP model developed by using the Expert Choice Software. Results: The obtained results revealed the possibility of successful application of the methodology proposed in this study. The results of this case study, conducted on 94 out of 186 traffic zones defined in the "Comprehensive Transportation Plan of Isfahan City," indicated that 10 zones, mainly located in the residential areas, are highly vulnerable to be exposed to the post-earthquake incidents. The results also showed that out of 19 medical centers located at the service area of the study region, which also contribute to the 80% of the medical services in Isfahan, four medical centers with the best accessibility in the shortest time, can provide services to these 10 zones. Conclusion: The results obtained from this case study indicated that the vulnerability of a traffic zone and its fatality rate in crisis events cannot be specified by only considering its physical conditions and other factors, e.g., population density and building density but also the lifetime of the buildings are also highly effective. In addition, due to the inappropriate positioning and being located in the narrow and vulnerable streets, some of the medical stations, such as Hojatieh Hospital and Amir-Al-Muminin Hospital, are vulnerable to postcrisis risk and there is a possibility of loss of access to these centers. [ABSTRACT FROM AUTHOR]

Sleep disorders commonly involve genetic susceptibility, environmental effects, and interactions between these factors. The heritability of sleep patterns has been shown in studies of monozygotic twins, and sleep electroencephalogram patterns offer a unique genetic fingerprint which may assist in the identification of genes involved in the regulation of sleep. Genetic factors are also thought to play a role in sleep disorders; narcolepsy is a disabling sleep condition and research has revealed the complexity of underlying genetic and environmental influences in the development of this disorder. An understanding of sleep regulation at the molecular level is essential in the identification of new targets for the treatment of sleep disorders, and genome-wide association studies for both normal sleep and sleep disorders may shed new light on the molecular architecture of mechanisms regulating these behaviours. [Copyright &y& Elsevier]

Employs microarray analysis to assess differential gene expression in the brain of short-chain acyl-coenzyme A dehydrogenase (Acads) mutant and wild-type mice. Involvement of the Acads gene in β-oxidation of short-chain fatty acids; Acads deficiency as molecular basis of slow theta oscillations; Indication that theta oscillations are affected only during sleep.

Rationale: Limited-channel portable monitors (PMs) are increasingly used as an alternative to polysomnography (PSG) for the diagnosis of obstructive sleep apnoea (OSA). However, recommendations for the scoring of PM recordings are still lacking. Pulse-wave amplitude (PWA) drops, considered as surrogates for EEG arousals, may increase the detection sensitivity for respiratory events in PM recordings.Objectives: To investigate the performance of four different hypopnoea scoring criteria, using 3% or 4% oxygen desaturation levels, including or not PWA drops as surrogates for EEG arousals, and to determine the impact of measured versus reported sleep time on OSA diagnosis.Methods: Subjects drawn from a population-based cohort underwent a complete home PSG. The PSG recordings were scored using the 2012 American Academy of Sleep Medicine criteria to determine the apnoea-hypopnoea index (AHI). Recordings were then rescored using only parameters available on type 3 PM devices according to different hypopnoea criteria and patients-reported sleep duration to determine the 'portable monitor AHIs' (PM-AHIs).Main Results: 312 subjects were included. Overall, PM-AHIs showed a good concordance with the PSG-based AHI although it tended to slightly underestimate it. The PM-AHI using 3% desaturation without PWA drops showed the best diagnostic accuracy for AHI thresholds of ≥ 5/h and ≥ 15/h (correctly classifying 94.55% and 93.27% of subjects, respectively, vs 80.13% and 87.50% with PWA drops). There was a significant but modest correlation between PWA drops and EEG arousals (r=0.20, p=0.0004).Conclusion: Interpretation of PM recordings using hypopnoea criteria which include 3% desaturation without PWA drops as EEG arousal surrogate showed the best diagnosis accuracy compared with full PSG. [ABSTRACT FROM AUTHOR]

Molecular and genetic approaches in several species have provided new insights into the mechanisms of rest-activity and sleep-wake regulation. Many of these discoveries are believed to support hypotheses about steep functions, which nevertheless remain elusive. In this review we discuss the specific contribution of both mammalian and invertebrate models to our understanding of the molecular basis of sleep. [ABSTRACT FROM AUTHOR]

Behavioural genetics is one of the most enticing fields in modern biology. Owing to straightforward and semiautomated techniques that can be used to measure locomotor activity, circadian rhythmicity is perhaps the best studied behaviour in animals. Thus, during the past decade, five essential circadian clock genes have been isolated in Drosophila, and homologous counterparts for all of these genes have also been found in mammals. As the sleep–wake cycle is under the control of the circadian clock, these circadian master genes are expected to influence sleeping behaviour. However, different vigilance states are regulated by additional mechanisms that also have a genetic basis. In this article we discuss molecular approaches that may prove useful in the search for sleep-related genes. [ABSTRACT FROM AUTHOR]

Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep-wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02. Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep-wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the 'narcoleptic borderland', including narcolepsy type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed. [ABSTRACT FROM AUTHOR]

Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans and in animal models. How these neuropeptides are produced and involved in diverse functions remain unknown. Here, we developed methods to sort and purify HCRT and MCH neurons from the mouse late embryonic hypothalamus. RNA sequencing revealed key factors of fate determination for HCRT (Peg3, Ahr1, Six6, Nr2f2, and Prrx1) and MCH (Lmx1, Gbx2, and Peg3) neurons. Loss of Peg3 in mice significantly reduces HCRT and MCH cell numbers, while knock-down of a Peg3 ortholog in zebrafish completely abolishes their expression, resulting in a 2-fold increase in sleep amount. We also found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in another orexigenic neuropeptide, QRFP, that might explain the metabolic syndrome in narcolepsy. The transcriptome results were used to develop protocols for the production of HCRT and MCH neurons from induced pluripotent stem cells and ascorbic acid was found necessary for HCRT and BMP7 for MCH cell differentiation. Our results provide a platform to understand the development and expression of HCRT and MCH and their multiple functions in health and disease. [ABSTRACT FROM AUTHOR]

Increased sleep time and intensity quantified as low-frequency brain electrical activity after sleep loss demonstrate that sleep need is homeostatically regulated, yet the underlying molecular mechanisms remain elusive. We here demonstrate that metabotropic glutamate receptors of subtype 5 (mGluR5) contribute to the molecular machinery governing sleep-wake homeostasis. Using positron emission tomography, magnetic resonance spectroscopy, and electroencephalography in humans, we find that increased mGluR5 availability after sleep loss tightly correlates with behavioral and electroencephalographic biomarkers of elevated sleep need. These changes are associated with altered cortical myo-inositol and glycine levels, suggesting sleep loss-induced modifications downstream of mGluR5 signaling. Knock-out mice without functional mGluR5 exhibit severe dysregulation of sleep-wake homeostasis, including lack of recovery sleep and impaired behavioral adjustment to a novel task after sleep deprivation. The data suggest that mGluR5 contribute to the brain's coping mechanisms with sleep deprivation and point to a novel target to improve disturbed wakefulness and sleep. [ABSTRACT FROM AUTHOR]

The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients. No mutations were found in healthy controls. Six of the eight narcolepsy-associated P2Y11 mutations resulted in significant functional deficits in P2Y11 signalling through both Ca2+ and cAMP signalling pathways. In conclusion, our data show that decreased P2Y11 signalling plays an important role in the development of narcolepsy with cataplexy. [ABSTRACT FROM AUTHOR]

Objective: Periodic limb movements during sleep (PLMS) are sleep phenomena characterized by periodic episodes of repetitive stereotyped limb movements. The aim of this study was to describe the prevalence and determinants of PLMS in a middle to older aged general population.Methods: Data from 2,162 subjects (51.2% women, mean age = 58.4 ± 11.1 years) participating in a population-based study (HypnoLaus, Lausanne, Switzerland) were collected. Assessments included laboratory tests, sociodemographic data, personal and treatment history, and full polysomnography at home. PLMS index (PLMSI) was determined, and PLMSI > 15/h was considered as significant.Results: Prevalence of PLMSI > 15/h was 28.6% (31.3% in men, 26% in women). Compared to subjects with PLMSI ≤ 15/h, subjects with PLMSI > 15/h were older (p < 0.001), were predominantly males (p = 0.007), had a higher proportion of restless legs syndrome (RLS; p < 0.001), had a higher body mass index (p = 0.001), and had a lower mean glomerular filtration rate (p < 0.001). Subjects with PLMSI > 15/h also had a higher prevalence of diabetes, hypertension, and beta-blocker or hypnotic treatments. The prevalence of antidepressant use was higher, but not statistically significant (p = 0.07). Single nucleotide polymorphisms (SNPs) within BTBD9 (rs3923809), TOX3 (rs3104788), and MEIS1 (rs2300478) genes were significantly associated with PLSMI > 15/h. Conversely, mean hemoglobin and ferritin levels were similar in both groups. In the multivariate analysis, age, male gender, antidepressant intake, RLS, and rs3923809, rs3104788, and rs2300478 SNPs were independently associated with PLMSI > 15/h.Interpretation: PLMS are highly prevalent in our middle-aged European population. Age, male gender, RLS, antidepressant treatment, and specific BTBD9, TOX3, and MEIS1 SNP distribution are independent predictors of PLMSI > 15/h. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to evaluate if there is a significant effect of lunar phases on subjective and objective sleep variables in the general population.Methods: A total of 2125 individuals (51.2% women, age 58.8 ± 11.2 years) participating in a population-based cohort study underwent a complete polysomnography (PSG) at home. Subjective sleep quality was evaluated by a self-rating scale. Sleep electroencephalography (EEG) spectral analysis was performed in 759 participants without significant sleep disorders. Salivary cortisol levels were assessed at awakening, 30 min after awakening, at 11 am, and at 8 pm. Lunar phases were grouped into full moon (FM), waxing/waning moon (WM), and new moon (NM).Results: Overall, there was no significant difference between lunar phases with regard to subjective sleep quality. We found only a nonsignificant (p = 0.08) trend toward a better sleep quality during the NM phase. Objective sleep duration was not different between phases (FM: 398 ± 3 min, WM: 402 ± 3 min, NM: 403 ± 3 min; p = 0.31). No difference was found with regard to other PSG-derived parameters, EEG spectral analysis, or in diurnal cortisol levels. When considering only subjects with apnea/hypopnea index of <15/h and periodic leg movements index of <15/h, we found a trend toward shorter total sleep time during FM (FM: 402 ± 4, WM: 407 ± 4, NM: 415 ± 4 min; p = 0.06) and shorter-stage N2 duration (FM: 178 ± 3, WM: 182 ± 3, NM: 188 ± 3 min; p = 0.05).Conclusion: Our large population-based study provides no evidence of a significant effect of lunar phases on human sleep. [ABSTRACT FROM AUTHOR]

Interactions of neurons with microglia may play a dominant role in sleep regulation. TNF may exert its somnogeneic effects by promoting attraction of microglia and their processes to the vicinity of dendrites and synapses. We found TNF to stimulate neurons (i) to produce CCL2, CCL7 and CXCL10, chemokines acting on mononuclear phagocytes and (ii) to stimulate the expression of the macrophage colony stimulating factor ( M-CSF / Csf1 ), which leads to elongation of microglia processes. TNF may also act on neurons by affecting the expression of genes essential in sleep–wake behavior. The neuronal expression of Homer1a mRNA, increases during spontaneous and enforced periods of wakefulness. Mice with a deletion of Homer1a show a reduced wakefulness with increased non-rapid eye movement (NREM) sleep during the dark period. Recently the TNF-dependent increase of NREM sleep in the dark period of mice with CD40-induced immune activation was found to be associated with decreased expression of Homer1a . In the present study we investigated the effects of TNF and IL-1β on gene expression in cultures of the neuronal cell line HT22 and cortical neurons. TNF slightly increased the expression of Homer1a and IL-1β profoundly enhanced the expression of Early growth response 2 ( Egr2 ) . The data presented here indicate that the decreased expression of Homer1a , which was found in the dark period of mice with CD40-induced increase of NREM sleep is not due to inhibitory effects of TNF and IL-1β on the expression of Homer1a in neurons . [ABSTRACT FROM AUTHOR]

Objective To examine the association of socioeconomic status (SES) with subjective and objective sleep disturbances and the role of socio-demographic, behavioural and psychological factors in explaining this association. Methods Analyses are based on 3391 participants (53% female, aged 40–81 years) of the follow-up of the CoLaus study (2009–2012), a population-based sample of the city of Lausanne, Switzerland. All participants completed a sleep questionnaire and a sub-sample ( N  = 1569) underwent polysomnography. Results Compared with men with a high SES, men with a low SES were more likely to suffer from poor sleep quality [prevalence ratio (PR) for occupational position = 1.68, 95% Confidence Interval (CI): 1.30–2.17], and to have long sleep latency (PR = 4.90, 95%CI: 2.14–11.17), insomnia (PR = 1.47, 95% CI: 1.12–1.93) and short sleep duration (PR = 3.03, 95% CI: 1.78–5.18). The same pattern was observed among women (PR = 1.29 for sleep quality, 2.34 for sleep latency, 2.01 for daytime sleepiness, 3.16 for sleep duration, 95%CIs ranging from 1.00 to 7.51). Use of sleep medications was not patterned by SES. SES differences in sleep disturbances were only marginally attenuated by adjustment for other socio-demographic, behavioural and psychological factors. Results from polysomnography confirmed poorer sleep patterns among participants with low SES ( p  <   0.05 for sleep efficiency/stage shifts), but no SES differences were found for sleep duration. Conclusions In this population-based sample, low SES was strongly associated with sleep disturbances, independently of socio-demographic, behavioural, and psychological factors. Further research should establish the extent to which social differences in sleep contribute to socioeconomic differences in health outcomes. [ABSTRACT FROM AUTHOR]

Summary The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin deficiency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifically hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic findings and now awaiting experimental testing are models of the possible immune mechanisms by which a specific and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identification of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems. [ABSTRACT FROM AUTHOR]

Astute control of brain activity states is critical for adaptive behaviours and survival. In mammals and birds, electroencephalographic recordings reveal alternating states of wakefulness, slow wave sleep and paradoxical sleep (or rapid eye movement sleep). This control is profoundly impaired in narcolepsy with cataplexy, a disease resulting from the loss of orexin/hypocretin neurotransmitter signalling in the brain. Narcolepsy with cataplexy is characterized by irresistible bouts of sleep during the day, sleep fragmentation during the night and episodes of cataplexy, a sudden loss of muscle tone while awake and experiencing emotions. The neural mechanisms underlying cataplexy are unknown, but commonly thought to involve those of rapid eye movement–sleep atonia, and cataplexy typically is considered as a rapid eye movement sleep disorder. Here we reassess cataplexy in hypocretin (Hcrt, also known as orexin) gene knockout mice. Using a novel video/electroencephalogram double-blind scoring method, we show that cataplexy is not a state per se, as believed previously, but a dynamic, multi-phased process involving a reproducible progression of states. A knockout-specific state and a stereotypical paroxysmal event were introduced to account for signals and electroencephalogram spectral characteristics not seen in wild-type littermates. Cataplexy almost invariably started with a brief phase of wake-like electroencephalogram, followed by a phase featuring high-amplitude irregular theta oscillations, defining an activity profile distinct from paradoxical sleep, referred to as cataplexy-associated state and in the course of which 1.5–2 s high-amplitude, highly regular, hypersynchronous paroxysmal theta bursts (∼7 Hz) occurred. In contrast to cataplexy onset, exit from cataplexy did not show a predictable sequence of activities. Altogether, these data contradict the hypothesis that cataplexy is a state similar to paradoxical sleep, even if long cataplexies may evolve into paradoxical sleep. Although not exclusive to overt cataplexy, cataplexy-associated state and hypersynchronous paroxysmal theta activities are highly enriched during cataplexy in hypocretin/orexin knockout mice. Their occurrence in an independent narcolepsy mouse model, the orexin/ataxin 3 transgenic mouse, undergoing loss of orexin neurons, was confirmed. Importantly, we document for the first time similar paroxysmal theta hypersynchronies (∼4 Hz) during cataplexy in narcoleptic children. Lastly, we show by deep recordings in mice that the cataplexy-associated state and hypersynchronous paroxysmal theta activities are independent of hippocampal theta and involve the frontal cortex. Cataplexy hypersynchronous paroxysmal theta bursts may represent medial prefrontal activity, associated in humans and rodents with reward-driven motor impulse, planning and conflict monitoring. [ABSTRACT FROM AUTHOR]

Although sleep is defined as a behavioral state, at the cortical level sleep has local and use-dependent features suggesting that it is a property of neuronal assemblies requiring sleep in function of the activation experienced during prior wakefulness. Here we show that mature cortical cultured neurons display a default state characterized by synchronized burst-pause firing activity reminiscent of sleep. This default sleep-like state can be changed to transient tonic firing reminiscent of wakefulness when cultures are stimulated with a mixture of waking neurotransmitters and spontaneously returns to sleep-like state. In addition to electrophysiological similarities, the transcriptome of stimulated cultures strikingly resembles the cortical transcriptome of sleep-deprived mice, and plastic changes as reflected by AMPA receptors phosphorylation are also similar. We used our in vitro model and sleep-deprived animals to map the metabolic pathways activated by waking. Only a few metabolic pathways were identified, including glycolysis, aminoacid, and lipids. Unexpectedly large increases in lysolipids were found both in vivo after sleep deprivation and in vitro after stimulation, strongly suggesting that sleep might play a major role in reestablishing the neuronal membrane homeostasis. With our in vitro model, the cellular and molecular consequences of sleep and wakefulness can now be investigated in a dish. [ABSTRACT FROM AUTHOR]

Abstract: To test whether mental activities collected from non-REM sleep are influenced by REM sleep, we suppressed REM sleep using clomipramine 50mg (an antidepressant) or placebo in the evening, in a double blind cross-over design, in 11 healthy young men. Subjects were awakened every hour and asked about their mental activity. The marked (81%, range 39–98%) REM-sleep suppression induced by clomipramine did not substantially affect any aspects of dream recall (report length, complexity, bizarreness, pleasantness and self-perception of dream or thought-like mentation). Since long, complex and bizarre dreams persist even after suppressing REM sleep either partially or totally, it suggests that the generation of mental activity during sleep is independent of sleep stage. [Copyright &y& Elsevier]

Abstract: Background: Positional therapy that prevents patients from sleeping supine has been used for many years to manage positional obstructive sleep apnea (OSA). However, patients’ usage at home and the long term efficacy of this therapy have never been objectively assessed. Methods: Sixteen patients with positional OSA who refused or could not tolerate continuous positive airway pressure (CPAP) were enrolled after a test night study (T0) to test the efficacy of the positional therapy device. The patients who had a successful test night were instructed to use the device every night for threemonths. Nightly usage was monitored by an actigraphic recorder placed inside the positional device. A follow-up night study (T3) was performed after threemonths of positional therapy. Results: Patients used the device on average 73.7±29.3% (mean±SD) of the nights for 8.0±2.0h/night. 10/16 patients used the device more than 80% of the nights. Compared to the baseline (diagnostic) night, mean apnea–hypopnea index (AHI) decreased from 26.7±17.5 to 6.0±3.4 with the positional device (p <0.0001) during T0 night. Oxygen desaturation (3%) index also fell from 18.4±11.1 to 7.1±5.7 (p =0.001). Time spent supine fell from 42.8±26.2% to 5.8±7.2% (p <0.0001). At threemonths (T3), the benefits persisted with no difference in AHI (p =0.58) or in time spent supine (p =0.98) compared to T0 night. The Epworth sleepiness scale showed a significant decrease from 9.4±4.5 to 6.6±4.7 (p =0.02) after threemonths. Conclusions: Selected patients with positional OSA can be effectively treated by a positional therapy with an objective compliance of 73.7% of the nights and a persistent efficacy after threemonths. [Copyright &y& Elsevier]

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. [Copyright &y& Elsevier]

γ-Hydroxybutyric acid (GHB) is an endogenous short-chain fatty acid popular as a recreational drug due to sedative and euphoric effects, but also often implicated in drug-facilitated sexual assaults owing to disinhibition and amnesic properties. Whilst discrimination between endogenous and exogenous GHB as required in intoxication cases may be achieved by the determination of the carbon isotope content, such information has not yet been exploited to answer source inference questions of forensic investigation and intelligence interests. However, potential isotopic fractionation effects occurring through the whole metabolism of GHB may be a major concern in this regard. Thus, urine specimens from six healthy male volunteers who ingested prescription GHB sodium salt, marketed as Xyrem®, were analysed by means of gas chromatography/combustion/isotope ratio mass spectrometry to assess this particular topic. A very narrow range of δC values, spreading from −24.81‰ to −25.06‰, was observed, whilst mean δC value of Xyrem® corresponded to −24.99‰. Since urine samples and prescription drug could not be distinguished by means of statistical analysis, carbon isotopic effects and subsequent influence on δC values through GHB metabolism as a whole could be ruled out. Thus, a link between GHB as a raw matrix and found in a biological fluid may be established, bringing relevant information regarding source inference evaluation. Therefore, this study supports a diversified scope of exploitation for stable isotopes characterized in biological matrices from investigations on intoxication cases to drug intelligence programmes. [ABSTRACT FROM AUTHOR]

The role of GABAB receptors in sleep is still poorly understood. GHB (γ-hydroxybutyric acid) targets these receptors and is the only drug approved to treat the sleep disorder narcolepsy. GABAB receptors are obligate dimers comprised of the GABAB2 subunit and either one of the two GABAB1 subunit isoforms, GABAB1a and GABAB1b. To better understand the role of GABAB receptors in sleep regulation, we performed electroencephalogram (EEG) recordings in mice devoid of functional GABAB receptors (1−/− and 2−/−) or lacking one of the subunit 1 isoforms (1a−/− and 1b−/−). The distribution of sleep over the day was profoundly altered in 1−/− and 2−/− mice, suggesting a role for GABAB receptors in the circadian organization of sleep. Several other sleep and EEG phenotypes pointed to a more prominent role for GABAB1a compared with the GABAB1b isoform. Moreover, we found that GABAB1a protects against the spontaneous seizure activity observed in 1−/− and 2−/− mice. We also evaluated the effects of the GHB-prodrug GBL (γ-butyrolactone) and of baclofen (BAC), a high-affinity GABAB receptor agonist. Both drugs induced a state distinct from physiological sleep that was not observed in 1−/− and 2−/− mice. Subsequent sleep was not affected by GBL whereas BAC was followed by a delayed hypersomnia even in 1−/− and 2−/− mice. The differential effects of GBL and BAC might be attributed to differences in GABAB-receptor affinity. These results also indicate that all GBL effects are mediated through GABAB receptors, although these receptors do not seem to be involved in mediating the BAC-induced hypersomnia. [ABSTRACT FROM AUTHOR]

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder. [ABSTRACT FROM AUTHOR]

Wake-promoting drugs are widely used to treat excessive daytime sleepiness. The neuronal pathways involved in wake promotion are multiple and often not well characterized. We tested d-amphetamine, modafinil, and YKP10A, a novel wake-promoting compound, in three inbred strains of mice. The wake duration induced by YKP10A and d-amphetamine depended similarly on genotype, whereas opposite strain differences were observed after modafinil. Electroencephalogram (EEG) analysis during drug-induced wakefulness revealed a transient ∼2 Hz slowing of theta oscillations and an increase in beta-2 (20–35 Hz) activity only after YKP10A. Gamma activity (35–60 Hz) was induced by all drugs in a drug- and genotype-dependent manner. Brain transcriptome and clustering analyses indicated that the three drugs have both common and specific molecular signatures. The correlation between specific EEG and gene-expression signatures suggests that the neuronal pathways activated to stay awake vary among drugs and genetic background.Neuropsychopharmacology (2009) 34, 1625–1640; doi:10.1038/npp.2009.3; published online 4 February 2009 [ABSTRACT FROM AUTHOR]

Sleep is regulated by a homeostatic process that determines its need and by a circadian process that determines its timing. By using sleep deprivation and transcriptome profiling in inbred mouse strains, we show that genetic background affects susceptibility to sleep loss at the transcriptional level in a tissue-dependent manner. In the brain, Homer1a expression best reflects the response to sleep loss. Time- course gene expression analysis suggests that 2,032 brain transcripts are under circadian control. However, only 391 remain rhythmic when mice are sleep-deprived at four time points around the clock, suggesting that most diurnal changes in gene transcription are, in fact, sleep-wake-dependent. By generating a transgenic mouse line, we show that in Homer1-expressing cells specifically, apart from Homer1a, three other activity-induced genes (Ptgs2, Jph3, and Nptx2) are overexpressed after sleep loss. All four genes play a role in recovery from glutamate-induced neuronal hyperactivity. The consistent activation of Homer1a suggests a role for sleep in intracellular calcium homeostasis for protecting and recovering from the neuronal activation imposed by wakefulness. [ABSTRACT FROM AUTHOR]

DBP (albumin D-site-binding protein), HLF (hepatic leukemia factor), and TEF (thyrotroph embryonic factor) are the three members of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family. All three of these transcriptional regulatory proteins accumulate with robust circadian rhythms in tissues with high amplitudes of clock gene expression, such as the suprachiasmatic nucleus (SCN) and the liver. However, they are expressed at nearly invariable levels in most brain regions, in which clock gene expression only cycles with low amplitude. Here we show that mice deficient for all three PAR bZip proteins are highly susceptible to generalized spontaneous and audiogenic epilepsies that frequently are lethal. Transcriptome profiling revealed pyridoxal kinase (Pdxk) as a target gene of PAR bZip proteins in both liver and brain. Pyridoxal kinase converts vitamin B6 derivatives into pyridoxal phosphate (PLP), the coenzyme of many enzymes involved in amino acid and neurotransmitter metabolism. PAR bZip-deficient mice show decreased brain levels of PLP, serotonin, and dopamine, and such changes have previously been reported to cause epilepsies in other systems. Hence, the expression of some clock-controlled genes, such as Pdxk, may have to remain within narrow limits in the brain. This could explain why the circadian oscillator has evolved to generate only low-amplitude cycles in most brain regions. [ABSTRACT FROM AUTHOR]

Alterations of peripheral magnesium (Mg) concentration have been reported in association with several behavioral disorders and sleep organization. Blood Mg regulation is under a strong genetic control, whereas brain Mg regulation does not seem to be affected. We have studied peripheral and central levels of Mg and analyzed sleep in two lines of mice selected for low (MGL) and high (MGH) red blood cell (RBC) Mg levels. The same variables were also studied in C57BL/6J mice before and after 3 weeks of Mg deficiency. Whereas blood Mg was highly affected by the selection, brain Mg exhibited only small differences between the two lines. In contrast, Mg deficiency strongly decreased both central and peripheral Mg levels. Sleep analysis indicated that in both models the amount of paradoxical sleep was lower in mice with higher Mg levels. The amplitude of daily variation in sleep and slow-wave sleep delta power was markedly decreased in MGH line. Quantitative electroencephalogram (EEG) analysis also revealed a faster theta peak frequency in MGH mice, irrespective of behavioral states. Central Mg showed significant correlations with the amount of paradoxical sleep and sleep consolidation. However, because the direction of these correlations was not consistent, it is concluded that optimal, (physiological) rather than high or low, Mg levels are needed for normal sleep regulation. [ABSTRACT FROM AUTHOR]

Sleep is a complex trait controlled by many genes, the environment, and probably by gene–environment interactions. Among different approaches to the genetics of sleep, analysis of quantitative traits (QTL) has the advantage of being able to detect, along with major genes, minor and/or modifier genes influencing different quantitative aspects of sleep. We have used QTL analysis in two different sets of recombinant inbred (RI) strains and sought for confirmation of several localizations in eight histocompatibility congenic strains. Several QTLs were identified which influenced the amount of vigilance states. In a first RI series (seven strains) the only QTLs identified were those affecting paradoxical sleep (PS), whereas analysis in a second RI series (25 strains) revealed QTLs influencing PS, slow-wave sleep, and total sleep. Among these, a single QTL on chromosome 5 was associated with all vigilance states, suggesting the presence of a major gene influencing a basic aspect of sleep amount. Search for candidate genes around the identified QTLs indicated several immune related genes that have been implicated in sleep regulation. Transgenic animals carrying loss-of-function and/or gain-of-function mutations affecting these candidate genes should confirm these findings. [ABSTRACT FROM AUTHOR]

Delta oscillations, characteristic of the electroencephalogram (EEC) of slow wave sleep, estimate sleep depth and need and are thought to be closely linked to the recovery function of sleep. The cellular mechanisms underlying the generation of delta waves at the cortical and thalamic levels are well documented, but the molecular regulatory mechanisms remain elusive. Here we demonstrate in the mouse that the gene encoding the retinoic acid receptor beta determines the contribution of delta oscillations to the sleep EEG. Thus, retinoic acid signaling, which is involved in the patterning of the brain and dopaminergic pathways, regulates cortical synchrony in the adult. [ABSTRACT FROM AUTHOR]

Kleine‐Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural abnormalities but with often favourable prognosis. There is excess risk of KLS in first‐degree relatives, suggesting a strong genetic contribution. So far, no mutation is identified in KLS and comprehensive genetic analysis of affected individuals is lacking. Here we performed whole genome single‐nucleotide polymorphism (SNP) genotyping and exome sequencing in a large family with seven affected members. The identified gene with a mutation was resequenced in 38 sporadic KLS patients and the expression of the gene product was mapped in the mouse brain. Linkage analysis mapped the disease locus to chromosome 3 and exome analysis identified a heterozygous missense variant in LMOD3 (p.E142D) in the linkage interval. The variant was found to segregate in all affected and one presumably unaffected member of the family. Resequencing LMOD3 in 38 other KLS patients and their families revealed three other low frequency or rare missense variants in seven cases that were inherited with incomplete penetrance. LMOD3 is expressed in the brain and colocalized with major structures involved in the regulation of vigilance states. LMOD proteins are structural proteins and seem to be developmentally regulated. Our findings suggest that KLS might be a structural/neurodevelopmental brain disease. [ABSTRACT FROM AUTHOR]

Narcolepsy with cataplexy is thought to be a hypocretin ligand or hypocretin receptor deficiency syndrome caused by genetic and environmental factors. We looked for an abnormality of the hypocretin pathway in HLA-DQB1*0602-positive monozygotic twins who were concordant for narcolepsy-cataplexy. They had normal cerebrospinal fluid concentrations of hypocretin-1, and we found no mutation in the prepro-hypocretin gene or either hypocretin receptor gene. Our finding points to the existence of presumably genetic forms of narcolepsy with cataplexy without any demonstrable defect in the hypocretin pathway. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the clinical efficacy of high-dose intravenous immunoglobulins near the onset if narcolepsy in a 10-year-old boy.

Abstract: Aging produces major changes in sleep structure and intensity which might be linked to cognitive impairment in the elderly. In this study, the genetic contribution to age-related changes in sleep was assessed in three inbred mouse strains of various ages. Baseline sleep and the response to 6 hours sleep deprivation (SD) achieved by gentle handling were quantified in young, middle-aged, and older male mice using electroencephalography. Total sleep time initially increased with age but then decreased in the oldest group mainly due to changes in sleep duration during the active phase. The effect of age on electroencephalographic (EEG) delta power depends on genotype and sleep pressure level with SD increasing the age-related differences. The strong effect of age upon the spectral profile of the different behavioral states was modulated by genetic background. Overall, our results suggest that sleep pressure can modulate the effect of age, that most sleep variables do not monotonically change with age in contrast to previous reports in humans and other species, and that genetic factors have a major impact on the aging processes affecting sleep. [Copyright &y& Elsevier]