Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial.

BACKGROUND: Obesity is strongly associated with prevalence of obstructive sleep apnea (OSA), and weight loss has been shown to reduce disease severity. OBJECTIVE: To investigate whether liraglutide 3.0 mg reduces OSA severity compared with placebo using the primary end point of change in apnea-hypopnea index (AHI) after 32 weeks. Liraglutide's weight loss efficacy was also examined. SUBJECTS/METHODS: In this randomized, double-blind trial, non-diabetic participants with obesity who had moderate (AHI 15-29.9 events h(-1)) or severe (AHI ⩾30 events h(-1)) OSA and were unwilling/unable to use continuous positive airway pressure therapy were randomized for 32 weeks to liraglutide 3.0 mg (n=180) or placebo (n=179), both as adjunct to diet (500 kcal day(-1) deficit) and exercise. Baseline characteristics were similar between groups (mean age 48.5 years, males 71.9%, AHI 49.2 events h(-1), severe OSA 67.1%, body weight 117.6 kg, body mass index 39.1 kg m(-2), prediabetes 63.2%, HbA1c 5.7%). RESULTS: After 32 weeks, the mean reduction in AHI was greater with liraglutide than with placebo (-12.2 vs -6.1 events h(-1), estimated treatment difference: -6.1 events h(-1) (95% confidence interval (CI), -11.0 to -1.2), P=0.0150). Liraglutide produced greater mean percentage weight loss compared with placebo (-5.7% vs -1.6%, estimated treatment difference: -4.2% (95% CI, -5.2 to -3.1%), P<0.0001). A statistically significant association between the degree of weight loss and improvement in OSA end points (P<0.01, all) was demonstrated post hoc. Greater reductions in glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) were seen with liraglutide versus placebo (both P<0.001). The safety profile of liraglutide 3.0 mg was similar to that seen with doses ⩽1.8 mg. CONCLUSIONS: As an adjunct to diet and exercise, liraglutide 3.0 mg was generally well tolerated and produced significantly greater reductions than placebo in AHI, body weight, SBP and HbA1c in participants with obesity and moderate/severe OSA. The results confirm that weight loss improves OSA-related parameters.

HLA-DQ association and allele competition in Chinese narcolepsy.

In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1*06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1*15:01/3 and DQB1*06:02 in most populations. In this study, we studied human leucocyte antigen (HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1*06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1*06:02 and DRB1*15:01, we found that the presence of DQB1*06:02 and not DRB1*15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1*15:01-DQA1*01:02-DQB1*06:01 and DRB1*15:01-DQA1*01:02-DQB1*05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1*01 (non-DQA1*01:02) and susceptibility effects of DQB1*03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1*15:01 has no effect on narcolepsy susceptibility in the absence of DQB1*06:02. The results are also in line with a previously proposed 'HLA-DQ allelic competition model' that involves competition between non-DQA1*01:02, non-DQB1*06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQα*01:02/ DQß*06:02 narcolepsy heterodimer to reduce susceptibility.

Experiments and 3D simulations of flow structures in junctions and their influence on location of flowmeters.

Open-channel junctions are common occurrences in sewer networks and flow rate measurement often occurs near these singularities. Local flow structures are 3D, impact on the representativeness of the local flow measurements and thus lead to deviations in the flow rate estimation. The present study aims (i) to measure and simulate the flow pattern in a junction flow, (ii) to analyse the impact of the junction on the velocity distribution according to the distance from the junction and thus (iii) to evaluate the typical error derived from the computation of the flow rate close to the junction.

A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains.

We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.

Ventilatory chemoresponsiveness, narcolepsy-cataplexy and human leukocyte antigen DQB1*0602 status.

We hypothesised that hypocretin (orexin) plays a role in the determination of ventilatory chemosensitivity. 130 patients with narcolepsy-cataplexy (mean ± SD age 20 ± 10 yrs, 69% male) and 117 controls (22 ± 6.9 yrs, 62% male) were recruited and tested for human leukocyte antigen (HLA)-DQB1*0602 status, hyperoxia hypercapnic (change in minute ventilation (δV'(E))/carbon dioxide tension (δP(CO(2))) L·min(-1)·mmHg(-1)) and hypoxic (δV'(E) /change in arterial oxygen saturation measured by probe oximetry (δS(p,O(2))) L·min(-1) per %S(p,O(2))) responsiveness, and by spirometry. Hypocretin deficiency was determined either by measures of cerebrospinal fluid hypocretin-1 (37 patients) or by positive HLA-DQB1*0602 status. All patients and 49% of controls underwent polysomnography and multiple sleep latency testing. Despite similar spirometric values, patients had a higher apnoea/hypopnoea index (AHI) (2.8 ± 5.4 versus 0.8 ± 1.6 h(-1); p = 0.03) and lower minimal oxygen saturation during sleep (87% ± 7 versus 91 ± 4%; p = 0.0002), independent of age, sex and body mass index. Patients had depressed hypoxic responsiveness (0.13 ± 0.09 versus 0.19 ± 0.13 L·min(-1) per %S(p,O(2)); p<0.0001), independent of AHI, but hypercapnic responsiveness did not differ. Examined by HLA status, positive (26 out of 117) controls had lower hypoxic but similar hypercapnic responsiveness than those marker-negative (0.13 ± 0.08 versus 0.20 ± 0.14 L·min(-1) per %S(p,O(2)); p<0.0001). Thus, a lower hypoxic responsiveness in the narcolepsy-cataplexy group is a result of DQB1*0602 status rather than the clinical features of disease.

Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla.

Narcolepsy is a neurological disorder characterized by sleepiness and episodes of cataplexy. Cataplexy is an abrupt loss of muscle tone, most often triggered by sudden, strong emotions. A subset of cells in the medial medulla of the narcoleptic dog discharged at high rates only in cataplexy and rapid eye movement (REM) sleep. These cells were noncholinergic and were localized to ventromedial and caudal portions of the nucleus magnocellularis. The localization and discharge pattern of these cells indicate that cataplexy results from a triggering in waking of the neurons responsible for the suppression of muscle tone in REM sleep. However, most medullary cells were inactive during cataplexy but were active during REM sleep. These data demonstrate that cataplexy is a distinct behavioral state, differing from other sleep and waking states in its pattern of brainstem neuronal activity.

DOSED: A deep learning approach to detect multiple sleep micro-events in EEG signal.

BACKGROUND: Electroencephalography (EEG) monitors brain activity during sleep and is used to identify sleep disorders. In sleep medicine, clinicians interpret raw EEG signals in so-called sleep stages, which are assigned by experts to every 30s window of signal. For diagnosis, they also rely on shorter prototypical micro-architecture events which exhibit variable durations and shapes, such as spindles, K-complexes or arousals. Annotating such events is traditionally performed by a trained sleep expert, making the process time consuming, tedious and subject to inter-scorer variability. To automate this procedure, various methods have been developed, yet these are event-specific and rely on the extraction of hand-crafted features. NEW METHOD: We propose a novel deep learning architecture called Dreem One Shot Event Detector (DOSED). DOSED jointly predicts locations, durations and types of events in EEG time series. The proposed approach, applied here on sleep related micro-architecture events, is inspired by object detectors developed for computer vision such as YOLO and SSD. It relies on a convolutional neural network that builds a feature representation from raw EEG signals, as well as two modules performing localization and classification respectively. RESULTS AND COMPARISON WITH OTHER METHODS: The proposed approach is tested on 4 datasets and 3 types of events (spindles, K-complexes, arousals) and compared to the current state-of-the-art detection algorithms. CONCLUSIONS: Results demonstrate the versatility of this new approach and improved performance compared to the current state-of-the-art detection methods.

Role of central alpha-1 adrenoceptors in canine narcolepsy.

The role of central alpha-1 adrenergic receptors in cataplexy was investigated in genetically narcoleptic Doberman pinschers. Treatment of narcoleptic dogs with 25-600 micrograms/kg prazosin, a selective alpha-1 adrenergic receptor blocker, exacerbated cataplexy, whereas treatment with the alpha-1 agonist, methoxamine, ameliorated it. Subsequent studies showed that the beneficial effects of classical treatments of human narcolepsy (amphetamines and tricyclic antidepressants) are antagonized by prazosin, suggesting that these drugs are active through an indirect alpha-1 stimulation (via an increase of norepinephrine in the synaptic cleft). Other studies confirmed that the observed effects were not due to peripheral alpha-1 cardiovascular involvement. Atropine, a central anticholinergic agent, but not methylatropine, a peripheral one, completely suppressed the prazosin effect, which suggests that adrenergic and cholinergic systems act sequentially and not independently to generate cataplexy. Little is known about the physiological role of central alpha-1 adrenoceptors. This series of experiments implicates these receptors in narcolepsy-cataplexy.

The development of hypocretin (orexin) deficiency in hypocretin/ataxin-3 transgenic rats.

Narcolepsy is linked to a widespread loss of neurons containing the neuropeptide hypocretin (HCRT), also named orexin. A transgenic (TG) rat model has been developed to mimic the neuronal loss found in narcoleptic humans. In these rats, HCRT neurons gradually die as a result of the expression of a poly-glutamine repeat under the control of the HCRT promoter. To better characterize the changes in HCRT-1 levels in response to the gradual HCRT neuronal loss cerebrospinal fluid (CSF) HCRT-1 levels were measured in various age groups (2-82 weeks) of wild-type (WT) and TG Sprague-Dawley rats. TG rats showed a sharp decline in CSF HCRT-1 level at week 4 with levels remaining consistently low (26%+/-9%, mean+/-S.D.) thereafter compared with WT rats. In TG rats, HCRT-1 levels were dramatically lower in target regions such as the cortex and brainstem (100-fold), indicating decreased HCRT-1 levels at terminals. In TG rats, CSF HCRT-1 levels significantly increased in response to 6 h of prolonged waking, indicating that the remaining HCRT neurons can be stimulated to release more neuropeptide. Rapid eye movement (REM) sleep in TG rats (n=5) was consistent with a HCRT deficiency. In TG rats HCRT immunoreactive (HCRT-ir) neurons were present in the lateral hypothalamus (LH), even in old rats (24 months) but some HCRT-ir somata were in various stages of disintegration. The low output of these neurons is consistent with a widespread dysfunction of these neurons, and establishes this model as a tool to investigate the consequences of partial hypocretin deficiency.

Kleine-Levin syndrome: a systematic review of 186 cases in the literature.

Kleine-Levin syndrome (KLS) is a rare disorder with symptoms that include periodic hypersomnia, cognitive and behavioural disturbances. Large series of patients are lacking. In order to report on various KLS symptoms, identify risk factors and analyse treatment response, we performed a systematic review of 195 articles, written in English and non-English languages, which are available on Medline dating from 1962 to 2004. Doubtful or duplicate cases, case series without individual details and reviews (n = 56 articles) were excluded. In addition, the details of 186 patients from 139 articles were compiled. Primary KLS cases (n = 168) were found mostly in men (68%) and occurred sporadically worldwide. The median age of onset was 15 years (range 4-82 years, 81% during the second decade) and the syndrome lasted 8 years, with seven episodes of 10 days, recurring every 3.5 months (median values) with the disease lasting longer in women and in patients with less frequent episodes during the first year. It was precipitated most frequently by infections (38.2%), head trauma (9%), or alcohol consumption (5.4%). Common symptoms were hypersomnia (100%), cognitive changes (96%, including a specific feeling of derealization), eating disturbances (80%), hypersexuality (43%), compulsions (29%), and depressed mood (48%). In 75 treated patients (213 trials), somnolence decreased using stimulants (mainly amphetamines) in 40% of cases, while neuroleptics and antidepressants were of poor benefit. Only lithium (but not carbamazepine or other antiepileptics) had a higher reported response rate (41%) for stopping relapses when compared to medical abstention (19%). Secondary KLS (n = 18) patients were older and had more frequent and longer episodes, but had clinical symptoms and treatment responses similar to primary cases. In conclusion, KLS is a unique disease which may be more severe in female and secondary cases.

Pharmacological aspects of human and canine narcolepsy.

Narcolepsy-cataplexy is a disabling neurological disorder that affects 1/2000 individuals. The main clinical features of narcolepsy, excessive daytime sleepiness and symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are currently treated using amphetamine-like compounds or modafinil and antidepressants. Pharmacological research in the area is facilitated greatly by the existence of a canine model of the disorder. The mode of action of these compounds involves presynaptic activation of adrenergic transmission for the anticataplectic effects of antidepressant compounds and presynaptic activation of dopaminergic transmission for the EEG arousal effects of amphetamine-like stimulants. The mode of action of modafmil is still uncertain, and other neurochemical systems may offer interesting avenues for therapeutic development. Pharmacological and physiological studies using the canine model have identified primary neurochemical and neuroanatomical systems that underlie the expression of abnormal REM sleep and excessive sleepiness in narcolepsy. These involve mostly the pontine and basal forebrain cholinergic, the pontine adrenergic and the mesolimbic and mesocortical dopaminergic systems. These studies confirm a continuing need for basic research in both human and canine narcolepsy, and new treatments that act directly at the level of the primary defect in narcolepsy might be forthcoming.

Comparison of numerical and experimental simulations of a flood in a dense urban area.

Although various numerical methods were used to simulate real floods occurring in cities, the validation of the models was never accurate because of the lack of data about location and event description and about observation for validation. In order to check the capacities of our 2-dimensional shallow water equations model to simulate an urban flood, we then decided to simulate numerically an experimental event with well known characteristics and accurate flow measurements. The physical model presented in (Ishigaki et al, 2003) represents the flooding of the city center of Kyoto in Japan due to an overflow from the Kamo river. The 2-dimensional numerical simulation of this event was then set up and the experimental and computed data were compared. It appears that the event was calculated quite fairly in terms of flow depth and flow rates in the streets and in terms of timing. However, some discrepancies appear between the measurements and the numerical results, mostly due to some topographical local uncertainties and to the capacities of the equations to model the complex flows in the crossroads.

One-dimensional GIS-based model compared with a two-dimensional model in urban floods simulation.

A GIS-based one-dimensional flood simulation model is presented and applied to the centre of the city of Nîmes (Gard, France), for mapping flow depths or velocities in the streets network. The geometry of the one-dimensional elements is derived from the Digital Elevation Model (DEM). The flow is routed from one element to the next using the kinematic wave approximation. At the crossroads, the flows in the downstream branches are computed using a conceptual scheme. This scheme was previously designed to fit Y-shaped pipes junctions, and has been modified here to fit X-shaped crossroads. The results were compared with the results of a two-dimensional hydrodynamic model based on the full shallow water equations. The comparison shows that good agreements can be found in the steepest streets of the study zone, but differences may be important in the other streets. Some reasons that can explain the differences between the two models are given and some research possibilities are proposed.

Dopaminergic role in stimulant-induced wakefulness.

The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil.

Platelet alpha 2 adrenoceptors in human and canine narcolepsy.

We have recently established that canine narcolepsy (an autosomal recessive genetic model of the human disorder) is dramatically improved by treatment with alpha 2 antagonists such as yohimbine (Nishino et al: J Pharmacol Exp Ther 253:1145-1152, 1990). To further investigate the role of alpha 2 adrenoceptors in narcolepsy, receptors labeled with [3H] yohimbine were examined on platelets from human and canine narcoleptic subjects. Twenty-eight Doberman pinschers were studied, 7 controls (C), 7 heterozygous (Hz), and 14 narcoleptics (N) (age and sex matched), including eight animals born in a backcross setting (narcoleptic x heterozygous; 5 narcoleptics and 3 heterozygous). The Kd and Bmax of each group respectively, were as follows: C, Kd = 2.86 +/- 0.76 nmol/L, Bmax = 295.78 +/- 31.89 fmol/mg protein; Hz, Kd = 2.06 +/- 0.23 nmol/L, Bmax = 307.02 +/- 22.21 fmol/mg protein; and N, Kd = 2.72 +/- 0.45 nmol/L, Bmax = 267.52 +/- 19.47 fmol/mg protein. No statistical differences were found between groups using nonparametric (Kruskall-Wallis) statistical procedures, and there were no correlations between any binding parameter and symptom severity within the narcoleptic group. Platelet alpha 2 receptor affinity and density also did not differ between narcoleptic and heterozygous dogs in the backcross litter (N [n = 5], Kd = 1.94 +/- 0.59 nmol/L, Bmax = 290.6 +/- 64.7 fmol/mg protein; Hz [n = 3], Kd = 2.83 +/- 0.47 nmol/L, Bmax = 294.2 +/- 42.9 fmol/mg protein). Fourteen human subjects, seven control and seven narcoleptic patients (age and sex matched), were included in the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin E2 levels in cerebrospinal fluid of normal and narcoleptic dogs.

It has been shown that endogenous prostaglandin D2 and prostaglandin E2 (PGE2) are involved in sleep-wake regulation. Our recent experimental result that exogenously administered PGE2 significantly reduces canine cataplexy (a pathological equivalent of rapid-eye-movement sleep atonia and a symptom of narcolepsy) suggests that PGE2 is involved in the pathophysiology of canine narcolepsy. In order to further investigate the role of prostaglandins (PGs) in this disorder, PG levels in cerebrospinal fluid (CSF) of genetically homozygous narcoleptic, heterozygous (unaffected), and control Doberman pinschers were studied. PGE2 levels were measured by direct radioimmunoassay (RIA) and after high-grade purification using PG affinity columns and high-performance liquid chromatography. PGD2 and PGF2 alpha levels were measured by RIA after high-grade purification. There was no significant difference in PGE2 levels between homozygous narcoleptic and heterozygous or controls dogs, and PGD2 and PGF2 alpha levels were undetectable in most cases. Our results do not favor the hypothesis that central PGE2 levels are modified in canine narcolepsy, assuming that PGE2 levels in cisternal CSF properly reflect PGE2 production in the brain.

Free and conjugated plasma homovanillic acid in schizophrenic patients.

It has recently been suggested that the plasma level of homovanillic acid (HVA) may provide an index of central dopaminergic activity in humans. Clinical studies have shown that in schizophrenic patients, plasma HVA levels increase with the severity of psychopathology. However, these studies only considered the plasma free HVA fraction whereas investigations on conjugated HVA in humans are sparse and results remain controversial. The aim of this study was to measure both plasma free and conjugated HVA in healthy volunteers and drug-free schizophrenic patients. The mean values and the ranges of plasma free HVA in volunteers and patients were similar to those described in the literature. A substantial and significant increase in plasma free HVA was observed in schizophrenic patients compared with normal subjects. In contrast, plasma conjugated HVA was significatively decreased in schizophrenics. The plasma total HVA was nevertheless higher in schizophrenics compared with controls. No significant correlations were observed between plasma HVA levels and the clinical features of schizophrenic patients rated by various psychiatric scales. These findings suggest that there is an imbalance between plasma free and conjugated HVA in schizophrenic patients, who present an increase in total HVA when compared with controls. Paranoid schizophrenic patients, who present mainly positive symptoms, show the most marked plasma free/conjugated HVA imbalance.

Mesopontine organization of cholinergic and catecholaminergic cell groups in the normal and narcoleptic dog.

Canine narcolepsy is a unique experimental model of a human sleep disorder characterized by excessive daytime sleepiness and cataplexy. There is a consensus recognition of an imbalance between cholinergic and catecholaminergic systems in narcolepsy although the underlying mechanisms remain poorly understood. Possible substrates could be an abnormal organization, numbers and/or ratio of cholinergic to catecholaminergic cells in the brain of narcoleptic dogs. Therefore, we sought to characterize the corresponding neuronal populations in normal and narcoleptic dogs (Doberman Pinscher) by using choline acetyltransferase (ChAT), nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase, tyrosine hydroxylase (TH), and dopamine beta-hydroxylase (DBH). Cholinergic cell groups were found in an area extending from the central to the gigantocellular tegmental field and the periventricular gray corresponding to the pedunculopontine tegmental nucleus (PPT), the laterodorsal tegmental nucleus (LDT), and the parabrachial nucleus. An almost perfect co-localization of ChAT and NADPH-diaphorase was also observed. Catecholaminergic cell groups detected included the ventral tegmental area, the substantia nigra, and the locus coeruleus nucleus (LC). The anatomical distribution of catecholaminergic neurons was unusual in the dog in two important aspects: i) TH- and/or DBH-immunoreactive neurons of the LC were found almost exclusively in the reticular formation and not within the periventricular gray, ii) very few, if any TH-positive neurons were found in the central gray and dorsal raphe. Quantitative analysis did not reveal any significant differences in the organization and the number of cells identified in the LDT, PPT, and LC of normal and narcoleptic dogs. Moreover, the cholinergic to catecholaminergic ratio was found identical in the two groups. In conclusion, the present results do not support the hypothesis that the neurochemical imbalance in narcolepsy could result from abnormal organization, numbers, or ratio of the corresponding neuronal populations.

Genetic and familial aspects of narcolepsy.

Narcolepsy-cataplexy is a disabling sleep disorder characterized by excessive daytime sleepiness and abnormal REM sleep. The development of human narcolepsy involves environmental factors acting on a specific genetic background. The importance of environmental factors is evidenced by the reported 25 to 31% of monozygotic twins who are concordant for narcolepsy. One of the predisposing genetic factors is located in the MHC DQ region. More than 85% of all narcoleptic patients with definite cataplexy share a specific HLA allele, HLA DQB1*0602 (most often in combination with HLA DR2), compared with 12 to 38% of the general population, as evaluated in various ethnic groups. Genetic factors other than HLA are also likely to be involved. Even if genuine multiplex families are rare, 1 to 2% of the first-degree relatives of narcolepsy patients manifest the disorder, compared with 0.02 to 0.18% in the general population. Studies using a canine model of narcolepsy illustrate the importance of non-MHC genes in disease predisposition. In this model, narcolepsy is transmitted as a single autosomal recessive trait, canarc-1. In spite of an association with immune-related polymorphisms, narcolepsy does not appear to be a classic autoimmune disease. Other pathophysiologic models involving the microglia and the release of specific cytokines in the CNS may be involved and are being explored. This approach, together with positional cloning studies in humans and canines, should reveal the cause of narcolepsy and open new therapeutic avenues.

Polymorphisms in the vicinity of the hypocretin/orexin are not associated with human narcolepsy.

Human narcolepsy/cataplexy is associated with reduced hypocretin (orexin) transmission. A common preprophypocretin (HCRT) polymorphism (-909C/T) was identified and tested in 502 subjects (105 trio families, 80 Caucasian narcolepsy cases, and 107 Caucasian control subjects). This polymorphism was not associated with the disease. The promoter and 5' untranslated (5'URT) regions of the HCRT gene (-320 to +21 from ATG) were also sequenced in 281 subjects. None of the subjects carried -22T, a rare 5'UTR polymorphism previously reported to be associated with narcolepsy. The HCRT locus is not a major narcolepsy susceptibility locus.