Comparative Analysis of the Vlasiator Simulations and MMS Observations of Multiple X-Line Reconnection and Flux Transfer Events.

The Vlasiator hybrid-Vlasov code was developed to investigate global magnetospheric dynamics at ion-kinetic scales. Here we focus on the role of magnetic reconnection in the formation and evolution of magnetic islands at the low-latitude magnetopause, under southward interplanetary magnetic field conditions. The simulation results indicate that (1) the magnetic reconnection ion kinetics, including the Earthward pointing Larmor electric field on the magnetospheric side of an X-point and anisotropic ion distributions, are well-captured by Vlasiator, thus enabling the study of reconnection-driven magnetic island evolution processes, (2) magnetic islands evolve due to continuous reconnection at adjacent X-points, "coalescence" which refers to the merging of neighboring islands to create a larger island, "erosion" during which an island loses magnetic flux due to reconnection, and "division" which involves the splitting of an island into smaller islands, and (3) continuous reconnection at adjacent X-points is the dominant source of magnetic flux and plasma to the outer layers of magnetic islands resulting in cross-sectional growth rates up to + 0.3 RE 2/min. The simulation results are compared to the Magnetospheric Multiscale (MMS) measurements of a chain of ion-scale flux transfer events (FTEs) sandwiched between two dominant X-lines. The MMS measurements similarly reveal (1) anisotropic ion populations and (2) normalized reconnection rate ~0.18, in agreement with theory and the Vlasiator predictions. Based on the simulation results and the MMS measurements, it is estimated that the observed ion-scale FTEs may grow Earth-sized within ~10 min, which is comparable to the average transport time for FTEs formed in the subsolar region to the high-latitude magnetopause. Future simulations shall revisit reconnection-driven island evolution processes with improved spatial resolutions.

Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study.

BACKGROUND: Sleep-disordered breathing is associated with major morbidity and mortality. However, its prevalence has mainly been selectively studied in populations at risk for sleep-disordered breathing or cardiovascular diseases. Taking into account improvements in recording techniques and new criteria used to define respiratory events, we aimed to assess the prevalence of sleep-disordered breathing and associated clinical features in a large population-based sample. METHODS: Between Sept 1, 2009, and June 30, 2013, we did a population-based study (HypnoLaus) in Lausanne, Switzerland. We invited a cohort of 3043 consecutive participants of the CoLaus/PsyCoLaus study to take part. Polysomnography data from 2121 people were included in the final analysis. 1024 (48%) participants were men, with a median age of 57 years (IQR 49-68, range 40-85) and mean body-mass index (BMI) of 25·6 kg/m(2) (SD 4·1). Participants underwent complete polysomnographic recordings at home and had extensive phenotyping for diabetes, hypertension, metabolic syndrome, and depression. The primary outcome was prevalence of sleep-disordered breathing, assessed by the apnoea-hypopnoea index. FINDINGS: The median apnoea-hypopnoea index was 6·9 events per h (IQR 2·7-14·1) in women and 14·9 per h (7·2-27·1) in men. The prevalence of moderate-to-severe sleep-disordered breathing (≥15 events per h) was 23·4% (95% CI 20·9-26·0) in women and 49·7% (46·6-52·8) in men. After multivariable adjustment, the upper quartile for the apnoea-hypopnoea index (>20·6 events per h) was associated independently with the presence of hypertension (odds ratio 1·60, 95% CI 1·14-2·26; p=0·0292 for trend across severity quartiles), diabetes (2·00, 1·05-3·99; p=0·0467), metabolic syndrome (2·80, 1·86-4·29; p<0·0001), and depression (1·92, 1·01-3·64; p=0·0292). INTERPRETATION: The high prevalence of sleep-disordered breathing recorded in our population-based sample might be attributable to the increased sensitivity of current recording techniques and scoring criteria. These results suggest that sleep-disordered breathing is highly prevalent, with important public health outcomes, and that the definition of the disorder should be revised. FUNDING: Faculty of Biology and Medicine of Lausanne, Lausanne University Hospital, Swiss National Science Foundation, Leenaards Foundation, GlaxoSmithKline, Ligue Pulmonaire Vaudoise.

Comparison of the diagnostic value of CBCT and Digital Panoramic Radiography with surgical findings to determine the proximity of an impacted third mandibular molar to the inferior alveolar nerve canal.

Background: This study evaluated and determined the proximity of an impacted third mandibular molar (TMM) to the inferior alveolar canal (IAC) by using CBCT and digital panoramic radiography. Materials and Methods: This descriptive-analytic research applied CBCT and panoramic radiographs for 60 subjects (28 men, 32 women). Subjects selected showed a close proximity about the TMM to the inferior nerve canal on panoramic radiographs; these subjects then received CBCT radiographs. The CBCT findings for the proximity of the TMM to inferior nerve canal used the outcomes of surgical findings as the standard of comparison. Results: Eight cases showed positive surgical findings indicating vicinity of the third molar and the mandibular nerve canal. Only 13.3% of the cases in which panoramic views showed the proximity of the TMM and the IAC were confirmed during surgery. The result for CBCT radiographic diagnosis was 95%. Conclusion: It can be concluded that CBCT is preferred over panoramic radiography to determine the proximity of the impacted TMM to the IAC. Narrowing of the mandibular canal or root canal, disconnection of root borders in panoramic radiography, and the inferior-lingual proximity of the tooth to the root in CBCT strongly indicated the close nearness of the impacted TMM to the IAC.

Gastrointestinal helminths of camels (Camelus dromedarius) in center of Iran.

Camels are multipurpose animals in Iran. As parasitic diseases are the major cause of impaired meat and milk production in this animal, the present study aimed at determining gastrointestinal helminthic infections of Iranian camels in the center of the country. Gastrointestinal (GI) tract of 144 carcasses of one-humped camels (Camelus dromedarius) slaughtered in Yazd, Esfahan and Kerman provinces' abattoirs were examined for adult helminths. Camels were from both sexes and different ages. Recovered parasites were identified according to described keys by light microscope. Of 144 tested camels, 117 were infected with at least one helminth species (81.3%). A total of 28 worm species from 14 genera were identified in the digestive tract of infected animals, including 26 species of nematodes and two species of cestodes. The infection rates in stomach, small intestine, and caecum/large intestine were 86.3%, 91.5% and 11.1%, respectively. However, no worm was found in the oesophagus. The recovered worms with infection rates are discussed in this paper. In the present study, Haemonchus tataricus, Trichostrongylus hamatus and Trichuris infundibulus are reported from Iranian dromedaries for the first time. Regarding high prevalence of infection, using anthelminthic drugs seemed necessary to improve the health and productivity of camels. On the other hand, the high rate of zoonotic species indicated that camels have important role in maintaining and transmitting infection to humans.

Comparing letrozole with medroxyprogesterone acetate (MPA) as hormonal therapy for simple endometrial hyperplasia without atypia in adult and middle-aged women.

BACKGROUND: The aim of this survey was to compare the effect of letrozole with medroxyprogesterone acetate (MPA) in treatment of simple endometrial hyperplasia to preserve fertility in young women. MATERIALS AND METHODS: Forty-five patients referred to Shahid Sadoughi gynecology clinics from 2009 until 2011 who suffered from abnormal vaginal bleeding or endometrial thickness, that underwent curettage with diagnosis of simple endometrial hyperplasia without atypia were enrolled. The patients were divided randomly into two groups. First group including 22 women receive ten mg MPA, for ten days during a month for three months. All cases were followed by interview, endometrial curetage, and vaginal sonography. Serum level of estradiol was checked before and after treatment. At the end of the study, biopsy was retaken in 41 patients. All the patients were under observation by two gynecologists. RESULTS: Age range of patients was 20 to 42 years. Mean body mass index (BMI) in the MPA and letrozole groups was 29.13 +/- 4.8 and 25.42 +/- 4.2, respectively. Fifty and 34.8 percent of cases had history of obesity or polycystic ovarian syndrome (PCOS) in MPA and letrozole groups, respectively. Forty-one selected cases (20 of the MPA and 21 of the letrozole groups) continued the treatment for three months. The endometrial thicknesses decreased in both groups. Serum estradiol level also decreased in both groups. The most common complication in the MPA and letrozole groups was headache (27.3%) and flashing and dizziness, respectively. The side-effects were reported less in the letrozole group and the most common ones in this group were dizziness and flashing. DISCUSSION: In women suffering from simple endometrial hyperplasia without atypia, letrozole can lead to decrease of serum estradiol level and endometrial thickness like MPA. In both groups, there was no simple hyperplasia report in curettage report following treatment. It should be noted that there was an incomplete response to treat case with pathology of disordered proliferative type. CONCLUSION: Letrozole is a good therapeutic option in simple endometrial hyperplasia without atypia: cases candidate for medical treatment. To confirm the effect and safety of letrozole, more studies with larger samples are recommended.

[HypnoLaus sleep cohort study]. / HypnoLaus: le sommeil sous la loupe.

Normal sleep patterns and prevalence of sleep disorders in the general population are largely unknown. The aim of HypnoLaus cohort study is to record sleep and analyze sleep characteristics in a large population-based sample, which had undergone comprehensive genetic, somatic, and psychiatric investigations. Full polysomnography has already been performed in more than 1100 middle aged men and women randomly selected from Lausanne general population (goal 2000-3000 sleep recordings). Over 4000 additional subjects from the same population have filled various questionnaires on their sleep habits and complaints. These results combined with genetic, cardiovascular, metabolic, and psychiatric data provide a unique opportunity to determine the interaction between sleep, its genetic determinants and cardiovascular, psychiatric, or metabolic diseases.

[Narcolepsy with cataplexy associated with H1N1 vaccination]. / Narcolepsie avec cataplexie après vaccination anti-H1N1.

INTRODUCTION: It has been suggested that the H1N1 vaccine may be a trigger for the onset of narcolepsy-cataplexy, a rare disease whose autoimmune origin is suspected. OBSERVATIONS: We report two patients (a 9-year-old boy and an 18-year-old man) with severe narcolepsy-cataplexy, in whom the illness appeared within 3-4 weeks after H1N1 vaccination. In both cases, symptoms developed unusually abruptly and they presented with severe daytime sleepiness and multiple daily cataplexy attacks. Other similar cases have been recently reported associated with H1N1 vaccine. CONCLUSION: Although no formal link can be established, the unusual characteristics of the reported cases and the striking temporal relationship suggests that narcolepsy may be the result of an autoimmune reaction triggered by H1N1 vaccination in susceptible individuals.

Molecular analysis of sleep.

Rest or sleep in all animal species constitutes a period of quiescence necessary for recovery from activity. Whether rest and activity observed in all organisms share a similar fundamental molecular basis with sleep and wakefulness in mammals has not yet been established. In addition and in contrast to the circadian system, strong evidence that sleep is regulated at the transcriptional level is lacking. Nevertheless, several studies indicate that single genesmay regulate some specific aspects of sleep. Efforts to better understand or confirm the role of known neurotransmission pathways in sleep-wake regulation using transgenic approaches resulted so far in only limited new insights. Recent gene expression profiling efforts in rats, mice, and fruit flies are promising and suggest that only a few gene categories are differentially regulated by behavioral state. How molecular analysis can help us to understand sleep is the focus of this chapter.

CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions.

OBJECTIVE: To determine the role of CSF hypocretin-1 in narcolepsy with and without cataplexy, Kleine-Levin syndrome (KLS), idiopathic and other hypersomnias, and several neurological conditions. PATIENTS: 26 narcoleptic patients with cataplexy, 9 narcoleptic patients without cataplexy, 2 patients with abnormal REM-sleep-associated hypersomnia, 7 patients with idiopathic hypersomnia, 2 patients with post-traumatic hypersomnia, 4 patients with KLS, and 88 patients with other neurological disorders. RESULTS: 23 patients with narcolepsy-cataplexy had low CSF hypocretin-1 levels, while one patient had a normal hypocretin level (HLA-DQB1*0602 negative) and the other two had intermediate levels (familial forms). One narcoleptic patient without cataplexy had a low hypocretin level. One patient affected with post-traumatic hypersomnia had intermediate hypocretin levels. The KLS patients had normal hypocretin levels while asymptomatic, but one KLS patient (also affected with Prader-Willi syndrome) showed a twofold decrease in hypocretin levels during a symptomatic episode. Among the patients without hypersomnia, two patients with normal pressure hydrocephalus and one with unclear central vertigo had intermediate levels. CONCLUSION: Low CSF hypocretin-1 is highly specific (99.1%) and sensitive (88.5%) for narcolepsy with cataplexy. Hypocretin ligand deficiency appears not to be the major cause for other hypersomnias, with a possible continuum in the pathophysiology of narcolepsy without cataplexy and idiopathic hypersomnia. However, partial hypocretin lesions without low CSF hypocretin-1 consequences cannot be definitely excluded in those disorders. The existence of normal hypocretin levels in narcoleptic patients and intermediate levels in other rare aetiologies needs further investigation, especially for KLS, to establish the functional significance of hypocretin neurotransmission alterations.

HLA and genetic susceptibility to sleepwalking.

HLA-DQB1 typing was performed in 60 Caucasian subjects with sleepwalking (SW) disorder and their families and 60 ethnically matched subjects without any diagnosed sleep disorder. A total of 21 sleepwalkers (35.0%) were DQB1*0501 positive vs eight (13.3%) controls (P = 0.0056; odds ratio = 3.5, 95% CI = 1.4-8.7). The family data for all HLA subtypes were further assessed for allelic association with SW using the transmission-disequilibrium test. A significant excess transmission was observed for DQB1*05 and *04 alleles in familial cases, strongly suggesting that a DQB1 polymorphic amino acid might be more tightly associated than any single allele. Sequence screening revealed that Ser74 in the second exon shared by all DQB1*05 and *04 was 20 times transmitted against 4 times non-transmitted (P = 0.001) in familial cases of SW. Thus, together with narcolepsy and REM sleep behavior disorder, these findings suggest that specific DQB1 genes are implicated in disorders of motor control during sleep.

Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses.

BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder of unknown etiology. Pathophysiologic hypotheses include a hypothalamic dysfunction and abnormalities in the central serotonin and dopamine metabolism. Several clinical symptoms also suggest an underlying autoimmune process. OBJECTIVE: To systematically investigate patients with KLS with reference to the available hypotheses. METHODS: The authors collected clinical, polysomnographic, CSF, CT, and MRI records and analyzed gene polymorphisms of HLA-DQB1, tryptophan hydroxylase (TpH), and catechol-O-methyltransferase (COMT) in 30 unrelated patients with KLS and their families. The genotype data were contrasted with data from a normal control population. RESULTS: Only human leukocyte antigen (HLA)-DQB1*0201 allele frequency was significantly increased in patients with KLS. Three patients with KLS but none of the control subjects were DQB1*0201 homozygous. Two affected subjects from the same family were DQB1*0201 homozygous. In 17 DQB1*0201 heterozygous parents, 11 (64.7%) had transmitted this allele, suggesting a preferential transmission. CONCLUSION: These findings, together with the young age at onset, the recurrence of symptoms, and the frequent infectious precipitating factors, suggest an autoimmune etiology for Kleine-Levin syndrome.

Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil.

The gene for catechol-O-methyltransferase (COMT) plays a key modulatory role in dopaminergic and noradrenergic neurotransmission. Recent evidence suggests that modafinil, like other stimulants, might act through the dopaminergic system. We have reported a sexual dimorphism and a strong effect of the COMT genotype on narcolepsy symptoms and hypothesized that response to modafinil treatment may be associated with the COMT genotype. Here we confirm that COMT genotype distribution between men and women narcoleptics is associated with response to modafinil. In addition, the optimal daily dose of modafinil is approximately 100 mg lower in women narcoleptics and lower in all narcoleptics with low activity COMT genotype. Our results suggest that a sexual dimorphism in COMT activity affects the response to modafinil and probably to other dopaminergic stimulants.

MAO-A and COMT polymorphisms and gene effects in narcolepsy.

Narcolepsy presents one of the tightest associations with a specific HLA antigen (DQB1*0602) but there is strong evidence that non-HLA genes also confer susceptibility. Recent observations have implicated the hypocretin/orexin system in narcolepsy in both humans and animals. In addition, the implication of monoaminergic systems in the pathophysiology of narcolepsy is well established and a significant association between the monoamine oxydase-A (MAO-A) gene and human narcolepsy has recently provided a possible genetic link. We investigated polymorphisms of MAO-A and catechol-O-methyltransferase (COMT) in 97 Caucasians with well-defined narcolepsy-cataplexy and sought for genotypic effects on disease symptoms. No evidence of association between genotype or allele frequencies of both MAO-A or COMT gene and narcolepsy was found. However, a sexual dimorphism and a strong effect of COMT genotype on disease severity were found. Women narcoleptics with high COMT activity fell asleep twice as fast as those with low COMT activity during the multiple sleep latency test (MSLT) while the opposite was true for men. COMT genotype also strongly affected the presence of sleep paralysis and the number of REM sleep onsets during the MSLT. In agreement with well-documented pharmacological results in canine narcolepsy, this study reports the first genetic evidence for the critical involvement of the dopaminergic and/or noradrenergic systems in human narcolepsy.

The homeostatic regulation of sleep need is under genetic control.

Delta power, a measure of EEG activity in the 1-4 Hz range, in slow-wave sleep (SWS) is in a quantitative and predictive relationship with prior wakefulness. Thus, sleep loss evokes a proportional increase in delta power, and excess sleep a decrease. Therefore, delta power is thought to reflect SWS need and its underlying homeostatically regulated recovery process. The neurophysiological substrate of this process is unknown and forward genetics might help elucidate the nature of what is depleted during wakefulness and recovered during SWS. We applied a mathematical method that quantifies the relationship between the sleep-wake distribution and delta power to sleep data of six inbred mouse strains. The results demonstrated that the rate at which SWS need accumulated varied greatly with genotype. This conclusion was confirmed in a "dose-response" study of sleep loss and changes in delta power; delta power strongly depended on both the duration of prior wakefulness and genotype. We followed the segregation of the rebound of delta power after sleep deprivation in 25 BXD recombinant inbred strains by quantitative trait loci (QTL) analysis. One "significant" QTL was identified on chromosome 13 that accounted for 49% of the genetic variance in this trait. Interestingly, the rate at which SWS need decreases did not vary with genotype in any of the 31 inbred strains studied. These results demonstrate, for the first time, that the increase of SWS need is under a strong genetic control, and they provide a basis for identifying genes underlying SWS homeostasis.

[Genetics of human narcolepsy]. / Génétique de la narcolepsie humaine.

Narcolepsy is known to be a complex disorder; both genetic and environmental factors play a role in its pathophysiology. Although narcolepsy presents one of the tightest association with a specific HLA antigen (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility, both monoaminergic and hypocretinergic systems seem to be involved and may interfere with the phenotype. Implication of the hypocretin system is well-established in both canine and murine narcolepsy (caused by mutation) and a consistent reduction in hypocretin neuron seems to be the cause of human narcolepsy. An autoimmune process is probable.

Magnesium involvement in sleep: genetic and nutritional models.

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.

Blood and brain magnesium in inbred mice and their correlation with sleep quality.

A strong genetic component in the regulation of blood magnesium (Mg) levels has been demonstrated. The regulation and distribution of brain Mg levels, however, have never been assessed. Herein we report on the genetic variation of peripheral and central Mg levels in six inbred strains of mice. In addition, the possible involvement of Mg in sleep regulation was assessed by establishing correlations between Mg and sleep parameters obtained before and after a 6-h sleep deprivation. Although genotype strongly determined blood Mg levels, it did not affect brain Mg, suggesting that central and peripheral Mg are regulated differently. Central Mg displayed a highly structure-specific distribution with frontal cortex having the highest and brain stem the lowest values. Whereas for the amount and distribution of baseline sleep only marginal correlations with Mg were found, Mg contents in four of nine brain structures were highly positively correlated with the length of slow-wave sleep episodes during recovery. This relationship suggests that higher levels of Mg in specific brain sites promote sleep quality as part of a recovery process.