NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss.

A loss in the necessary amount of sleep alters expression of genes and proteins implicated in brain plasticity, but key proteins that render neuronal circuits sensitive to sleep disturbance are unknown. We show that mild (4-6 h) sleep deprivation (SD) selectively augmented the number of NR2A subunits of NMDA receptors on postsynaptic densities of adult mouse CA1 synapses. The greater synaptic NR2A content facilitated induction of CA3-CA1 long-term depression in the theta frequency stimulation range and augmented the synaptic modification threshold. NR2A-knock-out mice maintained behavioral response to SD, including compensatory increase in post-deprivation resting time, but hippocampal synaptic plasticity was insensitive to sleep loss. After SD, the balance between synaptically activated and slowly recruited NMDA receptor pools during temporal summation was disrupted. Together, these results indicate that NR2A is obligatory for the consequences of sleep loss on hippocampal synaptic plasticity. These findings could advance pharmacological strategies aiming to sustain hippocampal function during sleep restriction.

Differential effects of GABAB receptor subtypes, {gamma}-hydroxybutyric Acid, and Baclofen on EEG activity and sleep regulation.

The role of GABA(B) 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. GABA(B) receptors are obligate dimers comprised of the GABA(B2) subunit and either one of the two GABA(B1) subunit isoforms, GABA(B1a) and GABA(B1b). To better understand the role of GABA(B) receptors in sleep regulation, we performed electroencephalogram (EEG) recordings in mice devoid of functional GABA(B) 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 GABA(B) receptors in the circadian organization of sleep. Several other sleep and EEG phenotypes pointed to a more prominent role for GABA(B1a) compared with the GABA(B1b) isoform. Moreover, we found that GABA(B1a) 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 GABA(B) 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 GABA(B)-receptor affinity. These results also indicate that all GBL effects are mediated through GABA(B) receptors, although these receptors do not seem to be involved in mediating the BAC-induced hypersomnia.

Effect of transnasal insufflation on sleep disordered breathing in acute stroke: a preliminary study.

BACKGROUND AND PURPOSE: Sleep disordered breathing (SDB) is frequent in acute stroke patients and is associated with early neurologic worsening and poor outcome. Although continuous positive airway pressure (CPAP) effectively treats SDB, compliance is low. The objective of the present study was to assess the tolerance and the efficacy of a continuous high-flow-rate air administered through an open nasal cannula (transnasal insufflation, TNI), a less-intrusive method, to treat SDB in acute stroke patients. METHODS: Ten patients (age, 56.8 ± 10.7 years), with SDB ranging from moderate to severe (apnea-hypopnea index, AHI, >15/h of sleep) and on a standard sleep study at a mean of 4.8 ± 3.7 days after ischemic stroke (range, 1-15 days), were selected. The night after, they underwent a second sleep study while receiving TNI (18 L/min). RESULTS: TNI was well tolerated by all patients. For the entire group, TNI decreased the AHI from 40.4 ± 25.7 to 30.8 ± 25.7/h (p = 0.001) and the oxygen desaturation index >3% from 40.7 ± 28.4 to 31 ± 22.5/h (p = 0.02). All participants except one showed a decrease in AHI. The percentage of slow-wave sleep significantly increased with TNI from 16.7 ± 8.2% to 22.3 ± 7.4% (p = 0.01). There was also a trend toward a reduction in markers of sleep disruption (number of awakenings, arousal index). CONCLUSIONS: TNI improves SDB indices, and possibly sleep parameters, in stroke patients. Although these changes are modest, our findings suggest that TNI is a viable treatment alternative to CPAP in patients with SDB in the acute phase of ischemic stroke.

Pathogenesis of adult-onset Still's disease: new insights from the juvenile counterpart.

Adult-onset Still's disease (AOSD) is a rare inflammatory disease characterized by the classical triad of daily fever, arthritis, and typical salmon-colored rash. Recent accumulation of knowledge, mostly arising from hereditary autoinflammatory diseases and from the systemic-onset juvenile idiopathic arthritis (sJIA), has given raise to new hypotheses on the pathophysiology of AOSD. In this review, we first discuss on the continuum between AOSD and sJIA. Then, we summarize current hypotheses on the underlying pathogenesis: (1) an infectious hypothesis; (2) an autoinflammatory hypothesis; (3) a lymphohistiocytic hypothesis; and (4) a hyperferritinemic hypothesis. Finally, we present the recent data suggesting that patients with AOSD fall into two distinct subgroups with different courses, one with prominent systemic features and one with chronic arthritis.

cGMP-dependent protein kinase type I is implicated in the regulation of the timing and quality of sleep and wakefulness.

Many effects of nitric oxide (NO) are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3',5'-monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases (PRKGs), which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1) in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS) duration and in non-REM sleep (NREMS) consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG) power in the delta frequency range (1-4 Hz) under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep.

Effect of transnasal insufflation on sleep disordered breathing in acute stroke: a preliminary study.

BACKGROUND AND PURPOSE: Sleep disordered breathing (SDB) is frequent in acute stroke patients and is associated with early neurologic worsening and poor outcome. Although continuous positive airway pressure (CPAP) effectively treats SDB, compliance is low. The objective of the present study was to assess the tolerance and the efficacy of a continuous high-flow-rate air administered through an open nasal cannula (transnasal insufflation, TNI), a less-intrusive method, to treat SDB in acute stroke patients. METHODS: Ten patients (age, 56.8 ± 10.7 years), with SDB ranging from moderate to severe (apnea-hypopnea index, AHI, >15/h of sleep) and on a standard sleep study at a mean of 4.8 ± 3.7 days after ischemic stroke (range, 1-15 days), were selected. The night after, they underwent a second sleep study while receiving TNI (18 L/min). RESULTS: TNI was well tolerated by all patients. For the entire group, TNI decreased the AHI from 40.4 ± 25.7 to 30.8 ± 25.7/h (p = 0.001) and the oxygen desaturation index >3% from 40.7 ± 28.4 to 31 ± 22.5/h (p = 0.02). All participants except one showed a decrease in AHI. The percentage of slow-wave sleep significantly increased with TNI from 16.7 ± 8.2% to 22.3 ± 7.4% (p = 0.01). There was also a trend toward a reduction in markers of sleep disruption (number of awakenings, arousal index). CONCLUSIONS: TNI improves SDB indices, and possibly sleep parameters, in stroke patients. Although these changes are modest, our findings suggest that TNI is a viable treatment alternative to CPAP in patients with SDB in the acute phase of ischemic stroke.

Childhood epilepsy with neuropsychological regression and continuous spike waves during sleep: epilepsy surgery in a young adult.

We describe the case of a man with a history of complex partial seizures and severe language, cognitive and behavioural regression during early childhood (3.5 years), who underwent epilepsy surgery at the age of 25 years. His early epilepsy had clinical and electroencephalogram features of the syndromes of epilepsy with continuous spike waves during sleep and acquired epileptic aphasia (Landau-Kleffner syndrome), which we considered initially to be of idiopathic origin. Seizures recurred at 19 years and presurgical investigations at 25 years showed a lateral frontal epileptic focus with spread to Broca's area and the frontal orbital regions. Histopathology revealed a focal cortical dysplasia, not visible on magnetic resonance imaging. The prolonged but reversible early regression and the residual neuropsychological disorders during adulthood were probably the result of an active left frontal epilepsy, which interfered with language and behaviour during development. Our findings raise the question of the role of focal cortical dysplasia as an aetiology in the syndromes of epilepsy with continuous spike waves during sleep and acquired epileptic aphasia.

Viral- and myelin-specific cellular immune response in patients treated with natalizumab: a cross-sectional and a longitudinal prospective study

Introduction: Natalizumab, a monoclonal antibody binding to the alpha4 integrins, is efficient in preventing relapses and progression of disability in multiple sclerosis (MS) patients. However, a total of seven MS patients treated with natalizumab suffered from progressive multifocal leukoencephalopathy (PML), on a total of 53?000 patients (data of March 6, 2009) treated with this drug. PML is a disease affecting immunosuppressed people, which is caused by the polyomavirus JC (JCV). This virus produces a lytic infection of the oligodendrocytes. Yet, natalizumab cannot be considered as a classical immunosuppressant, such as suggested by the fact that no increased incidence of other opportunistic infections was reported with this drug. It has been postulated that, by closing the blood-brain, natalizumab might prevent JCV-specific CD8_ T cells to reach the CNS and perform immune surveillance. Alternatively, it has been suggested that this drug acts by releasing JCV from the bone marrow, one of its site of latency. In this study, we address the question whether there is an increased activity of JCV in the blood of natalizumab-treated MS patients. Material and Methods: In this prospective longitudinal study, we are following a cohort of 24 MS patients receiving monthly injections of natalizumab. Blood and urine are drawn every one to three months, up to 12 months. As a control group, we follow 16 MS patients treated with IFN-beta. For this control group, there are two time-points: before and 1094 months after treatment onset. We are analysing the viral (JCV-, EBV- and CMV-) as well as the myelin- (MOG-, MOBP-) specific cellular immune responses using proliferation and ELISPOT (IFNgamma) assays. For JCV, we study the response against VP1, the major capsid protein. For JCV VP1, MOG and MOBP, we use 15-mer peptides overlapping by 10 amino acids, thus eliciting CD4_ as well as CD8_ T cell response. These peptides encompasse the whole sequence of the proteins. For EBV and CMV, we use pools of immunodominant 8- to 10-mer peptides eliciting CD8_ T cells. At the same time-points, using RTPCR, we determine the presence of JCV DNA coding for the VP1 protein in the PBMC, plasma, and urine. Results: At the time of writing this abstract, 16 patients have reached the 9-month (T9), and 11 the T12 time-point. We expect that by the ISNV meeting in June 2009, 18 and 14 patients will be at T9 and T12, respectively. Virological and immunological results will be presented. 9th International Symposium on NeuroVirology 2_6 June 2009 39 J Neurovirol Downloaded from informahealthcare.com by Cantonale et Universitaire on 06/25/10 For personal use only. Conclusions: This ongoing longitudinal prospective study should tell us whether there is an enhanced JCV activity in the peripheral blood of patients on natalizumab. This work is supported by the FNS (PP00B-106716), the Swiss MS Society and a research grant from Biogen Dompe.

Reduction in the use of diagnostic tests in infants with risk factors for early-onset neonatal sepsis does not delay antibiotic treatment.

Despite a low positive predictive value, diagnostic tests such as complete blood count (CBC) and C-reactive protein (CRP) are commonly used to evaluate whether infants with risk factors for early-onset neonatal sepsis (EOS) should be treated with antibiotics. We investigated the impact of implementing a protocol aiming at reducing the number of diagnostic tests in infants with risk factors for EOS in order to compare the diagnostic performance of repeated clinical examination with CBC and CRP measurement. The primary outcome was the time between birth and the first dose of antibiotics in infants treated for suspected EOS. Among the 11,503 infants born at ≥35 weeks during the study period, 222 were treated with antibiotics for suspected EOS. The proportion of infants receiving antibiotics for suspected EOS was 2.1% and 1.7% before and after the change of protocol (p = 0.09). Reduction of diagnostic tests was associated with earlier antibiotic treatment in infants treated for suspected EOS (hazard ratio 1.58; 95% confidence interval [CI] 1.20-2.07; p <0.001), and in infants with neonatal infection (hazard ratio 2.20; 95% CI 1.19-4.06; p = 0.01). There was no difference in the duration of hospital stay nor in the proportion of infants requiring respiratory or cardiovascular support before and after the change of protocol. Reduction of diagnostic tests such as CBC and CRP does not delay initiation of antibiotic treatment in infants with suspected EOS. The importance of clinical examination in infants with risk factors for EOS should be emphasised.

Systemic-onset juvenile idiopathic arthritis: the changing life of a rare disease.

Systemic-onset juvenile idiopathic arthritis (SoJIA), sometimes called Still's disease, is a systemic inflammatory disease classified within the spectrum of juvenile idiopathic arthritis (JIA). It is an orphan disease with often a chronic course and a major impact on the affected children and their families. This disorder is unique in terms of clinical manifestations, prognosis and response to conventional immunosuppressants. The objectives of this review are to describe SoJIA and emphasise the recent advances in the pathogenesis and treatment, which have transformed the care and the prognosis of this potentially life-threatening paediatric condition.

Sporadic late-onset nemaline myopathy with MGUS: Long-term follow-up after melphalan and SCT.

OBJECTIVE: Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset myopathy that progresses subacutely. If associated with a monoclonal gammopathy of unknown significance (MGUS), the outcome is unfavorable: the majority of these patients die within 1 to 5 years of respiratory failure. This study aims to qualitatively assess the long-term treatment effect of high-dose melphalan (HDM) followed by autologous stem cell transplantation (SCT) in a series of 8 patients with SLONM-MGUS. METHODS: We performed a retrospective case series study (n = 8) on the long-term (1-8 years) treatment effect of HDM followed by autologous SCT (HDM-SCT) on survival, muscle strength, and functional capacities. RESULTS: Seven patients showed a lasting moderate-good clinical response, 2 of them after the second HDM-SCT. All of them had a complete, a very good partial, or a partial hematologic response. One patient showed no clinical or hematologic response and died. CONCLUSIONS: This case series shows the positive effect of HDM-SCT in this rare disorder. Factors that may portend an unfavorable outcome are a long disease course before the hematologic treatment and a poor hematologic response. Age at onset, level and type of M protein (κ vs λ), and severity of muscle weakness were not associated with a specific outcome. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with SLONM-MGUS, HDM-SCT increases the probability of survival and functional improvement.

Of great tits and fleas: sleep baby sleep

Many bird parasites reduce their hosts' fitness and, as a consequence, anti-parasite behaviour such as preening and nest sanitation has evolved. These activities are time consuming and, during the day, compete directly with time devoted to foraging and food provisioning to nestlings. Moreover, infested hosts may have to allocate extra time to foraging in order to compensate for the energy loss that ectoparasites impose on the nestlings and parents. Alternatively, brooding females could, at the expense of sleeping, allocate more time to preening and nest sanitation at night. If sleeping has a short-term restoring function, one may then expect a reduction in feeding efficiency of sleep-deprived females. In this study, the effect of a haematophagous ectoparasite, the hen flea, on the activity budgets of breeding female great tits during the day and at night was investigated experimentally. Time allocated to nest sanitation increased only slightly from 0.6 % of daytime in ectoparasite-free nests to 2.8% of daytime in infested nests, thus demonstrating the higher priority given to food provisioning than parasite control. Females in infested nests reduced their sleeping time significantly (73.5% of night-time in parasite-free nests versus 48.1% in infested nests). The time freed from the reduction of sleeping time was mainly used for nest sanitation (8.3% of night-time in parasite-free nests versus 27.1% in infested nests). Despite this strong decrease in sleeping time, there was no effect of ectoparasites on the females' rate of food provisioning to nestlings.