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Gharib, Sina A.; Dayyat, Ehab A.; Khalyfa, Abdelnaby; Kim, Jinkwan; Clair, Heather B.; Kucia, Magdalena; Gozal, David
doi: 10.1093/sleep/33.11.1439pmid: 21102985
AbstractBackground:Obstructive sleep apnea is a prevalent disorder associated with cognitive dysfunction and cardiovascular and metabolic morbidity and is characterized by recurrent episodes of hypoxia during sleep. Bone marrow-derived very small embryonic-like (VSEL) pluripotent stem cells represent a recruitable pool that may play an important role in organ repair after injury. We hypothesized that exposure to intermittent hypoxia (IH) can mobilize VSELs from the bone marrow (BM) to peripheral blood (PB) in mice and can activate distinct transcriptional programs.Methods:Adult mice were exposed to IH or normoxia for 48 hours. VSELs were sorted from BM and PB using flow cytometry. Plasma levels of stem cell chemokines, stromal cell derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and leukemia inhibitory factor (LIF) were measured. Transcriptional profiling of VSELs was performed, and differentially expressed genes were mapped to enriched functional categories and genetic networks.Results:Exposure to IH elicited migration of VSELs from BM to PB and elevations in plasma levels of chemokines. More than 1100 unique genes were differentially expressed in VSELs in response to IH. Gene Ontology and network analysis revealed the activation of organ-specific developmental programs among these genes.Conclusions:Exposure to IH mobilizes VSELs from the BM to PB and activates distinct transcriptional programs in VSELs that are enriched in developmental pathways, including central nervous system development and angiogenesis. Thus, VSELs may serve as a reserve mobile pool of pluripotent stem cells that can be recruited into PB and may play an important role in promoting end-organ repair during IH.
Beebe, Dean W.; Ris, M. Douglas; Kramer, Megan E.; Long, Elizabeth; Amin, Raouf
doi: 10.1093/sleep/33.11.1447pmid: 21102986
AbstractStudy Objectives:(1) to determine the associations of sleep disordered breathing (SDB) with behavioral functioning, cognitive test scores, and school grades during middle- to late-childhood, an under-researched developmental period in the SDB literature, and (2) to clarify whether associations between SDB and school grades are mediated by deflcits in cognitive or behavioral functioning.Design:Cross-sectional correlative study.Setting:Office/hospital, plus reported functioning at home and at school.Participants:163 overweight subjects aged 10–16.9 years were divided into 4 groups based upon their obstructive apnea+hypopnea index (AHI) during overnight polysomnography and parent report of snoring: Moderate-Severe OSA (AHI > 5, n = 42), Mild OSA (AHI = 1–5, n = 58), Snorers (AHI < 1 + snoring, n = 26), and No SDB (AHI < 1 and nonsnoring, n = 37).Measurements:Inpatient overnight polysomnography, parent- and self-report of school grades and sleep, parent- and teacher-report of daytime behaviors, and office-based neuropsychological testing.Results:The 4 groups significantly differed in academic grades and parent- and teacher-reported behaviors, particularly inattention and learning problems. These findings remained significant after adjusting for subject sex, race, socioeconomic status, and school night sleep duration. Associations with SDB were confined to reports of behavioral difficulties in real-world situations, and did not extend to office-based neuropsychological tests. Findings from secondary analyses were consistent with, but could not definitively confirm, a causal model in which SDB affects school grades via its impact on behavioral functioning.Conclusions:SDB during middle- to late-childhood is related to important aspects of behavioral functioning, especially inattention and learning difficulties, that may result in significant functional impairment at school.
Aran, Adi; Einen, Mali; Lin, Ling; Plazzi, Guiseppe; Nishino, Seiji; Mignot, Emmanuel
doi: 10.1093/sleep/33.11.1457pmid: 21102987
AbstractStudy Objective:To report on symptoms and therapies used in childhood narcolepsy-cataplexy.Design, Patients, and Setting:Retrospective series of 51 children who completed the Stanford Sleep Inventory. HLA-DQB1*0602 typing (all tested, and 100% positive), polysomnography or Multiple Sleep Latency Test (76%), and cerebrospinal fluid hypocretin-1 measurements (26%, all with low levels) were also conducted. Prospective data on medication response was collected in 78% using a specially designed questionnaire.Measurements and Results:Patients were separated into children with onset of narcolepsy prior to (53%), around (29%), and after (18%) puberty. None of the children had secondary narcolepsy. Clinical features were similar across puberty groups, except for sleep paralysis, which increased in frequency with age. Common features included excessive weight gain (84% ≥ 4 kg within 6 months of onset of narcolepsy) and earlier puberty (when compared with family members), notably in subjects who gained the most weight. Streptococcus-positive throat infections were reported in 20% of cases within 6 months of onset of narcolepsy. Polysomnographic features were similar across groups, but 3 prepubertal children did not meet Multiple Sleep Latency Test diagnostic criteria. Regarding treatment, the most used and continued medications were modafinil (84% continued), sodium oxybate (79%), and venlafaxine (68%). Drugs such as methylphenidate, tricyclic antidepressants, or selective serotonin reuptake inhibitors were often tried but rarely continued. Modafinil was reported to be effective for treating sleepiness, venlafaxine for cataplexy, and sodium oxybate for all symptoms, across all puberty groups. At the conclusion of the study, half of children with prepubertal onset of narcolepsy were treated “off label” with sodium oxybate alone or with the addition of one other compound. In older children, however, most patients needed more than 2 drugs.Conclusion:This study reports on the clinical features of childhood narcolepsy and documents the safe use of treatments commonly used in adults in young children.
Hagewoud, Roelina; Havekes, Robbert; Tiba, Paula A.; Novati, Arianna; Hogenelst, Koen; Weinreder, Pim; Van der Zee, Eddy A.; Meerlo, Peter
doi: 10.1093/sleep/33.11.1465pmid: 21102988
AbstractStudy Objectives:Dissociable cognitive strategies are used for place navigation. Spatial strategies rely on the hippocampus, an area important for flexible integration of novel information. Response strategies are more rigid and involve the dorsal striatum. These memory systems can compensate for each other in case of temporal or permanent damage. Sleep deprivation has adverse effects on hippocampal function. However, whether the striatal memory system can compensate for sleep-deprivation-induced hippocampal impairments is unknown.Design:With a symmetrical maze paradigm for mice, we examined the effect of sleep deprivation on learning the location of a food reward (training) and on learning that a previously nonrewarded arm was now rewarded (reversal training).Measurements and Results:Five hours of sleep deprivation after each daily training session did not affect performance during training. However, in contrast with controls, sleep-deprived mice avoided a hippocampus-dependent spatial strategy and preferentially used a striatum-dependent response strategy. In line with this, the training-induced increase in phosphorylation of the transcription factor cAMP response-element binding protein (CREB) shifted from hippocampus to dorsal striatum. Importantly, although sleep-deprived mice performed well during training, performance during reversal training was attenuated, most likely due to rigidity of the striatal system they used.Conclusions:Together, these findings suggest that the brain compensates for negative effects of sleep deprivation on the hippocampal memory system by promoting the use of a striatal memory system. However, effects of sleep deprivation can still appear later on because the alternative learning mechanisms and brain regions involved may result in reduced flexibility under conditions requiring adaptation of previously formed memories.
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doi: 10.1093/sleep/33.11.1428pmid: 21102981