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Research Notes: Hypoxia - Effects and TreatmentSleep. 2007 Mar 1. STUDY OBJECTIVES: Obstructive sleep apnoea syndrome (OSAS) causes sleep related oxygen desaturation, excessive daytime sleepiness (EDS), and cognitive impairment. The role of hypoxic brain damage, sleep fragmentation, and the associated comorbidities (hypertension, vascular disorders) in the pathogenesis of cognitive deficits remains controversial. The aim of this study was to evaluate the cerebral metabolism of OSAS patients in vivo before and after CPAP treatment. DESIGN AND PATIENTS: Fourteen OSAS patients without cardiovascular or cerebrovascular impairment underwent the same protocol before and after 6 months of CPAP including: overnight videopolysomnography (VPSG), Multiple Sleep Latency Test (MSLT), and within the next 2 days neuropsychological and 1H-MRS evaluations. Single voxel 1H-MRS was performed in the parietal-occipital cortex, and absolute concentrations of N-acetyl-aspartate (NAA), creatine, and choline were measured, acquiring spectra at multiple echo-times and using water as internal standard. Ten matched controls were also studied. RESULTS: OSAS patients had a mean RDI of 58/hr, a mean arousal index of 57/hr, and a mean nadir SpO2 of 71%. Before CPAP, all patients showed a normal global cognitive functioning, with only a small number of pathological tasks in working memory and attention tests in a minority of patients. CPAP therapy was effective in resolving sleep apnoea and normalizing sleep structure, and improving EDS and neuropsychological alterations. Before CPAP treatment cortical [NAA] in OSAS (11.86 mM +/- 0.80, mean +/- SD) was significantly lower than in controls (12.85 +/- 0.93; P = 0.01) and positively correlated with minimum SpO2 during sleep (r = 0.69; P = 0.006) and MSLT scores (r = 0.62; P = 0.01). Cortical [NAA] reduction persisted after therapy (11.94 +/- 1.33; P = 0.87 versus pre-CPAP). CONCLUSIONS: OSAS patients have cortical metabolic changes consistent with neuronal loss even in the absence of vascular comorbidities. Metabolic changes persisted after CPAP in the absence of EDS, nocturnal arousals, and major cognitive deficits, likely related to hypoxic damage prior to CPAP treatment. Biochem Biophys Res Commun. 2006 Oct 13. cDNA arrays compared gene expression in kidneys of neonatal mice subjected to 1, 2, and 4 weeks of chronic constant (CCH) or intermittent (CIH) hypoxia with normoxic littermates. Five to twenty percent of genes were regulated in each condition, with greater changes in CCH. Up-regulation of 42% of the solute carriers after 1 week of CCH suggests a strong activation of pH controlling pathways. Significant reduction in expression change of genes important in growth, development, and aging as a function of time indicates reduced maturation rate in CIH and CCH treatments. Regulated genes showed gender dependence in CCH, being higher in females than males at 1 week and higher in males than females thereafter. Transcriptional control was enhanced in CCH but not in CIH. Thus, CCH and CIH both alter gene expression and retard maturation with the more profound changes occurring in CCH than in CIH. Intern Med. 2006 Sep 15. Since first cloned and reported by Zhang et al in 1994 (Nature 372:425), the obese gene and its product - leptin - has been studied profoundly. Our knowledge in body weight regulation and the role played by leptin has increased substantially. Leptin serves as an adiposity signal to inform the brain of the adipose tissue mass in a negative feedback loop regulating food intake and energy expenditure. Many articles have reported weight loss at high altitude, but the explanation has been limited to loss of appetite. New ideas were highlighted after studies by Grosfeld et al and Ambrosini et al on the obese gene under hypoxia condition. Cells with hypoxia treatment upregulated obese gene transcription and suggested that enhancement of leptin secretion in vivo under hypoxia environment may be one of the potential therapeutic methods for obesity treatment. Exp Physiol. 2006 Sep. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor composed of HIF-1alpha and HIF-1beta subunits that functions as a master regulator of oxygen homeostasis. Oxygen-dependent hydroxylation of HIF-1alpha provides a mechanism that allows changes in oxygenation to be transduced to the nucleus, leading to changes in gene expression. Hypoxia-inducible factor 1 plays critical roles in development, physiology and disease pathogenesis. Analyses of mice that are heterozygous for a null allele at the locus encoding the HIF-1alpha subunit have demonstrated that partial deficiency of HIF-1 is sufficient to impair multiple physiological responses to continuous and intermittent hypoxia. PLoS Med. 2006 Aug 22. Background: Childhood obstructive sleep apnea (OSA) is associated with neuropsychological deficits of memory, learning, and executive function. There is no evidence of neuronal brain injury in children with OSA. We hypothesized that childhood OSA is associated with neuropsychological performance dysfunction, and with neuronal metabolite alterations in the brain, indicative of neuronal injury in areas corresponding to neuropsychological function. Methods and findings: We conducted a cross-sectional study of 31 children (19 with OSA and 12 healthy controls, aged 6-16 y) group-matched by age, ethnicity, gender, and socioeconomic status. Participants underwent polysomnography and neuropsychological assessments. Proton magnetic resonance spectroscopic imaging was performed on a subset of children with OSA and on matched controls. Neuropsychological test scores and mean neuronal metabolite ratios of target brain areas were compared. Relative to controls, children with severe OSA had significant deficits in IQ and executive functions (verbal working memory and verbal fluency). Children with OSA demonstrated decreases of the mean neuronal metabolite ratio N-acetyl aspartate/choline in the left hippocampus (controls: 1.29, standard deviation [SD] 0.21; OSA: 0.91, SD 0.05; p = 0.001) and right frontal cortex (controls: 2.2, SD 0.4; OSA: 1.6, SD 0.4; p = 0.03). Conclusions: Childhood OSA is associated with deficits of IQ and executive function and also with possible neuronal injury in the hippocampus and frontal cortex. We speculate that untreated childhood OSA could permanently alter a developing child's cognitive potential. Excerpts from the full text article: Editors' Summary Background. Sleep is essential for health, and in children it is crucial to normal development. Symptomatic childhood sleep-disordered breathing (SDB) is the name for a range of conditions in which children have difficulties with breathing when they are asleep. The conditions range from simple snoring to the most severe condition, known as obstructive sleep apnea (OSA). Apnea means a temporary absence of breathing, and in OSA this is caused by a temporary but repeated blockage of the flow of air to the lungs. In children, OSA occurs for a number of reasons including enlarged tonsils, long-term allergy, and obesity. About two in every hundred children have OSA. The symptoms of OSA are loud snoring at night, disrupted, restless sleep, undue tiredness, and difficulties in concentration. The main test for it is a sleep study (polysomnography). If untreated, researchers believe that it may lead to a number of long-term problems with health and learning; children with disorders of sleep have been shown to have memory problems, lower general intelligence, and worse executive function (the ability to adapt to new situations), and may have behavioral problems similar to those of attention deficit hyperactivity disorder (ADHD). Why Was This Study Done? Adults with sleep apnea have been shown to have abnormalities of parts of their brain, specifically the frontal cortex, cerebellum, and hippocampus, but so far there are no data on whether there are similar changes in children. Children with sleep apnea may have cognitive deficits, but the research on this topic is limited. What Did the Researchers Do and Find? The researchers wanted to investigate the brains of children with OSA to see if there was any evidence of changes in the brain and if these changes were associated with any learning problems. They studied 31 children (19 with OSA and 12 healthy controls, aged 6-16 y). Participants underwent polysomnography and neuropsychological assessments, such as IQ tests and tests of their ability to perform tasks involving decision making. Some of the children also had specialized scans of their brains (known as proton magnetic resonance spectroscopic imaging) that can measure the levels of certain metabolites - substances that are produced as a result of brain activity. The researchers then compared the neuropsychological test scores with the levels of the metabolites. They found that relative to controls, children with severe OSA had lower IQ and ability to perform tasks involving decision making. Children with OSA also had changes in metabolites in the brain similar to those seen in diseases in which there is damage to brain cells. What Do These Findings Mean? It seems clear that OSA in children is associated with learning problems, and that these learning problems may in turn be associated with changes in brain metabolites. The changes in metabolites are not necessarily permanent - in other diseases where changes have been found they can be reversed with treatment. If these results are confirmed in other children with OSA, it will highlight the importance of treating children for OSA as soon as possible. In addition, the measurement of metabolites may be a way of measuring how well children are responding to treatment. Introduction Individuals require a wide range of cognitive skills in order to function in society, so if the acquisition of these skills is perturbed during development, there may be a long-term effect on cognitive and psychological function. Obstructive sleep apnea (OSA) - defined as obstructed breathing efforts during sleep [1] with resultant gas exchange abnormalities and sleep fragmentation [2] - has been linked to increased cardiovascular mortality, increased automobile accidents, and cognitive function impairments in adults. Untreated childhood OSA enormously increases health resource utilization [3], and has been associated with growth problems, cardiovascular consequences, and neuropsychological dysfunctions such as learning and memory problems [4,5], decreased attention, and poor school performance [6]. From a cognitive standpoint, adult OSA has been linked to deficits of executive function (flexible adaptation to novel situations with an organized, goal-directed approach) [7]. In children, gains of executive function skills occur during developmental periods corresponding to the neuronal myelination and maturation of the prefrontal cortex [8,9]. Executive function is considered critical for school-age children to develop complex problem solving [10] and perform other volitional tasks in response to new situations with demands on working memory [11]. If untreated OSA causes neuropsychological or executive dysfunction in developing children, and if these skills are permanently impaired before maturation of the prefrontal cortex, it could severely alter a child's cognitive potential, ultimately impacting both the child's health and his or her functioning level in society. Symptomatic childhood sleep-disordered breathing (SDB), which includes simple snoring and labored breathing, and partial obstructions that might not meet the adult criteria for OSA [12,13], has long been associated with behavioral dysfunctions including aggression, impulsivity, hyperactivity, and decreased attention based on subjective data provided by parents or teachers [14-21]. These behaviors mimic those associated with attention deficit hyperactivity disorder (ADHD), a disorder that presents with alterations in executive function [22]. Objective measurements of specific neuropsychological performance deficits related to sleep problems in children have been limited; however, recent studies have begun to identify significant differences in cognitive function between children with SDB and healthy controls. For example, Gottlieb and colleagues found significantly lower performance on measures of memory, executive function, and general intelligence in 5-y-old children with symptoms of SDB than in asymptomatic children [23]. O'Brien et al. demonstrated decreased general intelligence, language, and visual-spatial skills in 87 habitually snoring children [24]. O'Brien's group demonstrated even more significant neuropsychological deficits in children with more severe apnea [25]. The mechanisms causing these neuropsychological deficits have not been fully delineated. While sleepiness and sleep fragmentation might be readily reversible with treatment, neuronal injury resulting from long-term oxygen saturation abnormalities might represent a more pervasive health risk. There is evidence of altered brain function associated with blood gas abnormalities. Patients with sleep apnea have reduced cerebral blood flow and altered cerebrovascular responses to hypercapnia [26,27]. Hypoxia causes neuronal injury in vulnerable parts of the brain, especially the cerebellum and hippocampus, where the formation of lactate and free radicals is thought to lead to cellular injury [28,29]. The hippocampus is critically involved in learning and memory. Sleep deprivation in rats alters the synaptic plasticity of the hippocampus [30], and impairs hippocampus-mediated contextual learning [31] and spatial learning [32]. Intermittent hypoxia also causes spatial learning deficits and increased motor activity in juvenile rats [33]. The mechanism proposed for the spatial learning deficits observed in rats involved apoptosis of subpopulations of hippocampal neurons [34]. The authors suggested that the behaviors demonstrated by rats exposed to intermittent hypoxia were similar to those demonstrated by children with sleep apnea. Imaging studies of adults with sleep apnea have identified abnormal morphology of the frontal cortex, cerebellum, and hippocampus [35,36]. Functioning in a complex integrated network, these brain areas are important for executive function, motor regulation of breathing [35,37], and memory function, respectively. Altered central nervous system metabolites of neuronal white and gray matter in OSA patients have been demonstrated using proton magnetic resonance spectroscopy imaging (MRSI). The authors suggested that hypoxemia resulting from sleep apnea might have caused cerebral neuronal injury. There is recent evidence that suggests a link between hippocampal metabolite alterations and deficits of cognitive function in adults with OSA [38]. These studies provide evidence that SDB is associated with observable reductions in cognitive function in both adults and children. In adults with sleep apnea, there are measurable morphological abnormalities in the brain, but adults with OSA often suffer from comorbid health problems such as diabetes [39], hypertension, and cardiovascular disease [40], which could confound the association. There have been no studies demonstrating such neuronal injury in children with sleep apnea. These studies are crucial, since childhood OSA impacts a rapidly developing brain, and thus the long-term consequences of neuronal injury may be far greater than those seen in adults. The purpose of this study was to examine the neuropsychological deficits associated with moderate to severe childhood sleep apnea, and to determine whether these deficits are associated with neuronal changes in vulnerable target areas of the brain. We hypothesized that SDB would be associated with neuropsychological dysfunction in the areas of executive function, learning, and memory; and that central nervous system metabolite alterations would be observed in brain regions associated with these functions, i.e., the hippocampus and frontal cortex. Methods [...] This was a cross-sectional study of participants aged 6-16 y with moderate to severe OSA compared to non-snoring healthy children group-matched by age, ethnicity, gender, and socioeconomic status (SES). OSA patients were identified by polysomnographic sleep studies performed at the Johns Hopkins sleep lab. All tests were performed while the OSA patients were awaiting surgical management. OSA participants met enrollment criteria if they had moderate to severe OSA by our definition, i.e., an apnea hypopnea index (AHI) = 8 (see "Polysomnography" for definition of apnea). All participants underwent polysomnography and a battery of neuropsychological tests. Proton MRSI of the brain was performed on a subset of OSA participants and control children (those who met inclusion criteria and could tolerate imaging time without sedation). [...] The age range for this study was selected based on several criteria. The selected neuropsychological tests have been standardized and validated in this age range. Furthermore, there is a track record of success of brain imaging in children of this age range at our center, without the need for behavior training or sedation. Additionally, normal neuronal metabolite concentrations in the brain have been established for children in this age range [41-43]. Imaging studies in childhood OSA have not been performed previously, therefore we chose children with severe sleep apnea to more likely identify possible neuronal injury associated with OSA. Exclusionary criteria. Exclusionary criteria included a full scale IQ score < or = 75 on initial testing, neurological abnormalities revealed by history or radiological or electroencephalogram (EEG) studies, use of psychotropic or sedative medications for the last 2 wk before study, or non-English speakers because of the difficulty of performing neuropsychological tests through an interpreter. Children were also excluded if there was a history of significant medical, psychiatric, vision, or hearing impairment, or mental retardation. Children with life-threatening sleep apnea requiring emergency management were also excluded. Children with other sleep problems such as insomnia, parasomnias, bedtime behavior difficulties, restless legs syndrome, or abnormal movement during sleep were excluded. Children with sleep apnea who had a previous diagnosis or symptoms of ADHD or a history of chronic hyperactivity (n = 5) were not excluded because of the common overlap of these disorders with OSA; however, data analyses were performed both with and without these children for comparison. Furthermore, the children with OSA and ADHD were assessed only while off psychotropic medication for more than 2 wk. All participants were screened to ensure that they had no contraindications for MRI, namely claustrophobia, cardiac pacemaker, orthodontics (braces), or other non-magnetic-resonance-compatible surgical/ferromagnetic implant. If contraindications were noted, children were allowed to proceed with neuropsychological testing but MRI was not performed. Normal control children were not excluded for ADHD if they otherwise met criteria (healthy, non-snoring, no other exclusion criteria or psychotropic medications). Control children with subsequent findings of AHI >1, or prolonged hypercapnia (>50 mm Hg for >20% of total sleep time) measured by polysomnogrpahy were excluded, and there was no crossover to the OSA group. Polysomnography Polysomnography was performed on all participants. During the sleep study, surface electrodes and monitoring devices measured signals from central EEG, right and left electro-oculogram, surface EMG, ECG, chest and abdominal wall motion, and end-tidal PCO2 (Novametrix, Wallingford, Connecticut, United States). Pulse oximetry with an 8-s averaging time was used to record the time in minutes of any oxygen saturation less than 95% to detect brief oxygen saturation changes (Masimo, Irvine, California, United States). Airflow was measured by oro-nasal thermistor in all children. Additionally, nasal pressure was monitored in order to obtain a more quantitative flow signal (Protech, Mukilteo, Washington, United States). Polysomnogram data were displayed digitally (Alice 4, Atlanta, Georgia, United States). All studies were monitored with real-time video for motion analysis and snoring recording. Respiratory parameters of interest included arousals, apneas, and hypopneas, low oxygen saturation time (SaO2T), hypercapnia time, and oxygen saturation nadir (SaO2N). The arousal index (AI) was the number of arousals and awakenings measured by a shift of EEG signal to the alpha or beta range for greater than 3s (as previously defined by the American Sleep Disorders Association [44]) divided by the total sleep time in hours. An apnea was defined as an absence of airflow for two or more breath cycles. Hypopnea was a visible decrease in airflow by nasal pressure signal (or by thermistor when pressure signal was unavailable) and either an EEG arousal or a drop in oxygen saturation of 3% or greater. A mixed apnea was an obstructive apnea in combination with a central (absent effort) apnea. The AHI comprised the obstructive, mixed, and hypopnea events divided by total sleep time in hours; central apneas were not included in the AHI. SaO2T was the time (in minutes) with oxygen saturations less than 95% (in order to detect mild intermittent desaturations), and SaO2N was the severity of oxygen desaturation. Hypercapnia time was the time in minutes that the end-tidal CO2 monitor detected a CO2 level greater than 50 mm Hg. There is no established definition of mild, moderate, or severe sleep apnea in children. OSA in adults is defined by the AHI: the number of apnea or hypopnea (partial obstruction) events per hour. However, continuous partial obstruction is underestimated by these criteria, and is considered significant by the Johns Hopkins Sleep Program. The AHI in normal non-snoring children has been determined to be less than 1.0 with little hypercapnia (time with CO2 > 50 mm Hg) [45-47]. For this protocol, mild OSA was defined as AHI 1-5, moderate OSA as AHI 5-10, and severe OSA as AHI greater than 10. Neuropsychological Evaluation [...] The protocol was selected to include areas considered to be vulnerable in children with OSA - executive function and memory - as abnormalities of these brain systems may negatively impact psychosocial function and have been shown to be affected in adults with sleep apnea [48]. In addition, domains hypothesized to be less affected in children with OSA (visual-spatial perception and motor speed) were also included for comparison. Global intelligence was measured using the full scale IQ scores from WISC-III [49] (n=15) or WISC-IV [50] (n=16). In addition to IQ, the assessment protocol included measures of executive function (i.e., response preparation, inhibition, and working memory), attention, verbal and visual memory, neuromotor function, cerebellar function (i.e., perceptual and motor timing), and visual-spatial perception. [...] Polysomnography Results Respiratory parameters for OSA and control groups are listed in Table 2. The mean and median AHI in the OSA group fell into the severe range by our criteria, although there was a large standard deviation in time with oxygen saturation less than 95% (SaO2T; 0-271 min), SaO2N (48%-96%), and time with CO2 levels greater than 50 mm Hg (0-371 min). Neuropsychological Function Results of neuropsychological test performance for all groups are listed in Table 3. Children with OSA had significantly lower scores than matched controls on full scale IQ. The OSA group also had significantly lower performance on measures of executive function, including verbal working memory (sentence span) and word fluency (measured by the Delis-Kaplan Executive Function System (D-KEFS) category fluency test). In contrast, the executive functions reported to be impaired in adult sleep apnea [5,56,57] (i.e., problem solving and planning, inhibitory control, sustained attention, and vigilance) were not affected in children with severe sleep apnea. There were no significant differences between groups on any of the other neuropsychological variables; however, both visual-spatial memory (Children's Memory Scale Dot Locations, η2 = 0.10) and verbal memory (California Verbal Learning Test for Children, η2 = 0.09) demonstrated large effect sizes, suggesting that, with a larger sample, statistically significant differences between groups on these measures might be detected. Motor speed, perceptual timing, and motor timing (dependent on cerebellar functioning) were also not affected in our full sample of sleep apnea patients; however, when the children with ADHD were excluded from the OSA group, there was a significant deficit noted on the perceptual timing task (η2 = 0.29, p < 0.05). The group differences in full scale IQ, verbal working memory, and word fluency remained significant after the children with ADHD were excluded. BMI was noted to correlate with decreased IQ (r = -0.45, p = 0.019); however, when BMI was controlled for the AHI (after confirming BMI overlap between the groups), this effect was no longer significant (r = -0.32, p = 0.106). Proton MRSI Proton MRSI studies of the brain were performed in a subset of children with OSA and controls. Children with ADHD were analyzed and reported separately (see Tables 4 and 5; the OSA group excluding ADHD are labeled as "OSA/not ADHD" in the tables). Of the 31 eligible children successfully completing a polysomnogram, 26 underwent some or all of the brain imaging studies. Dropouts or exclusions from brain imaging included the following: one with metal dental work and four who could not tolerate the MRI (three obese children complained of claustrophobia). Regions of interest in the brain scan corresponded to areas hypothesized to be linked to neuropsychological deficits, including white and gray matter of the frontal and parietal lobes, assessed by MRSI, and the middle left hippocampus and cerebellum, assessed by the single voxel method. The total scan time was 1 h. The children were not sedated; therefore, some regions of interest were unable to be analyzed because of motion artifact (n varies depending on the image reported). Single voxel spectroscopy measurements of the body of the left hippocampus were analyzed in 12 children (six patients with OSA and six controls; see Figure 1), and results are reported in Table 4. Within this subsample, there were no significant differences between groups in age, maternal education, gender distribution (χ2 = 4.4, p = 0.08), handedness (χ2 = 0.1, p = 0.65), or race (χ2 = 0.02, p = 0.73). The group differences in neuropsychological test scores in this subsample continued to show a large effect size. Compared to controls, the OSA group had a significant decrease in hippocampal NAA/Cho (p = 0.001) and a significant increase of Cho/Cr (p = 0.03), indicating abnormal neuronal metabolism in the static state. These differences remained when the subsample was analyzed excluding the child with ADHD from the OSA group. There was little overlap of results between the two groups in this subsample aged 9-16 y (see Figure 2). Only two children under age 9 underwent single voxel MRSI of the hippocampus (one 7-y-old in each group; the control was male and the OSA patient was female). The OSA patient had an AHI of 33.8, but her NAA/Cr ratio demonstrated an unusual value (2.16), more than twice that of all the other OSA patients, and significantly higher than that of all the normal children (range of NAA/Cr levels for all OSA and control participants: 0.89-1.98). When results were compared including these younger children, the increased Cho/Cr in the OSA group remained significant (p = 0.05), while NAA/Cho was no longer significantly decreased because of the unusual value of NAA/Cr in the OSA patient driven by the increased NAA spectral peak (see Discussion). MRSI of cortical structures was performed in 13 children (seven OSA patients and six controls), and results are presented in Table 5. Within this subsample, there were no significant differences between groups in age, maternal education, gender distribution (χ2 = 1.6, p = 0.23), handedness (χ2 = 0.1, p = 0.57), or race (χ2 = 1.4, p = 0.51). There continued to be a large effect size difference in neuropsychological test scores between groups. Metabolite ratios were compared between groups in frontal and parietal white and gray matter, as well as thalamus, putamen, and premotor cortex. There was a significant difference between groups in the NAA/Cho ratio in right frontal cortex (p = 0.03). This difference was even more significant when we excluded children with ADHD from the OSA sample (p = 0.008). There were no significant group differences (regardless of ADHD status) in the other brain areas measured using MRSI. Single voxel MRSI studies of the cerebellum in 12 children (five controls and seven OSA patients) showed no differences between groups on cerebellar metabolite ratios: Cho/Cr (p = 0.53, η2 = 0.04), NAA/Cr (p = 0.61, η2 = 0.03), or NAA/Cho (p = 0. 24, η2 = 0.14), although given the large effect size for NAA/Cho, the difference might be significant with a larger sample. Discussion To our knowledge, this is the first study utilizing MRSI to measure central nervous system metabolites in children with OSA, and to identify central nervous system changes associated with neuropsychological dysfunction in childhood OSA. This study demonstrated two primary findings: (A) neuronal metabolites in pediatric OSA patients were altered in the hippocampus and the right frontal cortex, indicating possible neuronal injury linked to severe childhood OSA, and (B) children with severe OSA had significantly lower IQ and executive control functions compared to normal children matched for age, gender, ethnicity, and SES. These cognitive functions depend on neuronal networks corresponding to the structures where we identified metabolite alterations. In the current study, children with sleep apnea and neuropsychological dysfunction demonstrated decreased levels of NAA/Cho in both the hippocampus and the right frontal cortex. The brain areas affected are important in IQ and executive function and corroborate the findings from morphological studies of adult OSA showing decreased gray matter in the same regions [35,36]. While these findings do not necessarily indicate a causal relationship between OSA and neuronal abnormality (i.e., it is not known whether sleep apnea causes brain damage or pre-existing brain damage causes sleep apnea), it will be important to determine to what extent these findings reverse with treatment. The NAA signal localizes predominantly to neurons, axons, and dendrites within the central nervous system. Decreased NAA signal is notably seen in diseases with neuro-axonal loss or dysfunction [58,59], while increases in Cho occur in pathological conditions during active demyelination, as well as with changes of membrane metabolism or glial cell reaction [60,61]. Normal changes in Cho are also seen during myelin maturation in early development [41], but tend to be stable after age 2 y [43]. Previous animal studies of irreversible cerebral ischemia demonstrated decreased NAA signals by proton MRSI within minutes of injury, and these metabolite signals were detected prior to changes noted by typical magnetic resonance imaging [51]. NAA/Cho alterations are not necessarily permanent, as noted in studies of childhood encephalopathy or acute multiple sclerosis where reduced NAA/Cho improved after resolution of illness [62,63]. Therefore, dysfunction or acute injury to the axon can lead to decreased NAA prior to axonal loss. It is not clear, however, whether long-standing metabolite alterations are reversible, or whether there is a vulnerable age of neuronal plasticity that leads to permanent brain injury with neuronal metabolite alterations [64,65]. The laterality of our findings to the right frontal cortex is interesting, particularly given the neuropsychological findings involving verbal working memory and fluency, thought to lateralize to the left frontal cortex. Executive functions are supported by a distributed neural network with cortical and subcortical components including the frontal cortex and its striatal-thalamic-cerebellar connections [7,11,57,66]. Volumetric studies of adults with OSA demonstrate diffuse gray matter loss bilaterally in the frontal lobes, but those participants may have had long-standing OSA [35]; therefore, our finding in children may reflect changes earlier in the course of disease. The neuronal metabolite levels of NAA/Cho in the hippocampus were significantly reduced in children with OSA aged 9-16 y compared to controls, as demonstrated in Figure 2, where there is virtually no overlap between the two groups. We identified a younger child (a 7-y-old female with OSA) with unusually high NAA/Cr and NAA/Cho levels driven by a high NAA spectral peak. There are regional variations of NAA and Cho concentrations in the brain, and NAA/Cho levels are known to increase with age, especially between birth and age 2 y, but increases are subtle after age 2, up to a peak at age 10 y [43]; therefore, the elevated NAA/Cho in the 7-y-old OSA patient would not be an expected age-related change [41,43,67,68]. An increase in NAA is associated with increasing axon density, increased dendrites, and increased synaptic connections [41]. In rats exposed to intermittent hypoxia, apoptosis of hippocampal neurons correlating with spatial memory dysfunction was later reversed by neurogenesis, which is a unique capability of the hippocampus [33]. Additionally, gender-specific protection from brain injury in females [69] has been seen in experiments using intermittent hypoxia, which caused decreased branching dendrites in male but not female rats during development. The increased NAA spectral peak noted in the 7-y-old female with OSA might be an outlier, or might represent neuronal recovery and neurogenesis in the damaged hippocampal neurons as seen in the animal studies. This finding requires validation with young participants in order to determine whether certain age groups or genders are more susceptible to neuronal injury or recovery. The findings of decreased IQ and altered executive function demonstrated by our study suggest that OSA can impact a child's ability to learn and adapt to new challenges, or to perform in school. The participants in our study had severe sleep apnea. Although the prevalence of severe childhood sleep apnea is not known, 17% of otherwise healthy children aged 6-16 y referred to our clinic from the local primary care providers for symptoms of SDB fall into this category. The neuropsychological deficits in this study of children with severe sleep apnea were more profound than those found in previous studies of mild OSA. However, these results corroborate the findings of several pediatric studies of cognition in childhood SDB, where deficits in general intelligence [23,25,55,70-73] and some measures of executive function [23,25,74] were noted. Compared to previous findings in adults with OSA, some executive functions (i.e., problem solving, planning, inhibitory control, and sustained attention) were not affected in children with severe sleep apnea [5,75]. Motor speed was also not affected in our sleep apnea patients. Unlike most other pediatric studies of neuropsychological deficits linked to mild or moderate SDB, we enrolled children with severe sleep apnea from a lower socioeconomic area with lower maternal education. The IQ levels were more profoundly impacted in our children with OSA compared to previous pediatric studies, with the exception of the Montgomery-Downs study of at-risk children [70], the O'Brien study of significant sleep apnea in children with a minority population of 60% (mean AHI 9.8) [25], and the Rhodes study of teenagers where the participants were morbidly obese [55]. These studies demonstrated that multiple risk factors may be additive in terms of neuropsychological consequences. In contrast to our study, the neuropsychological differences between apnea and control populations in the vast majority of pediatric studies may be underestimated because of enrollment of affluent populations with either high maternal education or high average IQ levels (conferring a possible protective effect on measurable neuropsychological deficits) [15,21,23,71,74,76], or because of design limitations such as the inclusion of children with snoring or mild OSA (AHI 1-5) in the control group [23,55,76] or the lack of confirmation of normal breathing in control groups defined with a polysomnogram [15,21,73,74,77]. The OSA participants in our study were significantly more overweight or obese than the control participants. This study limitation reflects the reality of our referral population, in which more than 40% of our general pediatric clinic patients are reported to be at risk for obesity. We were unable to recruit enough non-snoring obese controls to match for obesity, and snoring controls were excluded because of previous studies demonstrating that snoring is not normal [24]. Most studies focusing on the neuropsychological impacts of childhood sleep apnea do not include information on the BMI of the children enrolled. Obesity is a risk factor for SDB and is a common finding in children referred to sleep centers [78]. Both SDB and obesity can affect quality of life [79,80]. If obesity and SDB interact, these combined problems as well as lifestyle factors linked with obesity (such as television time) may play an important role in exacerbating neuropsychological impairments associated with sleep apnea. We admitted into our study five children with OSA who had symptoms or a diagnosis of ADHD given the common overlap of sleep disturbances and daytime symptoms in children with ADHD and with OSA [81]. It is difficult to distinguish ADHD as a premorbid versus comorbid feature associated with sleep apnea. Likewise, many children seen in the clinic have symptoms of hyperactivity or ADHD but have not undergone formal diagnostic testing, therefore underestimating the prevalence of a comorbid disorder. It has been previously shown that executive functions are impaired in children with ADHD [82], especially notably in children with average or less than average IQ levels [83]. When children with ADHD were excluded from the OSA population, the significance of our findings did not change, indicating that they were not influencing our results. In clinical studies of OSA, it is difficult to differentiate the effects of sleep fragmentation from hypoxemia on neuropsychological function, since by definition the AHI encompasses both sleep fragmentation and oxygen saturation abnormalities. This study was not designed to separate these factors. Although the magnitude of the association of respiratory parameters to cognitive deficits was stronger than that of the AI, the AI might play a significant role in cognitive deficits with a larger sample. Several pediatric studies of snoring children without gas exchange abnormalities (often termed "primary snoring") demonstrate effects on attention [24,71,72,74], IQ [23,24,71,72], or memory [23,72], indicating a possible role for sleep fragmentation or sleep disruption in neuropsychological dysfunction. The participants in our study were older, with more severe apnea, than the participants in studies of primary snoring, suggesting that age or severity of OSA may contribute to the relative neuropsychological impacts of sleep fragmentation versus oxygen deprivation injury. There may be a spectrum of SDB, from sleep fragmentation, to mild disease, to more severe disease. However, chronic sleep disruption during active brain development could potentially lead to permanent decreased cognitive potential, thus causing as serious a situation as oxygen deprivation to the brain. We were limited to the number of participants available in this study because of the expense of brain imaging. We acknowledge that some comparisons may have shown statistically significant group differences with larger samples, and effect sizes are reported to assist in the interpretation of effects for future research. For example, cerebellar neuronal abnormalities associated with childhood OSA and related neuropsychological dysfunction (e.g., perceptual timing) may indeed be observed in larger samples. Childhood OSA has a prevalence of about 2% in the general population [84,85], and severe sleep apnea cases represent 17% of the otherwise normal school-aged children referred to our sleep center. OSA in adults has been linked to increased cardiovascular morbidity and mortality, increased automobile accidents, and cognitive function impairments. We found that childhood OSA is associated with deficits of IQ and executive function and also with abnormal neuronal metabolites in the hippocampus and frontal cortex, indicating possible neuronal injury. We speculate that untreated childhood OSA could permanently alter the trajectory of a developing child's ultimate cognitive potential, resulting in a lifetime of health and economic impacts. It remains to be determined if early identification and treatment can reverse the neuronal and performance deficits identified in this study of childhood OSA. Future studies will need to address the effect of treatment, and explore gender- and age-related differences in vulnerability to help target early diagnosis and treatment most effectively. [...] References
Int J Pediatr Otorhinolaryngol. 2006 May. Objective: While otolaryngologists consider growth failure an absolute indication for tonsillectomy and adenoidectomy (T&A), they may not be accustomed to screening for poor growth, and thus unlikely to consider it when recommending a T&A. This paper will (a) familiarize otolaryngologists with the definition, prevalence, and etiology of growth failure and (b) review the published findings that examine the inter-relationship among sleep disordered breathing, growth failure, and adentonsillar hypertrophy in children. Methods: This paper is divided into three sections. The first section presents a brief overview of growth failure for the otolaryngologist. The second section reviews the evidence base linking sleep disordered breathing, growth failure, and adenotonsillar hypertrophy in children. The anthropometric outcomes of children presenting for T&A, or having sleep symptoms assessed, are presented. The third section presents pilot data (n=28) on the prevalence of growth failure and sleep disordered breathing among children presenting for T&A at our institution. Results: Among children presenting for T&A or having sleep symptoms assessed, growth failure was at least twice the expected rate in six of eight published studies. Across these six studies, this rate ranged from a low of 6% of children <3rd percentile for weight and 6% <3rd percentile for height in one study, to a high of 52% who were <3rd percentile in weight in a second study, and 44% who were <or= 5th percentile for height in a third. Among children presenting for T&A at our own institution, 14% were <or=5th percentile in height, and 11% were <or=5th percentile in weight. Among children under 6 years of age, 21% were either <or= 5th percentile in weight and/or height. Conclusions: Published studies, as well as our own pilot data support the hypothesis that SDB, secondary to adenotonsillar hypertrophy, increases the risk of growth failure in children. Adenotonsillar hypertrophy and sleep disordered breathing may be unrecognized risk factors in the etiology of growth failure. Otolaryngologists can play an important role in identifying growth failure and referring children to the appropriate specialists. J Pediatr Psychol. 2006 Apr. Objective: The purpose of the current study was to examine prevalence of and relations between a commonly used measure of nighttime breathing problems, the Respiratory Disturbance Index (RDI), and a range of problem behaviors in community children. Methods: Participants were 403 unreferred children aged 6-12 years. Recruitment was completed through public elementary schools. Overnight unattended in-home polysomnography was used to assess sleep and breathing. The RDI was used as the indicator of respiratory events during sleep. The Child Behavior Checklist and the Conners' Parent Rating Scales-Revised were used to assess behavior. Results: Prevalence rates for Attention, Cognitive Problems, Aggression, Oppositional behavior, and Social Problems were greatest for subjects with high RDIs. Prevalence for Internalizing behaviors was not greater for those subjects with high RDIs. Hyperactivity was not strongly related to higher RDIs. Conclusions: Behavioral problems may exist in the presence of nocturnal breathing events in unreferred children. Specific patterns of behavioral morbidity have still not been established. Some behaviors, such as hyperactivity, may show differing sensitivity and specificity in relation to the RDI. Am J Physiol Regul Integr Comp Physiol. 2006 Apr. Chronic hypoxia, whether continuous (CCH) or intermittent (CIH), occurs in many neonatal pathological conditions, such as bronchopulmonary dysplasia and obstructive sleep apnea. In this study, we explored the effect of CCH and CIH on cerebral capillary density and myelination. We subjected CD-1 mice starting at postnatal day 2 to either CCH 11% oxygen (O(2)), or CIH 11% O(2) (4-min cycles), for periods of 2 and 4 wk followed by reoxygenation for 4 wk. Mice were deeply anesthetized and perfused. Brains were removed to fixative for 24 h, then paraffin-embedded. Coronal brain sections were taken for analysis. Immunocytochemistry for glucose transporter 1 was used to assess angiogenesis, and Luxol fast blue and fluoromyelin stains were used to assess myelination. Capillary density increased after 2-wk exposure to CIH and CCH. By 4 wk, capillary density increased in both CIH and CCH by 25% and 47%, respectively, in cortex and by 29% and 44%, respectively, in hippocampus (P < 0.05). There was a decrease in myelination in the corpus callosum of mice exposed to CIH (75% of control) and CCH (50% of control) (P < 0.05). Reoxygenation reversed the increased capillary density seen in CCH to normoxic values. However, dysmyelination that occurred in CCH-exposed mice did not show any improvement upon reoxygenation. We conclude that neonatal chronic hypoxia 1) induces brain angiogenesis, which is reversible with reoxygenation, and 2) irreversibly reduces the extent of myelination in the corpus callosum. This potential irreversible effect on myelination in early life can, therefore, have long-term and devastating effects. Zhonghua Jie He He Hu Xi Za Zhi. 2006 Apr. Objective: To explore the regulation of hypothalamus-pituitary-adrenal (HPA) axis and growth hormone (GH) axis in obstructive sleep apnea-hypopnea syndrome (OSAHS). Methods: OSAHS patients (OSAHS group) and subjects with obesity alone (control group) were monitored by polysomnography (PSG). The corticotropin-releasing hormone (CRH), growth hormone releasing hormone (GHRH), corticotropin (ACTH), cortisol and growth hormone levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay before and after sleep. Their correlation were analyzed. Results: The CRH concentration [(1.66 +/- 0.34), (4.96 +/- 0.98) mmol/L before and after sleep] and cortisol content [(152.93 +/- 136.15), (445.53 +/- 123.09) microg/L before and after sleep] in the OSAHS group were significantly higher than those of the control group [CRH was (0.67 +/- 0.42), (2.27 +/- 1.10) mmol/L, cortisol concentration was (68.94 +/- 20.13), (146.05 +/- 30.48) microg/L, before and after sleep, respectively, all P < 0.01]; GHRH significantly decreased in the OSAHS group [(1.42 +/- 0.07), (1.01 +/- 0.05) mmol/L before and after sleep] compared with the control group [(1.99 +/- 0.34), (1.58 +/- 0.15) mmol/L, respectively; all P < 0.01]; but there was no difference in growth hormone. The ratio of the variation of CRH, GHRH level (DeltaCRH/DeltaGHRH) was significantly higher in the OSAHS group (285.02 +/- 143.32) than that in the control group (71.15 +/- 15.37, P < 0.01). The bivariate correlation analysis of the OSAHS group indicated that DeltaCRH/DeltaGHRH was correlated positively with average awake duration (r = 0.882), but negatively with average blood oxygen concentration (r = -0.696). The average blood oxygen concentration was negatively correlated with average awake duration (r = -0.729). Conclusions: There are abnormal changes of HPA axis and GH axis in OSAHS patients, and the feedback regulation is disordered. These abnormalities are related to sleep structure variation and hypoxia during sleep. Stroke. 2006 Feb. Background and purpose: Cerebral ischemic insults disrupt normal respiratory activity in mitochondria. Carnitine plays an essential role in mitochondrial metabolism and in modulating excess acyl-coenzyme A (acyl-CoA) levels. The effects of cerebral ischemia on carnitine metabolism are not well understood, although the newborn may be particularly vulnerable to carnitine deficiency. We used a newborn rat model of hypoxia-ischemia (HI) to test the hypothesis that HI alters acyl-CoA:CoA homeostasis and that this effect can be prevented by treatment with carnitine. Methods: A total of 120 postnatal day 7 rats were subjected to 70 minutes of HI after treatment with 16 mmol/kg intraperitoneal l-carnitine or diluent. Carnitine, acylcarnitines, and excitatory amino acids were measured by mass spectrometry, and carnitine acetyl transferase activity, superoxide, and levels of the mitochondrial phospholipid cardiolipin (CL) were measured at 2- and 24-hour recovery. Results: HI and hypoxia were associated with a significant increase in the ratio of acyl-CoA:CoA, which was prevented by treatment with carnitine. Carnitine treatment also prevented increases in glutamate, glycine, superoxide, and decrease of CL. Conclusions: Carnitine metabolic pathways are compromised in HI and hypoxia. The protective effect of carnitine treatment on HI injury may be attributable to maintaining mitochondrial function. J Appl Physiol. 2005 Nov. Obstructive sleep apnea (OSA), a condition tightly linked to obesity, leads to chronic intermittent hypoxia (CIH) during sleep. There is emerging evidence that OSA is independently associated with insulin resistance and fatty liver disease, suggesting that OSA may affect hepatic lipid metabolism. To test this hypothesis, leptin-deficient obese (ob/ob) mice were exposed to CIH during the light phase (9 AM-9 PM) for 12 wk. Liver lipid content and gene expression profile in the liver (Affymetrix 430 GeneChip with real-time PCR validation) were determined on completion of the exposure. CIH caused a 30% increase in triglyceride and phospholipid liver content (P < 0.05), whereas liver cholesterol content was unchanged. Gene expression analysis showed that CIH upregulated multiple genes controlling 1) cholesterol and fatty acid biosynthesis [malic enzyme and acetyl coenzyme A (CoA) synthetase], 2) predominantly fatty acid biosynthesis (acetyl-CoA carboxylase and stearoyl-CoA desaturases 1 and 2), and 3) triglyceride and phospholipid biosynthesis (mitochondrial glycerol-3-phosphate acyltransferase). A majority of overexpressed genes were transcriptionally regulated by sterol regulatory element-binding protein (SREBP) 1, a master regulator of lipogenesis. A 2.8-fold increase in SREBP-1 gene expression in CIH was confirmed by real-time PCR (P = 0.001). Expression of major genes of cholesterol biosynthesis, SREBP-2 and 3-hydroxy-3-methylglutaryl-CoA reductase, was unchanged. In conclusion, we have shown that CIH may exacerbate preexisting fatty liver of obesity via upregulation of the pathways of lipid biosynthesis in the liver. Am J Respir Crit Care Med. 2005 Oct 1. Rationale: Persons with obstructive sleep apnea may have significant residual hypersomnolence, despite therapy. Long-term hypoxia/reoxygenation events in adult mice, simulating oxygenation patterns of moderate-severe sleep apnea, result in lasting hypersomnolence, oxidative injury, and proinflammatory responses in wake-active brain regions. We hypothesized that long-term intermittent hypoxia activates brain NADPH oxidase and that this enzyme serves as a critical source of superoxide in the oxidation injury and in hypersomnolence. Objectives: We sought to determine whether long-term hypoxia/reoxygenation events in mice result in NADPH oxidase activation and whether NADPH oxidase is essential for the proinflammatory response and hypersomnolence. Methods: NADPH oxidase gene and protein responses were measured in wake-active brain regions in wild-type mice exposed to long-term hypoxia/reoxygenation. Sleep and oxidative and proinflammatory responses were measured in adult mice either devoid of NADPH oxidase activity (gp91phox-null mice) or in which NADPH oxidase activity was systemically inhibited with apocynin osmotic pumps throughout hypoxia/reoxygenation. Main results: Long-term intermittent hypoxia increased NADPH oxidase gene and protein responses in wake-active brain regions. Both transgenic absence and pharmacologic inhibition of NADPH oxidase activity throughout long-term hypoxia/reoxygenation conferred resistance to not only long-term hypoxia/reoxygenation hypersomnolence but also to carbonylation, lipid peroxidation injury, and the proinflammatory response, including inducible nitric oxide synthase activity in wake-active brain regions. Conclusions: Collectively, these findings strongly support a critical role for NADPH oxidase in the lasting hypersomnolence and oxidative and proinflammatory responses after hypoxia/reoxygenation patterns simulating severe obstructive sleep apnea oxygenation, highlighting the potential of inhibiting NADPH oxidase to prevent oxidation-mediated morbidities in obstructive sleep apnea. Circ Res. 2005 Sep 30. Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lep(ob) mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl-coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity. Physiol Genomics. 2005 Aug 11. Chronic constant hypoxia (CCH), such as in pulmonary diseases or high altitude, and chronic intermittent hypoxia (CIH), such as in sleep apnea, can lead to major changes in the heart. Molecular mechanisms underlying these cardiac alterations are not well understood. We hypothesized that changes in gene expression could help to delineate such mechanisms. The current study used a neonatal mouse model in CCH or CIH combined with cDNA microarrays to determine changes in gene expression in the CCH or CIH mouse heart. Both CCH and CIH induced substantial alterations in gene expression. In addition, a robust right ventricular hypertrophy and cardiac enlargement was found in CCH- but not in CIH-treated mouse heart. On one hand, upregulation in RNA and protein levels of eukaryotic translation initiation factor-2alpha and -4E (eIF-2alpha and eIF-4E) was found in CCH, whereas eIF-4E was downregulated in 1- and 2-wk CIH, suggesting that eIF-4E is likely to play an important role in the cardiac hypertrophy observed in CCH-treated mice. On the other hand, the specific downregulation of heart development-related genes (e.g., notch gene homolog-1, MAD homolog-4) and the upregulation of proteolysis genes (e.g., calpain-5) in the CIH heart can explain the lack of hypertrophy in CIH. Interestingly, apoptosis was enhanced in CCH but not CIH, and this was correlated with an upregulation of proapoptotic genes and downregulation of anti-apoptotic genes in CCH. In summary, our results indicate that 1) the pattern of gene response to CCH is different from that of CIH in mouse heart, and 2) the identified expression differences in certain gene groups are helpful in dissecting mechanisms responsible for phenotypes observed. Am J Respir Crit Care Med. 2005 Jun 15. Rationale: Long-term intermittent hypoxia (LTIH) exposure in adult mice, modeling oxygenation patterns of moderate-severe obstructive sleep apnea, results in lasting hypersomnolence and is associated with nitration and oxidation injuries in many brain regions, including wake-active regions. Objectives: We sought to determine if LTIH activates inducible nitric oxide synthase (iNOS) in sleep/wake regions, and if this source of NO contributes to the LTIH-induced proinflammatory gene response, oxidative injury, and wake impairments. Methods: Mice with genetic absence of iNOS activity and wild-type control animals were exposed to 6 weeks of long-term hypoxia/reoxygenation before behavioral state recordings, molecular and biochemical assays, and a pharmacologic intervention. Measurements and main results: Two weeks after recovery from hypoxia/reoxygenation exposures, wild-type mice showed increased iNOS activity in representative wake-active regions, increased sleep times, and shortened sleep latencies. Mutant mice, with higher baseline sleep times, showed no effect of long-term hypoxia/reoxygenation on sleep time latencies and were resistant to hypoxia/reoxygenation increases in lipid peroxidation and proinflammatory gene responses (tumor necrosis factor alpha and cyclooxygenase 2). Inhibition of iNOS after long-term hypoxia/reoxygenation in wild-type mice was effective in reversing the proinflammatory gene response. Conclusions: These data support a critical role for iNOS activity in the development of LTIH wake impairments, lipid peroxidation, and proinflammatory responses in wake-active brain regions, and suggest a potential role for inducible NO inhibition in protection from proinflammatory responses, oxidative injury, and residual hypersomnolence in obstructive sleep apnea. [Note: Interesting study that suggests that those with PWS with untreated sleep-related breathing disturbances may be at increased risk for sepsis and sepsis-like conditions due to increased iNOS activity as a result of long-term intermittent hypoxia.]] Pediatr Res. 2005 Jun. Elevated plasma homocysteine has been linked to pregnancy complications and developmental diseases. Whereas hyperhomocysteinemia is frequently observed in populations at risk of malnutrition, hypoxia may alter the remethylation of homocysteine in hepatocytes. We aimed to investigate the combined influences of early deficiency in nutritional determinants of hyperhomocysteinemia and of neonatal hypoxia on homocysteine metabolic pathways in developing rats. Dams were fed a standard diet or a diet deficient in vitamins B12, B2, folate, month, and choline from 1 mo before pregnancy until weaning of the offspring. The pups were divided into four treatment groups corresponding to "no hypoxia/standard diet," "hypoxia (100% N2 for 5 min at postnatal d 1)/standard diet," "no hypoxia/deficiency," and "hypoxia/deficiency," and homocysteine metabolism was analyzed in their liver at postnatal d 21. Hypoxia increased plasma homocysteine in deficient pups (21.2 +/- 1.6 versus 13.3 +/- 1.2 microM, p < 0.05). Whereas mRNA levels of cystathionine beta-synthase remained unaltered, deficiency reduced the enzyme activity (48.7 +/- 2.9 versus 83.6 +/- 6.3 nmol/h/mg, p < 0.01), an effect potentiated by hypoxia (29.4 +/- 4.7 nmol/h/mg, p < 0.05). The decrease in methylene-tetrahydrofolate reductase activity measured in deficient pups was attenuated by hypoxia (p < 0.05), and methionine-adenosyltransferase activity was slightly reduced only in the "hypoxia/deficiency" group (p < 0.05). Finally, hypoxia enhanced the deficiency-induced drop of the S-adenosylmethionine/S-adenosylhomocysteine ratio, which is known to influence DNA methylation and gene expression. In conclusion, neonatal hypoxia may increase homocysteinemia mainly by decreasing homocysteine transsulfuration in developing rats under methyl-deficient regimen. It could therefore potentiate the well-known adverse effects of hyperhomocysteinemia. Pediatrics. 2004 Dec. Objective: To assess whether sleep-disordered breathing (SDB), ranging from primary snoring to obstructive sleep apnea (OSA), is associated with increased behavioral morbidity. Methods: A cross-sectional study was conducted of school-aged children in an urban, community-based cohort, stratified for term or preterm (<37 weeks' gestation) birth status. A total of 829 children, 8 to 11 years old (50% female, 46% black, 46% former preterm birth) were recruited from a cohort study. All children had unattended in-home overnight cardiorespiratory recordings of airflow, respiratory effort, oximetry, and heart rate for measurement of the apnea hypopnea index (number of obstructive apneas and hypopneas per hour). SDB was defined by either parent-reported habitual snoring or objectively measured OSA. Functional outcomes were assessed with 2 well-validated parent ratings of behavior problems: the Child Behavioral Checklist and the Conners Parent Rating Scale-Revised:Long. Results: Forty (5%) children were classified as having OSA (median apnea hypopnea index: 7.1 per hour; interquartile range: 3.1-10.5), 122 (15%) had primary snoring without OSA, and the remaining 667 (80%) had neither snoring nor OSA. Children with SDB had significantly higher odds of elevated problem scores in the following domains: externalizing, hyperactive, emotional lability, oppositional, aggressive, internalizing, somatic complaints, and social problems. Conclusions: Children with relatively mild SDB, ranging from primary snoring to OSA, have a higher prevalence of problem behaviors, with the strongest, most consistent associations for externalizing, hyperactive-type behaviors. J Pediatr. 2004 Oct. Objective: To assess the relation of sleep-disordered breathing (SDB) symptoms in children to neurocognitive function. Study design: A cross-sectional, population-based study of 205 5-year-old children. A parent-completed questionnaire was used to ascertain SDB symptoms, defined as frequent snoring, loud or noisy breathing during sleep, or witnessed sleep apnea. Polysomnography (PSG) data were available in 85% of children. Standardized neurocognitive tests were administered by a trained psychometrist unaware of the children's SDB status. Children with (n=61) and without SDB symptoms were compared using analysis of variance to adjust for demographic and respiratory health variables. Results: Children with SDB symptoms scored significantly lower than those without SDB symptoms on tests of executive function (95.5 vs 99.9 on NEPSY Attention/Executive Core Domain, P=.02; 10.4 vs 11.2 on Wechsler Preschool and Primary Scale of Intelligence, Revised [WPPSI-R] Animal Pegs test, P=.03), memory (96.8 vs 103.0 on NEPSY Memory Domain, P=.02), and general intellectual ability (105.9 vs 111.7 on WPPSI-R Full Scale IQ, P=.02). There were no significant differences on a computerized continuous performance task. These findings persisted when children with PSG evidence of obstructive sleep apnea (OSA) were excluded from analysis. Conclusion: Even in the absence of OSA, SDB symptoms are associated with poorer executive function and memory skills and lower general intelligence in 5-year-old children. The following is the National Institute of Health press release about the above study: Breathing problems during sleep may affect mental development in infants and young children (7-Oct-2004) Children who have problems breathing during sleep tend to score lower on tests of mental development and intelligence than do other children their age, according to two studies funded by the National Institutes of Health (NIH). Both studies appear in the October issue of Journal of Pediatrics. The first study, funded by the National Institute of Child Health and Human Development (NICHD), found that at one year of age, infants who have multiple, brief breathing pauses (apnea) or slow heart rates during sleep scored lower on mental development tests than did other infants of the same age. The second study was funded primarily by the National Heart, Lung, and Blood Institute (NHLBI). Results show that 5-year-old children who had frequent snoring, loud or noisy breathing during sleep, or sleep apneas observed by parents scored lower on intelligence, memory, and other standard cognitive tests than other children their age. They were also more likely to have behavioral problems. "The findings from these studies support other research that has shown that breathing problems during sleep are associated with serious health consequences in children," said Carl E. Hunt, M.D., director of the NIH National Center on Sleep Disorders Research (NCSDR). "However, at this point we don't know if the sleep problems during these episodes cause the decline in test scores or if the sleep episodes and the lower test scores are both related to some common underlying mechanism." More than 10 percent of young children have habitual snoring, the mildest form of sleep-disordered breathing (SDB). One to three percent of children have obstructive sleep apnea, a more severe form of SDB in which breathing stops briefly and repeatedly during sleep. SDB is thought to be more common in toddlers and younger children than in older children because the younger ones are more likely to have large tonsils and adenoids, which can briefly block the airways in the back of the throat during sleep. African American children are twice as likely to develop SDB compared to white children. Children who are overweight or obese are also more likely to develop SDB. In the first study, researchers evaluated 256 full-term and preterm infants at one year of age with a standardized test that measured physical and mental development. The infants were part of the multi-center Collaborative Home Infant Monitoring Evaluation (CHIME) study. The CHIME study sought to identify factors that could put infants at risk for sudden infant death syndrome (SIDS). Participants included healthy infants as well as those at increased risk of SIDS because they had a history of prematurity, a life-threatening event during sleep, or a sibling who had died from SIDS. The infants' breathing, heart rates, and blood oxygen levels were monitored electronically at home for the first 4-6 months of age. The researchers found that infants who totaled more than five episodes of abnormally slowed heart rate or apnea during the period they were monitored scored lower on the mental development test at one year of age than did infants who experienced fewer or no such episodes. The episodes were often associated with drops in oxygen levels. The lower mental development scores persisted even after data were adjusted to correct for other factors known to affect mental development in preterm infants. The study also found that full-term infants who experienced the abnormal episodes scored lower on the tests than did other full term infants, according to Hunt, the lead author, who conducted the research while at the Medical College of Ohio in Toledo. The second study involved 205 children at 5 years of age. Researchers at Boston University School of Medicine compared neurocognitive function and behavior of 61 children with SDB symptoms to 144 children without symptoms. Symptoms of SDB, as reported by parents, included frequent snoring; heavy, loud, or noisy breathing during sleep; or observed apneas during sleep. An overnight sleep test (polysomnogram) was also performed to objectively measure the severity of SDB. The study found that children with SDB symptoms scored lower on standard tests measuring executive function (attention and planning), memory, and general intelligence. These children also had significantly more behavioral problems than children without SDB symptoms, based on parental survey scores. "One of the more remarkable findings in this study was that the neurocognitive effects were significant even among the children who had mild symptoms of sleep-disordered breathing but no actual sleep apneas," said Daniel Gottlieb, M.D., M.P.H., lead author of the study. "Parents need to be aware that their child's snoring could signal serious problems." The mild SDB symptoms associated primarily with snoring in these children result in frequent arousals and fragmented sleep, leading to poor sleep quality and hence to sleep deprivation. Today's findings are similar to other studies of children and adults that link poor sleep or sleep deprivation to problems with school (or job) performance, difficulties with memory and concentration, increased risk of injuries, and trouble controlling impulses, emotions, and behavior, especially in children. "Unfortunately, the effects of poor sleep are often overlooked or misinterpreted in children. Rather than appearing sleepy like adults who are sleep deprived, children may in fact seem to be more active or even hyperactive," comments Hunt. In an accompanying editorial, Hunt notes that brain development is not complete until at least late childhood, and hence children may be uniquely vulnerable to SDB symptoms and their consequences, especially if such symptoms begin during infancy or early childhood. Brain areas, such as the prefrontal cortex, which regulate executive function, might be particularly susceptible to damage from SDB, writes Hunt. In addition, other researchers have reported that the effects of SDB appear to have long-term consequences for children. For example, a University of Louisville study found that young children who snored loudly and frequently were more likely to have lower grades in middle school - even several years after the breathing problem was treated or resolved. "These two new studies point to the need for parents and pediatricians to be on the watch for what might appear to be less serious breathing problems in their babies and young children when they sleep," notes Hunt. "If we can identify these children before the effects on mental development have occurred, the challenge then will be to identify possible ways to intervene and prevent any reduced potential for doing their best in school." Scientists have not yet determined safe and effective ways to reduce cardiorespiratory episodes in infants. In children, however, treatment for SDB typically involves having the tonsils and adenoids surgically removed. In more severe cases, or for children who cannot have surgery, a machine known as continuous positive airway pressure (CPAP), which forces air into the air passages while the patient is sleeping, can be as effective in children as it is in adults with sleep apnea. The health consequences associated with SDB in children are gaining increasing recognition. In April 2002, the American Academy of Pediatrics established clinical practice guidelines on obstructive sleep apnea in children. The guidelines call for all children to be screened for snoring and for children diagnosed with obstructive sleep apnea to be treated. Pediatrics. 2004 Sep. Objectives: Excessive daytime sleepiness (EDS) is seen less frequently as a presenting complaint in children with sleep-disordered breathing than in adults. Instead, symptoms of hyperactivity are often described. We hypothesized that children with suspected sleep-disordered breathing (S-SDB) were both sleepier and more hyperactive than control subjects. Furthermore, we hypothesized that overnight polysomnographic parameters correlated with sleepiness and hyperactivity. Methods: A cross-sectional study was conducted at a university-affiliated hospital and a community-based pediatric clinic. A total of 108 patients with S-SDB (mean [standard deviation] age: 7 +/- 4 years) and 72 control subjects (8 +/- 4 years) were recruited. A modified Epworth Sleepiness Scale (ESS) and the Conners Abbreviated Symptom Questionnaire were administered. Polysomnography was performed in patients with S-SDB. Results: Patients with S-SDB had a higher ESS (8.1 +/- 4.9 vs 5.3 +/- 3.9) and a higher Conners score (12.8 +/- 7.6 vs 9.0 +/- 6.2) than control subjects. On the basis of adult criteria, 28% of patients had EDS. There was no difference in the ESS and Conners scores of patients with primary snoring and patients with obstructive sleep apnea. The ESS had weak correlations with polysomnographic parameters. Conclusions: Although the ESS score of children with S-SDB was within the normal range for adults, these children were sleepier and more hyperactive than control subjects. However, these data should be confirmed by a population-based study. J Sleep Res. 2004 Sep. To assess obstructive sleep apnea syndrome (OSAS) and periodic limb movement disorder (PLMD) in children with attention deficit/hyperactivity disorder (ADHD) compared with a control group. The ADHD was diagnosed based on Diagnostic and Statistical Manual, version IV (DSM-IV) criteria on successively seen elementary school children aged 6-12 years referred to a psychiatric clinic for suspected ADHD. A standardized interview (Kiddie-SADS-E), parents and teacher questionnaires, neuropsychological testing, and nocturnal polysomnography were completed for each child. Eighty-eight children (77 boys) with ADHD and 27 controls were involved in the study. Fifty children with ADHD (56.8%) had an apnea-hypopnea index (AHI) >1 event h(-1) and 17 (19.3%) had an AHI >5 event h(-1). Nine children (10.2%) had a periodic limb movement index (PLMI) >5 events h(-1). There is one child with AHI >1 and none with a PLMI > 5 in the control group. In the test of variables of attention (TOVA), the response time was significantly worse in ADHD with sleep disorders than those without them. The child behavior checklist (CBCL) showed a significant difference between groups in the hyperactivity subscale. The diagnostic criteria for ADHD based on DSM-IV do not differentiate between children with or without sleep disorders. Evaluation of sleep disorders should be considered before starting drug treatment for ADHD. Zhonghua Jie He He Hu Xi Za Zhi. 2004 Aug. Objective: To explore the changes of serum adiponectin levels in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). Methods: Polysomnography was performed in 71 obese OSAHS patients (obese OSAHS group), 21 OSAHS patients without obesity (non-obese OSAHS group), 26 obese controls (obese group) and 22 normal healthy adults (control group). In both the obese OSAHS group and obese group, the body mass index (BMI) was higher than 25 and there was no significant difference in BMI. Serum adiponectin levels were measured by radioimmunoassay. Results: The serum adiponectin level in the control group [(8.9 +/- 0.6) mg/L] was significantly higher than those in the obese group [(7.1 +/- 1.3) mg/L, P < 0.05], the non-obese OSAHS group [(5.4 +/- 0.6) mg/L, P < 0.01] and the obese OSAHS group [(5.0 +/- 1.0) mg/L, P < 0.01] respectively. The serum adiponectin level was significantly lower in both the obese OSAHS group and the non-obese OSAHS group (all P < 0.05). The serum adiponectin levels between the obese OSAHS group and the non-obese OSAHS group showed no statistical difference (P > 0.05). In the obese OSAHS patients and the obese patients serum adiponectin levels were negatively correlated with AHI (r = -0.78, P < 0.01), BMI (r = -0.21, P < 0.05), waist circumference (r = -0.36, P < 0.01), and neck circumference (r = -0.42, P < 0.01), but positively correlated with minimal pulse oxygen saturation (r = 0.48, P < 0.01). Conclusions: Serum adiponectin levels were significantly lower in OSAHS patients than in the normal control and the obese patients. In addition to increased waist and neck circumferences, OSAHS may contribute to the decreased serum adiponectin level. Am J Pathol. 2004 Jun. As the average age in many countries steadily rises, heart infarction, stroke, and cancer become the most common causes of death in the 21st century. The c |