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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 causes of these disorders are many and varied and include genetic predisposition and environmental influences, but they all share a common feature in that limitation of oxygen availability participates in the development of these pathological conditions. However, cells and organisms are able to trigger an adaptive response to hypoxic conditions that is aimed to help them to cope with these threatening conditions. This review provides a description of several systems able to sense oxygen concentration and of the responses they initiate both in the acute and also in long-term hypoxia adaptation. The role of hypoxia in three pathological conditions, myocardial and cerebral ischemia as well as tumorigenesis, is briefly discussed. Sleep. 2004 Mar 15. Study objectives: This study was designed to test the hypothesis that long-term intermittent hypoxia (LTIH), modeling the hypoxia-reoxygenation events of sleep apnea, results in oxidative neural injury, including wake-promoting neural groups, and that this injury contributes to residual impaired maintenance of wakefulness. Design: Sleep times and oxidative-injury parameters were compared for mice exposed to LTIH and mice exposed to sham LTIH. Subjects: Adult male C57BL/6J mice were studied. Interventions: Mice were exposed to LTIH or sham LTIH in the lights-on period daily for 8 weeks. Electrophysiologic sleep-wake recordings and oxidative-injury measures were performed either immediately or 2 weeks following LTIH exposures. Measurements and results: At both intervals, total sleep time per 24 hours in LTIH-exposed mice was increased by more than 2 hours, (P<.01). Mean sleep latency was reduced in LTIH-exposed mice relative to sham LTIH mice (8.9 +/- 1.0 minutes vs 12.7 +/- 0.5 minutes, respectively, P<.01). Oxidative injury was present 2 weeks following LTIH in wake-promoting regions of the basal forebrain and brainstem: elevated isoprostane 8,12-iso-IPF2alpha-VI, 22%, P<.05; increased protein carbonylation, 50%, P<.05, increased nitration, 200%, P<.05, and induction of antioxidant enzymes glutathione reductase and methionine sulfoxide reductase A, P<.01. Conclusions: Exposure to LTIH results in an array of significant oxidative injuries in sleep-wake regions of the brain, and these biochemical changes are associated with marked hypersomnolence and increased susceptibility to short-term sleep loss. The residual forebrain redox alterations in wake-promoting brain regions may contribute to persistent sleepiness in a prevalent disorder, obstructive sleep apnea. Biol Res Nurs. 2004 Jan. In children, moderate or severe sleep-disordered breathing (SDB) may impair cognitive executive functions (EFs), including working memory, attention, and mental flexibility. The main objective of this study was to assess EFs in children with mild levels of SDB. Subjects for this descriptive study were 12 children (5 girls, 7 boys) aged 8.0 to 11.9 years (M = 9.0 +/- 0.85) participating in an ongoing study of the effects of adenotonsillectomy on behavior. Each subject had a nocturnal polysomnogram (PSG) and a multiple sleep latency test (MSLT). Mild SDB was considered present if the child's apnea/hypopnea index (AHI) was > or = 1 and < 10. Between MSLT nap attempts, each child completed standardized tests of EFs. The sample showed significant impairment of sustained attention and vigilance on a computerized continuous performance test. Children with low mental flexibility scores on the Children's Category Test (CCT) spent more time in stage 1 sleep (12.2% v. 9.5%, P = 0.028 on PSG) and showed a marginally higher arousal index (9.7 v. 6.5, P = 0.06 on PSG) than children with average or above-average CCT scores. AHI accounted for a significant proportion of the variance in CCT scores when 1 outlier was removed (N = 11, Rsq = 0.67, P = 0.002). Mild levels of SDB and associated sleep architecture disruptions may be associated with impairment of EFs in children. Neuroscience. 2004. Chronic intermittent hypoxia (CIH), as occurs in obstructive sleep apnea (SA), is associated with substantial cortico-hippocampal damage leading to impairments of neurocognitive, respiratory and cardiovascular functions. Previous studies in a rat model have shown that CIH increases brain cortical neuronal cell death. However, the molecular events leading to CIH-mediated neuronal cell death remain largely undefined. The oscillation of O2 concentrations during CIH remarkably mimics the processes of ischemia/re-oxygenation and could therefore increase cellular production of reactive oxygen species (ROS). We extended the CIH paradigm to a mouse model of SA to identify the molecular mechanisms underlying cortical neuronal cell death. A significant increase of ROS production in mouse brain cortex and cortical neuronal cells was detected by fluorescent oxidation assays upon exposure of mice to CIH, followed by increased expression of oxidative stress response markers, c-Fos, c-Jun and NF-kappaB in mouse brain cortex, as revealed by immunohistochemical and LacZ reporter assays respectively. Long-term exposure of mice to CIH increased the levels of protein oxidation, lipid peroxidation and nucleic acid oxidation in mouse brain cortex. Furthermore, exposure of mice to CIH induced caspase-3 activation and increased some cortical neuronal cell apoptosis. On the other hand, transgenic mice overexpressing Cu,Zn-superoxide dismutase exposed to CIH conditions had a lower level of steady-state ROS production and reduced neuronal apoptosis in brain cortex compared with that of normal control mice. Taken together, these findings suggest that the increased ROS production and oxidative stress propagation contribute, at least partially, to CIH-mediated cortical neuronal apoptosis and neurocognitive dysfunction. Neuro Endocrinol Lett. 2003 Dec. Objectives: Decreased libido and a decline in morning serum testosterone levels were reported in men with obstructive sleep apnea (OSA). Our study aimed to evaluate the pituitary-gonadal axis in middle age men with OSA before and after treatment with nasal continuous positive airway pressure (CPAP). Material and methods: Measurement of the nocturnal serum luteinizing hormone (LH) and testosterone levels and sleep recordings before and after nine months of CPAP treatment in five men with OSA aged 49.5+/-5.2 years. Patients were evaluated during nocturnal sleep at base line and during CPAP treatment. Serum LH and testosterone levels were determined at 20 minutes interval between 1900h and 0700h with concomitant determination of sleep quality, respiration and oxygen saturation. Results: At base line, patients had higher RDI and PaO2<90%, lower mean and integrated (AUC) values of LH and testosterone. During CPAP treatment, RDI and PaO2<90% were normal. Mean and AUC values of testosterone and LH increased. Conclusions: OSA in men is associated with dysfunction of the pituitary-gonadal axis. The central suppression of nocturnal testosterone in these patients is partially corrected during chronic CPAP treatment. Pediatrics. 2003 Oct. Objective: Sleep-disordered breathing (SDB) in children is reportedly associated with problem behaviors suggestive of attention-deficit/hyperactivity disorder; however, there are few data on the relation of SDB to problem behaviors in the general pediatric population. The goal of this study was to assess the prevalence of SDB symptoms in 5-year-old children and their relation to sleepiness and problem behaviors. Methods: A population-based, cross-sectional survey was conducted of a birth cohort of children who were born in eastern Massachusetts. Subjects were 3019 5-year-old children (1551 boys, 1468 girls) who were enrolled in the Infant Care Practices Study and whose mothers were contacted within 3 months of their child's fifth birthday. A parent-completed questionnaire was used to ascertain the presence and intensity of snoring and other SDB symptoms and the presence of daytime sleepiness and problem behaviors. Parent-reported hyperactivity, inattention, and aggressiveness were each assessed by a single question that was validated against the Conners' Parent Rating Scale. SDB was defined as frequent or loud snoring; trouble breathing or loud, noisy breathing during sleep; or witnessed sleep apnea. Results: Parent-reported hyperactivity (19%) and inattention (18%) were common, with aggressiveness (12%) and daytime sleepiness (10%) reported somewhat less often. SDB symptoms were present in 744 (25%) children. Compared with children without snoring or other symptoms of SDB, children with SDB symptoms were significantly more likely to have parent-reported daytime sleepiness (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.7-2.8) and problem behaviors, including hyperactivity (OR: 2.5; CI: 2.0-3.0), inattention (OR: 2.1; 95% CI: 1.7-2.6), and aggressiveness (OR: 2.1; 95% CI: 1.6-2.6). These associations remained significant after adjustment for sex, race/ethnicity, maternal education level, maternal marital status, household income, and respiratory health history. Conclusions: SDB symptoms are common in 5-year-old children and are associated with an increased risk of daytime sleepiness and with problem behaviors suggestive of attention-deficit/hyperactivity disorder. Can J Psychiatry. 2003 Jun. Objectives: To investigate the psychological status of patients with sleep apnea-hypopnea syndrome (SAHS) and to evaluate the association of SAHS with psychological symptoms, using the Symptom Checklist-90 (SCL-90) scale. Methods: The study comprised 30 SAHS patients (25 men, 5 women) and 30 matched, healthy control subjects. They all completed the SCL-90 and the Epworth Sleep Scale (ESS) and underwent a whole-night polysomnographic (PSG) examination. We used t-tests for group comparisons of nocturnal PSG characteristics, daytime sleepiness, and psychological symptoms. We employed Spearman's rank correlation analysis to indicate the effects of several nocturnal PSG variables (for example, total sleep time, percentage of wake at sleep, Apnea and Hypopnea Index [AHI], and oxygen desaturation) or subjective daytime sleepiness on psychological symptoms in SAHS. Results: SAHS patients suffered from fragmented sleep and decreased arterial oxygen saturations, compared with healthy control subjects. The General Severity Index (GSI) of SCL-90 was significantly higher in SAHS patients than in healthy control subjects, as were measures of somatization, obsession-compulsion, depression, anxiety, and hostility (P < 0.05). The severity of psychological symptoms in SAHS patients was negatively related to total sleep time and percentage of stage 2 nonrapid eye movement (NREM) sleep; it was positively related to percentage of wake time after sleep onset, percentage of stage 1 NREM sleep, and ESS scores. Conclusion: In our study population, SAHS patients had decreased psychological well-being, which could be explained by fragmented sleep or excessive daytime sleepiness. Pediatrics. 2003 Mar. Objectives: This study examined the hypothesis that domains of neurobehavioral function would be selectively affected by sleep-disordered breathing (SDB). Therefore, we assessed potential relationships between objectively measured sleep disturbances and neurobehavioral function in children with reported symptoms of attention-deficit/hyperactivity disorder (ADHD) and also determined the incidence of snoring and other sleep problems in 5- to 7-year-old children in the local community and potential relationships to parental snoring and passive smoking. Methods: Parents of 5- to 7-year-old children in public schools were surveyed about their child's sleeping habits using a validated questionnaire. The questionnaire also asked whether they believed their child to be hyperactive or have ADHD. Children with reported symptoms of ADHD and control children were randomly selected and invited to the Sleep Medicine Center for an overnight polysomnographic assessment and a battery of neurocognitive tests. Results: The questionnaire response rate was 47.6% (n = 5728). Frequent and loud snoring was reported for 673 children (11.7%). Similarly, 418 (7.3%) children were reported to have hyperactivity/ADHD, 313 (76.5%) of which were boys. Eighty-three children with parentally reported symptoms of ADHD were invited for full evaluation at the Sleep Medicine Center together with 34 control children. After assessment with the Conners' Parent Rating Scale, 44 children were designated as having "significant" symptoms of ADHD, 27 as "mild," and 39 designated as "none" (controls). Overnight polysomnography indicated that obstructive sleep apnea was present in 5% of those with significant ADHD symptoms, 26% of those with mild symptoms, and 5% of those with no symptoms. In the cohort, no sleep variable accounted for more than a negligible proportion of the variance in domains of neurobehavioral function. Conclusions: An unusually high prevalence of snoring was identified among a group of children designated as showing mild symptoms of ADHD based on the Conners' ADHD index identified from a community sample. However, whereas SDB is not more likely to occur among children with significant ADHD symptoms, it is significantly highly prevalent among children with mild hyperactive behaviors. Sleep studies further revealed that rapid eye movement disturbances are more likely to occur in children with significant symptoms, and they seem to impose significant but mild effects on daytime neurobehavioral functioning. We conclude that in children with significant symptoms of ADHD, the prevalence of SDB is not different from that of the general pediatric population and that rapid eye movement sleep in these children is disturbed and may contribute to the severity of their behavioral manifestations. Furthermore, SDB can lead to mild ADHD-like behaviors that can be readily misperceived and potentially delay the diagnosis and appropriate treatment. J Biol Chem. 2002 Nov 8. Increased placental leptin has been demonstrated in preeclampsia, a pregnancy disorder associated with placental hypoxia. This suggests that leptin gene expression is enhanced in response to oxygen deficiency in this organ. In support of this hypothesis, we have previously shown that hypoxia activates the leptin promoter in trophoblast-derived BeWo cells. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric HIF-1alpha/HIF-1beta complex that regulates the transcription of hypoxia-responsive genes. To test whether this factor is involved in hypoxia-induced leptin promoter activation, BeWo cells were transiently transfected with a HIF-1alpha expression vector. Exogenous HIF-1alpha markedly increased luciferase reporter activity driven by the leptin promoter when HIF-1beta was co-expressed in the same cells. This effect was similar to that elicited by CoCl2, an agent known to stabilize endogenous HIF-1alpha. These data suggest that HIF-1alpha/HIF-1beta dimers are involved in the effect of CoCl2 to activate the leptin promoter. To confirm the implication of HIF-1, the cells were transfected with a dominant negative form of HIF-1alpha producing transcriptionally inactive HIF-1beta/HIF-1alpha dimers. This mutant HIF-1alpha protein abolished CoCl2 activation of the leptin promoter, providing direct evidence that the effect of CoCl2 is mediated by endogenous HIF-1alpha. Deletion analysis and site-specific mutagenesis demonstrated that a HIF-1 consensus binding site (HRE) spanning -120 to -116 bp relative to the start site was required for CoCl2 and exogenous HIF-1alpha induction of leptin promoter activity. Electrophoretic mobility shift assays performed with in vitro-translated HIF-1alpha and HIF-1beta proteins demonstrated binding to this HRE and not to mutated sequences only when both subunits were used together. These data demonstrate that leptin is a new hypoxia-inducible gene, which is stimulated in a placental cell line through HIF-1 interaction with a consensus HRE site located at -116 in the proximal promoter. J Biol Chem. 2002 Sep 13. In addition to having a major role in energy homeostasis, leptin is emerging as a pleiotropic cytokine with multiple physiological effector functions. The recently discovered proangiogenic activity of leptin suggested the hypothesis that its production might be regulated by hypoxia, as are other angiogenic factors. To examine this proposal, the expression of leptin protein and mRNA was measured and found to be markedly up-regulated in response to ambient or chemical hypoxia (upon exposure to desferrioxamine or cobalt chloride), an effect that requires intact RNA synthesis, suggesting a transcriptional mechanism. Transient transfection of cultured cells with deletion constructs of the leptin gene promoter linked to a reporter gene revealed a functional hypoxia response element (HRE) located at position -116 within the proximal upstream region. This putative HRE harbors a characteristic 5'-RCGTG-3' core motif, a hallmark of hypoxia-sensitive genes and recognized by the hypoxia-inducible factor 1 (HIF1), which consists of a HIF1alpha/HIFbeta heterodimer. Constructs harboring this -116/HRE supported reporter gene expression in response to hypoxia but not when mutated. Expression of HIF1alpha cDNA in normoxic cells mimicked hypoxia-induced reporter gene expression in cells cotransfected with the wild type leptin -116/HRE construct but not with the mutant. Gel shift assays with a (32)P-labeled leptin promoter -116/HRE probe and nuclear extracts from hypoxia-treated cells indicated binding of the HIF1alpha/beta heterodimer, which was blocked with an excess of unlabeled -116/HRE probe or a HIF1-binding probe from the erythropoietin gene enhancer. Taken together, these observations demonstrate that the leptin gene is actively engaged by hypoxia through a transcriptional pathway commonly utilized by hypoxia-sensitive genes. J Clin Endocrinol Metab. 2002 Jul. Decreased libido is frequently reported in male patients with obstructive sleep apnea (OSA). The decline in morning serum testosterone levels previously reported in these patients was within the normal adult male range and does not explain the frequent association of OSA and sexual dysfunction. We determined serum LH and testosterone levels every 20 min between 2200-0700 h with simultaneous sleep recordings in 10 men with sleep apnea and in 5 normal men free of any breathing disorder in sleep. The mean levels and area under the curve of LH and testosterone were significantly lower in OSA patients compared with controls [LH, 24.9 +/- 10.2 IU/liter.h vs. 43.4 +/- 9.5 (P < 0.005); testosterone, 67.2 +/- 11.5 nmol/liter.h vs. 113.3 +/- 26.8 (P < 0.003)]. Four of 10 patients had hypogonadal morning (0700 h) serum testosterone levels. Analysis of covariance (ANCOVA) revealed that the 2 groups differed significantly in the amount of LH and testosterone secreted at night independent of age or degree of obesity. After partialing out body mass index, there was a significant negative correlation between the amounts of LH and testosterone secreted at night and the respiratory distress index, but not with degree of hypoxia. Our findings suggest that OSA in men is associated with dysfunction of the pituitary-gonadal axis. The relation between LH-testosterone profiles and the severity of OSA suggests that sleep fragmentation and, to a lesser extent, hypoxia in addition to the degree of obesity and aging may be responsible for the central suppression of testosterone in these patients. Pediatrics. 2002 Apr. Objective: The pathophysiological mechanisms of growth impairment frequently associated with the obstructive sleep apnea syndrome (OSAS) in children are poorly defined. The main objective of this study was to evaluate whether nighttime upper airway obstruction attributable to adenotonsillar hypertrophy and subsequent surgical treatment affect the circulating concentrations of insulin-like growth factor-I (IGF-I) and IGF-binding protein 3 (IGFBP-3) along with other growth parameters in children. Patients and methods: We initially studied 70 children (mean age: 5.8 years; range: 2.4-10.5 years) admitted to a university hospital because of clinical symptoms of OSAS. Their sleep was monitored with a 6-channel computerized polygraph. Data on anthropometry and circulating concentrations of IGF-I and IGFBP-3 were generated and compared with corresponding characteristics in control children (N = 35). Thirty children with an obstructive apnea-hypopnea index (OAHI) of 1 or more were categorized as children with OSAS (mean OAHI: 5.4 [95% confidence interval for mean (CI): 3.8-6.9]), whereas 40 children with an OAHI of <1 were considered as primary snorers (PS) (mean OAHI 0.13 [95% CI: 0.05-0.21]). Nineteen children with OAHI >2 underwent adenotonsillectomy attributable to OSAS and were reassessed 6 months later together with 34 nonoperated children with OAHI <2. Results: There were no initial differences in relative height and weight for height between the 3 groups of children. No differences were observed in peripheral IGF-I concentrations, but both OSAS and PS children had reduced peripheral IGFBP-3 levels. The operated children with initial OSAS experienced a highly significant reduction in their OAHI from 7.1 (95% CI: 5.1-9.1) to 0.37 (95% CI: 0.2-0.95). Weight-for-height, body mass index, body fat mass, and fat-free mass increased during the follow-up in the operated children with OSAS, whereas only fat-free mass and relative height increased in the PS children. Both the IGF-I and the IGFBP-3 concentrations increased significantly in the operated children, whereas no significant changes were seen in the PS children. Conclusions: These observations indicate that growth hormone secretion is impaired in children with OSAS and PS. Respiratory improvement after adenotonsillectomy in children with OSAS results in weight gain and restored growth hormone secretion. Excerpts from the full text article: Introduction Snoring is relatively common in children, with the prevalence of regular snoring about 10% in preschool-aged subjects.1–3 Obstructive sleep apnea syndrome (OSAS), a condition related to snoring, is estimated to affect 0.7% to 3.4% of all children according to epidemiologic surveys.1,2,4 Pediatric OSAS may occasionally lead to even life-threatening complications,5 but less serious complications, such as failure to thrive, are more commonly recognized. Retarded weight and height gain as complications of pediatric OSAS and "catch-up" growth after treatment have been well-documented.6–11 The prevalence of this phenomenon is unknown. The cause of poor growth is not known, although many different reasons have been implicated. Abnormal nocturnal growth hormone (GH) secretion has been suggested as one possible cause.5,9,12 Circulating concentrations of insulin-like growth factor-I (IGF-I) and IGF-binding protein 3 (IGFBP-3) are strongly related to diurnal GH secretion, reflecting mean daily GH levels, and seem to correlate well with physiologic changes in GH secretion.13,14 IGF-1 is perceived as the main mediator of the growth-promoting actions of GH,15 but its association with growth in children with OSAS has been poorly explored. The purpose of this study was to examine the growth of children with symptoms of obstructive sleep disorder, verified as OSAS or primary snoring on overnight sleep monitoring. The main objective was to analyze the relationship between obstructive sleep disturbance and biochemical growth factors, as well as the effect of surgical treatment (adenotonsillectomy) on growth and growth factors. Participants and Methods Participants The study population comprised children referred from primary health care to the Department of Otorhinolaryngology, Oulu University Hospital, during the period 1994–1997 for an assessment of their need for treatment because of nighttime snoring, apneas, or difficult breathing, presumably secondary to adenotonsillar hypertrophy. Children with known upper airway anomalies, any underlying disease predisposing to upper airway obstruction, asthma, or perennial allergy were excluded. The parents completed a detailed questionnaire regarding their child’s day and nighttime symptoms. After a review of the questionnaires, the children with symptoms for >6 months were invited for an ear, nose, and throat evaluation and a thorough update of patient history. If upper airway anomalies or abnormal facial morphology were recognized, the children were excluded. Previous adenoidectomy did not lead to exclusion. Seventy-eight children fulfilled the inclusion criteria. They had all symptoms suggestive of OSAS, were regular snorers and/or were observed to have apneas during sleep, and were scheduled for 2 visits 6 months apart. [...] Methods [...] An obstructive apnea-hypopnea index (OAHI) of 1 or higher, including episodes lasting for 10 seconds or more, was considered abnormal in this study based on earlier findings18 and on our own reference data.19 Although short obstructive apneas lasting for 5 to 10 seconds were not included into the criterion index, they were also scored. An obstructive apneic episode was defined as complete cessation of the oronasal airflow as detected by the thermistor in the presence of continuous breathing efforts revealed by the thoracoabdominal strain gauge or the static charge sensitive bed. Hypopnea was defined as a reduction of at least 50% in the airflow signal.20 Mixed apneas and hypopneas starting with a central and continuing with an obstructive component were classified into the obstructive apnea/hypopnea category. Central apnea was defined as cessation of the airflow in the absence of breathing efforts. Central apneas were not included into the criterion index. Intervals of periodic obstructive hypopneas with a <50% decrease in the oronasal signal amplitude linked to a pulse increase at the termination of the hypopneas were scored. [...] Within a fortnight after the first visit children with OAHI 2 (19 children) underwent tonsillectomy (and adenoidectomy, if not previously performed). Children with OAHI <2 were observed without intervention (34 children), including those with mildly abnormal sleep monitoring (1<OAHI<2). [...] Results First Visit Thirty of the children studied had OSAS (OAHI 1), whereas 40 were considered as PSs (OAHI<1; Table 1). The relative height and weight for height did not differ between the groups (Table 2). The OSAS and PS children showed a similar trend toward a target height deficit compared with the controls. Mean relative height was lower in both groups than mean target height. The BMIs were similar in the 3 groups (Table 2). All the children studied were prepubertal, and the anthropometric data were therefore not presented according to sex. Bone age was only available from 27 children in the control group (Table 3). The children with OSAS and PS had a retarded relative bone age, whereas the controls had an advanced bone age. The mean circulating concentrations of IGF-I were of the same magnitude in the 3 groups (Table 2). Both the OSAS and the PS children had lower IGFBP-3 concentrations than the control subjects (P = .001) (Table 2). This was also true after adjustment for age. No significant correlation was found between the OAHI and the IGF-1 and IGFBP-3 concentrations after adjustment for age. Follow-up Visit On the second visit, significant improvements could be seen in the respiratory parameters in the surgically treated group of 19 children (OAHI>2; Table 4). In the nonsurgery group of 34 children (OAHI<2), no significant changes were observed. Weight for height and BMI had increased significantly in the operated group (P = .001 and P = .01, respectively). The increase in the weight for height in the operated group seemed to be primarily attributable to an increase of body fat (P = .02); because although the mean fat-free mass increased more in the operated group, the difference was not significant according to the linear regression model with age and intervention status as independent variables (B = 0.59; r2 = 0.21; P = .08). Relative height increased significantly only in the nonsurgery group (P = .02). There were no significant changes in bone age between the 2 visits in either group. The peripheral concentrations of IGF-I and IGFBP-3 were significantly higher on the second occasion in the operated children (P = .002 and P < .001; Fig 1 and 2). In the nonsurgery group, the increases in the circulating IGF-I and IGFBP-3 levels were insignificant. The initially significant difference in IGFBP-3 levels between the operated children and the controls (P = .001) had disappeared at the second visit (Fig 2). Only in 2 cases (10%) out of 19 were the IGF-I and IGFBP-3 concentrations lower on the second visit in the operated group, whereas in the nonoperated group the IGF-I and IGFBP-3 levels were lower at the second visit in 44% (15/34) and 29% (10/34) of the cases, respectively. Discussion Improved growth, especially weight gain, after resolved OSAS was accompanied by a significant increase in the circulating IGF-I and IGFBP-3 concentrations. The pattern of growth improvement after surgical treatment of OSAS was consistent with earlier studies.6–11 A detailed analysis of the different body mass components showed that the weight increase after treatment of OSAS was attributable to an increased amount of fat rather than an increase in fat-free mass. The possible role of abnormal GH secretion in the observed growth impairment in OSAS children has been addressed in a series of studies.5,7–11 Recently, Bar et al9 demonstrated a significant increase in weight and serum IGF-1 concentrations after surgical treatment of OSAS in 10 prepubertal children. In the present study, this was confirmed in 19 children operated on and assessed twice. Moreover, 34 children with similar symptoms without significant OSAS were observed without surgical intervention. At baseline, altogether 70 children with obstructive sleep disorder were assessed for overnight sleep monitoring, and their anthropometric data and growth factor concentrations were compared with those found in the control subjects.16,17 GH stimulates the synthesis of IGF-I in the liver and other target tissues.29 IGF-I is considered as the main mediator of the growth-promoting actions of GH,15 reflecting the daily mean GH levels, and it has been reported to correlate well with the physiologic changes in GH secretion.13 Among prepubertal children, IGF-I is not clearly sex-dependent.30 In this study, the children remained in prepuberty, when the peripheral IGF-I levels increase fairly slowly,30 so the increase in age over the relatively short time interval between the first and second measurements must have very modestly affected the circulating IGF-I concentrations, as shown by the insignificant increase observed in the nonoperated children. Accordingly, the significant increase in peripheral IGF-1 levels observed in the operated children suggests that the alleviated airway obstruction resulted in increased GH secretion. IGFBP-3, the GH-dependent major carrier protein of IGF-I, has also been shown to correlate significantly with nocturnal GH secretion, but not as strongly as in the case of IGF-I.14 Although IGFBP-3 probably exerts some functions of its own on cells, its major role is to prolong the half-life of IGF-1.31 The major advantage of IGFBP-3 determinations in diagnostics is its relative stability over time,14 and it may therefore be a more reliable indicator of GH secretion over a longer time span than IGF-I. It is also less dependent of age than IGF-I.31 In contrast to the findings of Bar et al,9 we observed that the IGFBP-3 concentrations increased significantly along with the IGF-I levels in the operated children on the follow-up, further strengthening the assumption of increased GH secretion secondary to the relief of airway obstruction. The changes in circulating IGF-I and IGFBP-3 concentrations in the follow-up study were consistent in the sense that the peripheral concentrations only decreased slightly in 2 operated individuals. Our findings are consistent with the findings in adult OSAS patients, in whom it has been shown that successful treatment results in a significant increase in nocturnal GH secretion32 and peripheral IGF-I levels.33 GH is released in a pulsatile fashion, with the initial secretion probably synchronized with the onset of slow-wave sleep (SWS), with a strong correlation with -wave activity,34 within 90 to 120 minutes from the onset of sleep.29 In adults, there is convincing evidence of a consistent relationship between SWS and increased GH secretion and decreased GH secretion with awakenings.35 In OSAS children, the sleep architecture is relatively well-preserved,36 and the distribution pattern of apneas over the night is different from the profile of GH secretion.29,36 One of the limitations of the methods used in this study was the lack of electroencephalogram, electro-oculogram, and chin EMG tracing, so the different sleep stages could not be differentiated, but changes in the proportion of SWS do not seem to be significant after treatment of OSAS.37 Impaired GH secretion is probably not the only cause for the failure to thrive, because OSAS children may also be obese,38,39 but only the minority was overweight in this study. The children classified as having OSAS had a higher proportion of body fat, but only 2 children had a BMI over 20, 1 girl with OSAS (BMI: 21, OAHI: 11.8) and 1 boy who snored (BMI: 20.2), and both the OSAS and PS children had equal BMIs compared with the control group. Increased appetite11 or reduced nighttime caloric expenditure could explain some of the increase in fat accumulation after the treatment of OSAS.10 However, these do not explain the observed changes in IGF-I and IGFBP-3 concentrations. The finding that relative height increased significantly only in the nonoperated group may be attributable to natural variation in growth rate, as these children had lower relative height at both visits than the OSAS children. The fact that no significant differences could be observed initially in the anthropometric data or the circulating concentrations of IGF-I and IGFBP-3 between the children with OSAS and those with primary snoring might be explained by sleep abnormalities, which were also present in the children considered PSs. The children in this study had all symptoms suggestive of OSAS, although the majority were found to be PSs. This is consistent with the findings from other studies,40,41 where half or less of the children with such symptoms were actually confirmed to have OSAS. The criterion for OSAS, OAHI of 1 or higher, was based on normative data established by others18 and our own findings in a group of 30 normal children.19 Coincident desaturation with apnea/hypopnea was not a criterion for scoring in this study. The mean 4% desaturation index was significantly higher in the OSAS group than in the PS group, whereas the PS children had a significantly higher mean 4% desaturation index than the children in our normative data group.19 The PS children had also significantly more tachycardic episodes associated with prolonged partial obstructive hypoventilation than the children in our normative data group,19 although significantly less than the children with OSAS. Some of the PSs could perhaps have been classified differently based on the hypoventilation criterion,18 despite the lack of significant apneas and hypopneas. The significantly reduced IGFBP-3 concentrations in the PSs (as well as in the children with OSAS) seem to indicate some longer-term abnormality in GH secretion also in the PS group. The somewhat younger age of the PSs than the controls is hardly the explanation, because IGFBP-3 remained stable in the nonsurgical group during the follow-up. The fact that the snorers showed a similar target height deficit and retarded bone age as the children with OSAS further supports the idea of long-term abnormality in growth regulation also in the PSs. The selection of an OAHI of 2 or higher as the criteria for surgery in the follow-up study was based on the criteria of abnormal OAHI.18,19 The clinical impact of mild OSAS is still unknown, which means that children with OAHI <2 might well be observed for a period of 6 months, whereas symptomatic children with more abnormal sleep monitoring results could hardly be subjected to any follow-up or blinded study because of ethical reasons. We found here that the circulating IGF-I and IGFBP-3 concentrations increased significantly in children with OSAS after surgical treatment, along with a significant increase in weight. These findings suggest decreased nocturnal GH secretion secondary to upper airway obstruction in children. The mechanisms of the initially impaired GH axis have to be elucidated in additional studies. Pediatrics. 2002 Mar. Objective: Inattention and hyperactivity are frequent among children with sleep-disordered breathing (SDB) and often improve when SDB is treated. However, the frequency of SDB symptoms among inattentive and hyperactive children has received little study. Design: Cross-sectional survey. Setting: Two university-affiliated but community-based general pediatrics clinics. Patients: Patients consisted of N = 866 children (469 boys), aged 2.0 to 13.9 years (mean: 6.8 plus minus 3.2 years), with clinic appointments. Measures: A validated Pediatric Sleep Questionnaire assessed for habitual snoring (1 item), snoring severity (a 4-item subscale), sleepiness (4 items), and overall risk of SDB (16 items). Parents also completed 2 common behavioral measures, an inattention/hyperactivity scale (IHS) derived from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the hyperactivity index (HI, expressed as a t score) of the Conners' Parent Rating Scale. Results: Habitual snoring was reported in 16% (95% confidence interval [CI]: 13, 19) of the participants. High HI scores (>60) were found in 13% (95% CI: 11, 16) of all participants, 22% (95% CI: 15, 29) of habitual snorers, and 12% (95% CI: 9, 14) of nonsnorers. Odds ratios between HI >60 and each of the following were: habitual snoring, 2.2 (95% CI: 1.4, 3.6); 1 additional positive symptom-item on the snoring scale, 1.3 (95% CI: 1.1, 1.5); 1 additional positive item on the sleepiness scale, 1.6 (95% CI: 1.4, 2.0); and a 1-standard deviation increase in the overall SDB score, 1.7 (95% CI: 1.4, 2.0; all odds ratios age- and sex-adjusted). Results were similar for high IHS scores (>1.25). Stratification by age and sex showed that most of the association with snoring (but not sleepiness) derived from boys <8 years old. Conclusions: Inattention and hyperactivity among general pediatric patients are associated with increased daytime sleepiness and - especially in young boys - snoring and other symptoms of SDB. If sleepiness and SDB do influence daytime behavior, the current results suggest a major public health impact. J Appl Physiol. 2000 Nov. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates adaptive responses to the lack of oxygen in mammalian cells. HIF-1 consists of two proteins, HIF-1alpha and HIF-1beta. HIF-1alpha accumulates under hypoxic conditions, whereas HIF-1beta is constitutively expressed. HIF-1alpha and HIF-1beta expression were measured during adaptation to hypobaric hypoxia (0.5 atm) in rat cerebral cortex. Western blot analyses indicated that HIF-1alpha rapidly accumulated during the onset of hypoxia and did not fall for 14 days but fell to normal by 21 days despite the continuous low arterial oxygen tension. Immunostaining showed that neurons, astrocytes, ependymal cells, and possibly endothelial cells were the cell types expressing HIF-1alpha. Genes with hypoxia-responsive elements were activated under these conditions, as evidenced by elevated vascular endothelial growth factor and glucose transporter-1 mRNA levels. When 21-day-adapted rats were exposed to a more severe hypoxic challenge (8% oxygen), HIF-1alpha accumulated again. On the basis of these results, we speculate that the vascular remodeling and metabolic changes triggered during prolonged hypoxia are capable of restoring normal tissue oxygen levels. Nippon Rinsho. 2000 Aug. Sleep apnea may interact endocrine rhythms by a number of mechanisms. Repetitive apneas will cause sleep fragmentation and disorganization of sleep stages and cycles. How this compares with hormonal changes secondary to sleep deprivation is unclear. Hypoxia may have direct central effects on neurotransmitters, which in turn will affect hypothalamic-pituitary hormone production. And, sudden arousal from sleep may produce a central stress response leading to hormonal changes. These factors may interact and lead to changes in the central of sleep and endocrine rhythms. We describe Growth hormone and Androgens secretion during sleep with obstructive sleep apnea patients. Psychiatry Clin Neurosci. 1999 Apr. We report cases of four patients with mild obstructive sleep apnea syndrome (OSAS) with frequent breathing-related electroencephalogram (EEG) arousals which led to excessive daytime sleepiness. In spite of a relatively low apnea hypopnea index (AHI), sleep was disrupted by frequent EEG arousals associated with respiratory effort as observed in upper airway resistance syndrome. The effects of sleep stage and sleep position on EEG arousals were also investigated. We consider that AHI alone is not a sufficient index to assess severity of OSAS, and it is very important to examine microarousals by the alteration of esophageal pressure in addition to the effect of sleep position. Respir Med. 1999 Jan. We studied the effects of chronic nocturnal hypoxaemia due to obstructive sleep apnoea syndrome (OSAS) on the hypothalamic-pituitary-thyroid and hypothalamic-pituitary-testicular axes and on catecholamine and cortisol secretion. We investigated whether hormones other than catecholamines may serve as markers for chronic hypoxic stress and the possible effects of nasal continuous positive airway pressure (nCPAP) treatment on endocrine status. Nocturnal oximetry was performed in 16 male patients with OSAS diagnosed by polysomnography, immediately before nCPAP treatment and in 11 of the patients the oximetry was repeated after 7 months of nCPAP therapy. Plasma and urinary catecholamines, luteinizing hormone (LH) testosterone, cortisol, thyroid stimulating hormone (TSH), prolactin (PRL), and the response of TSH and PRL to a thyroid releasing hormone (TRH) challenge test were measured immediately before and after 7 months of nCPAP treatment. Subnormal LH and TSH and elevated serum cortisol as well as increased nocturnal urinary norepinephrine levels were found in patients prior to treatment; otherwise endocrine values were normal. There was a significant correlation between low pretreatment nocturnal arterial oxygen saturation and high plasma and urinary norepinephrine levels. The nCPAP treatment caused significant reduction in serum prolactin and TSH, and significant reduction in plasma epinephrine and urinary norepinephrine. The reduction in serum TSH and urinary norepinephrine was most pronounced in the subjects with the worst pretreatment nocturnal hypoxaemia. No other significant changes were found in basal hormone levels. The response to TRH challenge was normal before and after treatment and was not influenced by CPAP therapy. OSAS is associated with elevated catecholamine and cortisol and decreased TSH and LH levels but a normal response to TRH challenge and a normal androgen status. Apart from catecholamines, none of the hormones studied is likely to serve as a specific marker for chronic hypoxic stress. Brain Res Dev Brain Res. 1998 Dec 7. Bronchopulmonary dysplasia remains a major cause of neurodevelopmental handicap in preterm infants. Because bronchopulmonary dysplasia may be associated with prolonged hypoxemia without obvious changes in systemic blood pressure, we developed an animal model of chronic sublethal hypoxia to test the hypothesis that this insult results in significant alterations in corticogenesis in the developing brain. Three groups of newborn rats were placed in a chamber with FIO2 9.5% on postnatal day 3 (P3). One group was sacrificed at P13; a second group was sacrificed at P33, and the third group was removed at P33 and reared in normoxia until sacrifice at P63. Control rats were those raised in room air for the corresponding periods of time. Rats were transcardially perfused and the brains were embedded in celloidin and prepared for morphometric analysis using standard stereology methods. Although experimental rat pups in the third group demonstrated 'catch-up' of body weight following return to normoxia, these studies demonstrated both failure of brain growth (p<0.01) and progressive cerebral ventriculomegaly (p<0.01). Decreased subcortical white matter (p<0. 05) and corpus callosum size (p<0.01) were noted at P63 in pups reared under conditions of chronic hypoxia. Decreases in cortical volume (p<0.05) were noted at all three experimental time points for hypoxic-reared pups when compared to control animals. These data suggest that chronic sublethal hypoxia may lead to severe impairments in corticogenesis in an animal model of developing brain. EMBO J. 1998 Sep 1. Hypoxic stress induces the expression of genes associated with increased energy flux, including the glucose transporters Glut1 and Glut3, several glycolytic enzymes, nitric oxide synthase, tyrosine hydroxylase, erythropoietin and vascular endothelial growth factor (VEGF). Induction of these genes is mediated by a common basic helix-loop-helix-PAS transcription complex, the hypoxia-inducible factor-1alpha (HIF-1alpha)/aryl hydrocarbon nuclear translocator (ARNT). Insulin also induces some of these genes; however, the underlying mechanism is unestablished. We report here that insulin shares with hypoxia the ability to induce the HIF-1alpha/ARNT transcription complex in various cell types. This induction was demonstrated by electrophoretic mobility shift of the hypoxia response element (HRE), and abolished by specific antisera to HIF-1alpha and ARNT, and by transcription activation of HRE reporter vectors. Furthermore, basal and insulin-induced expression of Glut1, Glut3, aldolase A, phosphoglycerate kinase and VEGF was reduced in cells having a defective ARNT. Similarly, the insulin-induced activation of HRE reporter vectors and VEGF was impaired in these cells and was rescued by re-introduction of ARNT. Finally, insulin-like growth factor-I (IGF-I) also induced the HIF-1alpha/ARNT transcription complex. These observations establish a novel signal transduction pathway of insulin and IGF-I and broaden considerably the scope of activity of HIF-1alpha/ARNT. Nippon Jibiinkoka Gakkai Kaiho. 1998 Jul. Introduction: Recently it has been revealed that Obstructive Sleep Apnea Syndrome has an influence on the endocrine system, especially to the secretion of growth hormone (GH). It was previously reported that secretion of GH has a circadian rhythm along with a correlation with slow wave sleep. Normally in a pediatric patient, after 90 min of sleep the brain wave shows patterns of deep sleep, and a matching peak in GH secretion is observed. We have studied the effect of GH secretion in sleep breathing disorder of pediatric patients by observing the pre- and post-operative difference in GH secretion in children with tonsillar hypertrophy who had tonsillectomies. Material and methods: Ten pediatric patients who complained of sleep apnea or hypopnea, and were highly suspected of having sleep breathing disorders due to tonsil hypertrophy and underwent surgery were chosen. Pre and post-operative blood somatomedin C and urinary growth hormone levels were measured. In 6 of the 10 patients blood GH levels were measured after overnight collection of blood every 30 min through a catheter placed in the vein. Method of analysis: Integral blood GH calculated from GH levels of the blood samples taken every 30 min was used to express the efficacy of GH secretion during sleep, and was compared with blood somatomedin C and urinary GH levels. Pre- and post-operative somatomedin C and urinary GH measurements were compared. Results: 1) In 6 of the 10 patients, there was a positive correlation with integral GH and urinary GH, and no correlation with integral GH or somatomedin C. 2) Post-operatively, 7 of the 10 patients had increased urinary GH levels, 1 showed no change and 2 had decreased levels. There was a significant increase in the mean urinary GH levels from 18.6 +/- 16.1 pg/ml pre-operatively to 35.8 +/- 19.6 pg/ml post-operatively (P < 0.05). 3) Eight of the 10 patients had a post-operative increase in somatomedin C levels, 1 showed no change and the other patient had a decreased level. There was a significant increase in mean somatomedin C levels from 175.9 +/- 124.8 ng/ml pre-operatively to 226.6 +/- 134.3 ng/ml post-operatively (P < 0.01). Case: An 8-year-old-boy was diagnosed as having habitual tonsillitis and suspected sleep breathing disorder, and was admitted to our hospital for a tonsillectomy. Apnea and hypopnea were observed during sleep in the hospital. After receiving his parents' consent, GH secretion was evaluated before and after the tonsillectomy. Integrated GH measurements, somatomedin C and urinary GH increased significantly after the operation. Conclusion: In this study, the improvement of sleep breathing disorder by surgery was associated with a positive effect to the GH secretion. GH secretion is important for growth of a child. When the cause of sleep breathing disorder is evident in the upper airway system, active treatment and cure by surgery is advised. Measurement of urinary GH in the morning is useful and simple for evaluating the ability to secrete GH. Sleep. 1998 Jun 15. We have previously described impairments of cognitive executive functions in 17 patients with OSAS in comparison with 17 normal controls, as assessed by various frontal-lobe-related tests. In the present study, 10 of these OSAS patients treated with continuous positive airway pressure (CPAP) were reevaluated after 4-6 months of treatment. Neuropsychological tasks explored attention, short-term memory span, learning abilities, planning capacities, categorizing activities, and verbal fluency. Patients were found to have normalized most of their cognitive executive and learning disabilities, but all the short-term memory tests remained unchanged. These findings are discussed in light of the contribution of the frontal-lobe-related systems to short-term memory functions, and the eventual pathogenic role played by sleep fragmentation and nocturnal hypoxemia, which are related to the occurrence of apneic and hypopneic events. In conclusion, short-term memory impairment was persistent in OSAS patients despite CPAP treatment for 4-6 months. J Pediatr. 1998 Mar. We studied glucagon-induced growth hormone secretion in 9 patients with apnea of infancy and in 55 siblings of children who had died of sudden infant death syndrome, who were included as a comparison group. We observed a 33% decrease in growth hormone secretion in patients with apnea of infancy. However, linear growth remained normal. This finding could be related to either repeated episodes of hypoxia or to abnormal maturation of the autonomous nervous system. Curr Opin Pulm Med. 1997 Nov. Obstructive sleep-disordered breathing (SDB) is a common problem in children that may lead to growth failure, neurocognitive and behavioral abnormalities, cor pulmonale, and death. Primary snoring, upper airway resistance syndrome, and obstructive sleep apnea syndrome represent a spectrum of clinical manifestations accompanying increasing degrees of upper airway obstruction. Clearly, children with severe SDB need to be identified and treated promptly. Appropriate management strategies for milder forms of SDB are less clear. Some snoring children, for example, may have an increased frequency of obstructive apnea during sleep, with or without mild hypoxemia, but have essentially no daytime symptoms or apparent clinical consequences. Should these children be treated? If untreated, will these children eventually develop more severe obstructive SDB? Development of management strategies is hampered by the lack of data on the natural history of childhood SDB and on the correlation of specific polysomnographic abnormalities to symptoms and complications. In this review, we highlight recent information about the consequences of obstructive SDB in children, with particular emphasis on areas in which more data are needed. Sleep Apnea Problems In African-American Children Science Daily, September 11, 1997 African-American children with obstructive sleep apnea have significantly lower blood-oxygen levels compared to other groups, according to a study by sleep disorder researchers at the University of Illinois at Chicago College of Medicine. The study, conducted by researchers at UIC's Center for Sleep and Ventilatory Disorders, evaluated nearly 200 children, 128 of whom were diagnosed with obstructive sleep apnea, a potentially life-threatening disorder in which breathing intermittently stops during sleep. The researchers found that the blood-oxygen saturation for African-American children was nearly 10 percent lower than all other children during sleep apnea episodes. "We see many children with serious breathing problems because of sleep apnea," says researcher Edward Stepanski, associate professor of clinical psychology in medicine. "But we were surprised to find racial differences among children who experience dips in blood-oxygen levels even though they have similar severity of sleep apnea. African-American children with obstructive sleep apnea are experiencing faster and further drops in blood-oxygen levels." "We don't know why this is happening," Stepanski adds. "Perhaps, it's related to hemoglobin or it could be the result of undiagnosed sickle cell anemia; or it might be the result of some physiological difference such as larger tonsils. We need to do further study to determine what biological processes account for this." Previous studies have suggested that sleep apnea should be considered a risk factor for hypertension and cardiovascular problems, and can have a significant impact on cognitive function, mood, and reaction time. Neurosci Lett. 1997 Feb 28. The effect of acetyl-L-carnitine (ALC) on behavioral deficits following neonatal anoxia (N2 100% for 25 min at 30 h after birth) was studied in the rat. Transient hyperactivity at P20-P45 postnatal days and permanent spatial memory deficits were shown by anoxic rats. A chronic ALC treatment (50 mg/kg per die injected intraperitoneally from P2, after anoxia, to P60) significantly reduced the transient increase in sniffing, rearing and locomotory activity of anoxic rats, but, mostly, ameliorated the spatial memory performances in a maze at P30-P40 and in a water maze at P50-P60. No behavioral changes were seen in ALC-treated animals that received sham-exposure at birth. On the basis of these results, the use of ALC for the treatment of perinatal asphyctic insults in children is suggested. J Clin Exp Neuropsychol. 1996 Apr. Patients with sleep apnea are typically hypersomnolent during the daytime and may demonstrate higher order cognitive dysfunction. A persistent problem in interpreting impaired neuropsychological test performance in such patients is whether the observed deficits can be explained wholly by impaired vigilance. We examined 37 sleep apnea patients prior to and immediately subsequent to successful sleep apnea treatment with nasal continuous positive airway pressure (CPAP). Patients were evaluated immediately after morning awakening in the sleep lab. A brief neuropsychological evaluation, was administered at that time. Following this, alertness was measured with a 30-min polysomnographically determined sleep latency test. Both test (approximately 50 min in duration) were performed once following a baseline (diagnostic) night in the sleep lab and once in the morning following a CPAP (therapeutic) night in the lab. Subgroup analyses indicted that while vigilance impairment can account for some of the decreased test performance seen in sleep apnea (auditory verbal learning) the effects of severe nocturnal hypoxemia appear to affect other function (sustained attention in repetitive arithmetic calculations) that were not easily modified by treatment. Thus, performance on the recall trial of the Rey Auditory Verbal Learning Test increased from pre-CPAP to post-CPAP for the increased alertness group but decreased significantly for the decreased alertness group. On the Wilkinson Addition Test, non-hypoxemic patients showed statistically significant improvement in problems correctly solved from pre-CPAP to post-CPAP, but the hypoxemic patients showed only a marginal increase. These results are compatible with other studies suggesting that patients having sleep apnea may incur deficits as a result of both decreased vigilance and hypoxemia, and that at least some of these deficits are immediately reversible. J Thorac Cardiovasc Surg. 1995 Oct. Coenzyme Q10 (CoQ10) is a natural mitochondrial respiratory chain constituent with antioxidant properties. This study tests the hypothesis that CoQ10 administered before the onset of reoxygenation on cardiopulmonary bypass, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass. The antioxidant properties of CoQ10 were confirmed by an in vitro study in which normal myocardial homogenates were incubated with the oxidant, t-butylhydroperoxide. Fifteen immature piglets (< 3 weeks old) were placed on 60 minutes of cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (oxygen tension about 400 mm Hg). Ten others became hypoxemic on cardiopulmonary bypass for 30 minutes by lowering oxygen tension to approximately 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 30 minutes. In five piglets, CoQ10 (45 mg/kg) was added to the cardiopulmonary bypass circuit 15 minutes before reoxygenation, and five others were not treated (no treatment). Myocardial function after cardiopulmonary bypass was evaluated from end-systolic elastance (conductance catheter), oxidant damage (lipid peroxidation) was assessed by measuring conjugated diene levels in coronary sinus blood, and antioxidant reserve capacity was determined by measuring malondialdehyde in myocardium after cardiopulmonary bypass incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant damage and allowed complete functional recovery. Reoxygenated hearts (no treatment) showed a progressive increase in conjugated diene levels in coronary sinus blood after reoxygenation (2.3 +/- 0.6 A233 nm/0.5 ml plasma at 30 minutes after reoxygenation) and reduced antioxidant reserve capacity (malondialdehyde: 1219 +/- 157 nmol/g protein at 4.0 mmol/L t-butylhydroperoxide), resulting in severe postbypass dysfunction (percent end-systolic elastance = 38 +/- 6). Conversely, CoQ10 treatment avoided the increase in conjugated diene levels (2.1 +/- 0.6 vs 1.1 +/- 0.3, p < 0.05 vs no treatment), retained normal antioxidant reserve (896 +/- 76 nmol/g protein, p < 0.05 vs no treatment), and allowed nearly complete recovery of function (94% +/- 7%, p < 0.05 vs no treatment). We conclude that reoxygenation of the hypoxemic immature heart on cardiopulmonary bypass causes oxygen-mediated myocardial injury, which can be limited by CoQ10 treatment before reoxygenation. These findings imply that coenzyme Q10 can be used to surgical advantage in cyanotic patients, because therapeutic blood levels can be achieved by preoperative oral administration of this approved drug. J Paediatr Child Health. 1995 Jun. Objective: To study the postoperative outcome of infants under the age of 18 months in whom an adenotonsillectomy had been performed, with particular emphasis on the pre- and postoperative weight gain and linear growth velocities, and the resolution of symptoms of obstructive sleep apnoea (OSA). Methodology: A retrospective study of all infants in whom an adenotonsillectomy had been performed during the 5 year period to January 1990. Details of pre- and postoperative outcome variables were obtained by review of hospital and office records and by telephone calls to the parents. Results: Complete data were available for 29 (76%) of the 38 infants in whom an adenotonsillectomy had been performed. The data from these infants are reported. Pre-operatively, all infants had clinical symptoms of OSA, and 52% of infants also presented with failure to thrive (FTT). Seven infants were dysmorphic: three had Down syndrome, three had a craniofacial anomaly and one infant had Mobius syndrome. Following adenotonsillectomy, 23 infants (79%) had complete resolution of their OSA symptoms. Two infants with Down syndrome required a tracheostomy to relieve persistent upper airway obstruction. Eighty-seven per cent of the infants with pre-operative FTT had a significant increase in weight gain velocity postoperatively (mean 195.1 +/- 80.8 s.d. vs 509.8 +/- 249.1 g/month; P < 0.001), including the infants with mild persistent symptoms of OSA. The weight gain velocity of infants who were not failing to thrive pre-operatively did not change significantly following adenotonsillectomy (328.1 +/- 106.9 vs 333.2 +/- 146.4 g/month; P = 0.82). The linear growth velocity of all infants did not change significantly postoperatively. Conclusions: OSA should be considered in infants with FTT, as adenotonsillectomy is an effective treatment for OSA in infancy, and the weight gain velocity of these infants may increase significantly postoperatively. Overnight oximetry or other physiological studies may be required if the clinical signs and symptoms of OSA are equivocal. Sleep. 1995 Apr. Nocturnal secretion of growth hormone is impaired in patients with obstructive sleep apnea (OSA), but the metabolic consequences have not been reported. We measured blood levels of the hormones insulin, C-peptide, growth hormone, cortisol and glucagon together with the intermediary metabolites of carbohydrate (glucose, pyruvate, lactate, alanine) and lipid metabolism [glycerol, nonesterified fatty acids (NEFA), 3-hydroxybutyrate] in six obese nondiabetic men with OSA on two nights. In the first study, the untreated subjects showed frequent apneas and consequent hypoxemia. The hormone and metabolite concentrations were compared with those obtained on the following night when the subjects were treated effectively with nasal continuous positive airway pressure (CPAP). There were no significant differences in the concentrations of insulin, C-peptide, cortisol or glucagon. We confirmed a marked reduction in growth hormone concentrations in OSA, with a significant increase on the CPAP night. The nocturnal profiles of glucose, pyruvate, lactate, alanine and glycerol showed no differences between the two nights, but concentrations of NEFA and 3-hydroxybutyrate, both products of lipolysis, were significantly greater on the treatment night. Because growth hormone has a lipolytic action, the results suggest that suppression of secretion of growth hormone in untreated OSA results in impaired lipolysis, which is rapidly reversed by nasal CPAP. Chest. 1993 Sep. Subjects with isolated complaints of chronic daytime sleepiness are usually classified as "idiopathic hypersomniacs" and treated symptomatically. A group of these subjects was investigated during nocturnal sleep and daytime naps. In a subgroup of them, sleep was fragmented by very short alpha EEG arousals throughout the sleeping period. These short arousals are usually ignored in sleep analyses, but their impact is significant (in the 15 subjects identified with the syndrome, the mean sleep latency in multiple sleep latency tests was 5.1 +/- 1 min). These arousals are directly related to an abnormal increase in respiratory efforts during sleep (the mean peak inspiratory esophageal pressure measured in our subjects in the respiratory cycle just preceding a transient arousal was -33 +/- 7 cm H2O). Typically, an arousal occurs within one to three breaths of flow limitation associated with abrupt but limited reduction in tidal volume (ie, abnormal increase in upper airway resistance during sleep). The arousal restores normal breathing. Snoring was noted in association with these transient arousals in 10 of the 15 subjects; however, snoring was neither sufficient nor necessary for the identification of the clinical syndrome. Both sexes were equally represented in the affected group. All studied subjects had upper airway anatomy that was mildly abnormal. Nasal continuous positive airway pressure, used as an experimental tool, eliminated the daytime sleepiness (multiple sleep latency mean score = 13.5 min), the transient arousals (mean alpha EEG arousal index decreased from 31.3 +/- 12.4 to 8 +/- 2 per hour of sleep), and the abnormal upper airway resistance. Chronic daytime sleepiness is a major cause of social, economic, and medical impairment. Recognition of this syndrome and its cause is important, as specific treatments can be developed to eliminate the problem. Horm Metab Res. 1993 Jul. The principal nocturnal GH peak normally coincides with the first episode of slow wave sleep (SWS). Obstructive sleep apnea (OSA) patients have low nocturnal GH levels which may be explained by their poor quality fragmented sleep but other factors are possibly involved. Obesity is frequently associated with OSA, and obese patients also manifest reduced GH secretion. The mechanisms reducing GH levels in obese subjects are not understood, but hyperinsulinaemia is a suggested factor. In this study nocturnal plasma and secretory GH profiles of OSA patients were examined in relation to the quality and quantity of sleep, together with plasma glucose and insulin levels. Eight OSA patients, (BMI 32.7 +/- 2.3 kg/m2), underwent 2 night studies. For one night no treatment was given and for the other continuous positive airway pressure (CPAP) treatment was administered for the first time. Blood was collected continuously throughout each night and plasma GH, insulin and glucose profiles established in 10 min interval samples. From the plasma data a deconvolution model was used to calculate GH secretion rates. Sleep was recorded during the studies. For the non-treatment night GH levels were low and increased significantly with treatment, p = 0.008 for plasma levels and p = 0.02 for secretion rates. Treatment significantly decreased the cumulative apnea duration and increased the quantity of SWS and Rapid Eye Movement (REM) sleep (p = 0.008), but the mean insulin and glucose profiles did not differ between the two nights. Individual GH plasma and secretion rates, on treatment, showed a tendency to correlate with the amount of SWS (p = 0.09). J Clin Exp Neuropsychol. 1993 Mar. The obstructive sleep apnea syndrome is characterized by nocturnal sleep disturbance, excessive daytime sleepiness and neuropsychological deficits in the areas of memory, attention, and executive tasks. In the present study, these clinical manifestations were assessed in apneic patients before and 6 months after treatment with nasally applied continuous positive airway pressure (CPAP). CPAP treatment was found to restore normal respiration during sleep and to normalize sleep organization. Daytime vigilance greatly improved with treatment but some degree of somnolence as compared to normal controls persisted. Similarly, most neuropsychological deficits normalized with treatment. The exception was for planning abilities and manual dexterity, two neuropsychological deficits that have been found to be highly correlated with the severity of nocturnal hypoxemia. These results raise the possibility that anoxic brain damage is a pathogenic factor in severe obstructive sleep apnea syndrome. Sleep. 1992 Dec. Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent apneas during sleep, resulting in repetitive hypoxemic episodes and a constant interruption of the normal sleep pattern. Vigilance impairment and neuropsychological deficits are among the main symptoms seen in this condition. One of the major questions in this field concerns the reciprocal interactions between nocturnal hypoxemia, sleep disruption, excessive daytime sleepiness and cognitive deficits. Results of this study suggest that vigilance impairment is attributable mostly to nocturnal hypoxemia. However, in cognitive deficits, hypoxemia seems to play a major role in executive and psychomotor tasks, whereas attention and memory functions appear to be related to vigilance impairment. After treatment, hypoxemia-related deficits and some degree of sleepiness persist. These results raise the possibility of an irreversible anoxic central nervous system (CNS) damage in severe OSAS. Am J Hypertens. 1989 Nov. In order to study blood pressure, adrenergic, and cholinergic activity in severe obstructive sleep apnea (OSA), 14 patients with apnea index (AI) greater than 30 apneas/h, mean apnea time index greater than 20 sec were studied before and with nasal Continuous Positive Airway Pressure (nCPAP). Sleep, respiration, arterial blood pressure, arterial plasma catecholamines [norepinephrine (NE) and epinephrine (E)], and plasma pancreatic polypeptide (PP) were measured without and after seven days treatment with nCPAP. Initially in the apnea, arterial blood pressure decreases, and thereafter steadily increases and shows a maximum during the first breath terminating the apnea. With nCPAP the arterial pressure variations disappeared. Awake morning systolic (SBP) and diastolic (DBP) blood pressure decreased the nCPAP treatment. A significant relation between the reduction in AI and the reduction in morning awake SBP and DBP with nCPAP treatment was observed. No significant changes in NE were observed with nCPAP treatment. Epinephrine decreased and PP increased significantly with nasal nCPAP treatment. The systolic and diastolic blood pressure reduction was significantly related to the decrease in E and the increase in PP. No association between sleep stages and plasma NE, E, and plasma-PP was found before treatment. With nCPAP treatment plasma-PP was higher during non-rapid eye movement (NREM) stage 2 to 4 sleep than during rapid eye movement (REM) sleep. Thus, morning awake arterial blood pressure and nocturnal arterial blood pressure decrease with nCPAP treatment in sleep apnea patients. These hemodynamic changes are related to the decrease in AI and sympathetic activity and the increase in parasympathetic activity. J Clin Endocrinol Metab. 1989 Feb. We studied the effects of sleep apnea on neuroendocrine function in a cross-sectional study of 225 consecutive men undergoing sleep studies and in a longitudinal study of 43 men with severe obstructive sleep apnea before and after 3 months of successful treatment with nasal continuous positive airways pressure to eliminate upper airways obstruction. Blood samples were collected at 0600-0630 h on awakening for measurement of plasma insulin-like growth factor I (IGF-I), total and free testosterone, sex hormone-binding globulin (SHBG), LH, FSH, PRL, T4, T4-binding globulin, and cortisol. The plasma hormone levels were analyzed in relation to the severity of sleep apnea, as indicated by the desaturation index (the hourly rate of episodes of arterial oxygen desaturation greater than 4% of the stable baseline) and the mean minimal oxygen saturation during the desaturation episodes. In the cross-sectional study plasma IGF-I, free and total testosterone, and SHBG levels were significantly lower in relation to the severity of sleep apnea, whereas plasma LH, FSH, PRL, T4, T4-binding globulin, and cortisol were not. The decreases in plasma IGF-I and total and free testosterone were independent of the effects of aging and adiposity by covariance analysis. In the longitudinal study plasma IGF-I, total testosterone, and SHBG, but not free testosterone, significantly increased after 3 months of nasal continuous positive airways pressure treatment. We conclude that sleep apnea causes reversible neuroendocrine dysfunction in men, which is manifested by decreased plasma. IGF-I, testosterone, and SHBG levels. This neuroendocrine dysfunction is related to the severity of the sleep apnea, as indicated by the nadir levels of arterial oxygen desaturation and the rate of desaturation episodes. These hormonal measurements may provide biochemical markers for both the severity of sleep apnea and its response to therapeutic intervention. In addition, sleep apnea may be a previously unrecognized confounder of the neuroendocrine correlates of aging. Int J Pediatr Otorhinolaryngol. 1988 Oct. Obstructive sleep apnea (OSA) was diagnosed in 14 infants less than 18 months of age. Snoring, apnea, failure to thrive, developmental delay and recurrent respiratory infections were the main presenting symptoms. The diagnosis was made by polysomnographic studies or overnight monitoring. Adenotonsillectomy resulted in the relief of symptoms and signs in 13 children. In one infant prolonged nasopharyngeal intubation was needed. An increased awareness of OSA in young infants may prevent the delay in diagnosis, will allow early treatment and thus prevent the development of sequela or complications associated with this syndrome. Int J Pediatr Otorhinolaryngol. 1985 Jul. Isolated failure to thrive in an infant caused by chronic hypoventilation due to hypertrophic adenoids and tonsils, has not been previously described. A 9 month-old infant presented with weight loss and mild clinical respiratory signs. Hypoxemia and CO2 retention, however, were documented by transcutaneous gas measurement, and ENT examination revealed enlarged tonsils and adenoids. Adenoidectomy and tonsillectomy at 9 1/2 months of age completely reversed the patient's hypoventilation and growth pattern. While the exact mechanism of failure to thrive secondary to upper airway obstruction in infancy is not clear, we conclude that routine ENT evaluation should be a regular part of the workup of infants under one year who suffer from failure to thrive. J Pediatr. 1982 Jan. Twenty-two infants and children were found to have clinically significant obstructive sleep apnea. A history suggesting complete or partial airway obstruction during sleep was obtained on all patients, and physical examination of the sleeping patient revealed snoring, retractions, or OSA in 21 patients. Nevertheless, the mean delay in referral for 20 patients first seen after the neonatal period was 23 +15 (+ SD) months. Sixteen of 22 patients (73%) developed serious sequelae: cor pulmonale in 12 (55%), failure to thrive in six (27%), permanent neurologic damage in two (9%), and behavioral disturbances, hypersomnolence, or developmental delays in five (23%). Clinical and radiologic evaluations revealed anatomic abnormalities which narrowed the upper airway in 21 patients; enlarged tonsils and/or adenoids in 14, micrognathia in three,generalized facial abnormalities in three, and cleft palate repair/tonsillar hypertrophy in one. In five patients, upper airway fluoroscopy was performed and was helpful in establishing the site and mechanism of obstruction. Polygraphic monitoring was utilized to quantify the frequency and duration of OSA. Prolonged partial airway obstruction during sleep resulted in significant hypercarbia in 11 patients and hypoxemia in five. Twenty patients improved after surgery which relieved or bypassed the pharyngeal airway obstruction; two cases are pending. Increased awareness of OSA and examination of the sleeping patient should result in earlier treatment and less morbidity for infants and children with OSA. Rev Electroencephalogr Neurophysiol Clin. 1980 Oct-Dec. The authors suggest the hypothesis that the obesity often associated with sleep apnea syndromes is related to changes in HG secretion. Indeed, as HG secretion is sleep related any disturbances due to apnea during may alter the GH secretion. In order to test their hypothesis the authors studied, during the course of 24-hour polygraphic recordings, the levels of HG, blood glucose and free fatty acids, in 16 subjects, 14 of whom were obese and 9 of whom had the sleep apnea syndrome. The results obtained confirmed the relationship between the number of apnea and the stability of sleep. They also demonstrated a relationship between GH secretion and both the stability of sleep and obesity. These results, therefore, suggest that apnea plays a role in obesity development. Sleep. 1980. A 20-year-old hypogonadal man was discovered to have had obstructive sleep apnea syndrome - secondary to hypertrophied tonsils, adenoids, and uvula - spanning the years of puberty. All-night polysomnographic recordings and 24 hr measurements of plasma luteinizing hormone (LH) concentrations (sampling at 20 min intervals) were performed before and after combined tonsillectomy, adenoidectomy, and uvulectomy. Two weeks preoperatively, nocturnal sleep was markedly disturbed by 407 apneic episodes, and the patient was found to be hypogonadotropic. Daytime LH concentrations were in the low-normal range for an adult male, and concentrations fell dramatically during nocturnal sleep. This contrasts with both the sleep-related elevation of LH normally seen in puberty and the adult pattern, where no difference is observed in mean concentrations during waking and sleep. Two week and 6 month postoperative evaluations revealed complete alleviation of the sleep apnea syndrome and normalization of the 24 hr pattern of plasma LH, although LH values remained in the low-normal range. Plasma testosterone concentrations were in the low to low-normal range both pre- and postoperatively. No evidence of continued sexual development, beyond that achieved preoperatively, was observed 20 months after surgery, despite continued relief from apnea. These data suggest that sleep apnea during puberty may impair sexual development by preventing the sleep-related elevation in LH secretion normally observed during a critical period spanning puberty. |