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Biomedical subjects

David Gozal

Publications and source records attributed to David Gozal.

At least 73 records · Page 4Linked to original sources
PubMed2005

Antioxidant responses to chronic hypoxia in the rat cerebellum and pons.

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH) and sleep fragmentation and deprivation. Exposure to CIH results in oxidative stress in the cortex, hippocampus and basal forebrain of rats and mice. We show that sustained and intermittent hypoxia induces antioxidant responses, an indicator of oxidative stress, in the rat cerebellum and pons. Increased glutathione reductase (GR) activity and thiobarbituric acid reactive substance (TBARS) levels were observed in the pons and cerebellum of rats exposed to CIH or chronic sustained hypoxia (CSH) compared with room air (RA) controls. Exposure to CIH or CSH increased GR activity in the pons, while exposure to CSH increased the level of TBARS in the cerebellum. The level of TBARS was increased to a greater extent after exposure to CSH than to CIH in the cerebellum and pons. Increased superoxide dismutase activity (SOD) and decreased total glutathione (GSHt) levels were observed after exposure to CIH compared with CSH only in the pons. We have previously shown that prolonged sleep deprivation decreased SOD activity in the rat hippocampus and brainstem, without affecting the cerebellum, cortex or hypothalamus. We therefore conclude that sleep deprivation and hypoxia differentially affect antioxidant responses in different brain regions.

Animals↗
PubMed2005

Intermittent hypoxia during development induces long-term alterations in spatial working memory, monoamines, and dendritic branching in rat frontal cortex.

Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with increased apoptosis in vulnerable brain regions as well as with spatial reference memory deficits in adult and developing rats. The latter are more susceptible to IH, suggesting that early exposure to IH may have long-term consequences. Rats were exposed to 14 d of room air (RA) or IH starting at postnatal d 10. Working memory was then assessed in the water maze at 4 mo of age using a delayed matching to place task in which the rats were required to locate a submerged platform hidden in a novel location on the first trial (T1 or acquisition trial), and then remember that position after a delay (T2 or test trial). Mean escape latencies and swim distances were derived and the savings (T1-T2) were used as a measure of working memory. Male but not female rats exposed to IH showed working memory deficits at both a 10- and 120-min delay (for both latency and pathlength). Additionally, Sholl analysis of Golgi-stained neurons revealed decreased dendritic branching in the frontal cortex, but not the hippocampus, of male rats exposed to IH. Norepinephrine concentrations, dopamine turnover, and tyrosine hydroxylase activity were increased similarly in males and females. However, increased dopamine concentrations were present only in the frontal cortex of female rats. In conclusion, exposure to IH during a critical developmental period is associated with long-term alterations in frontal cortical dopaminergic pathways that may underlie gender differences in neurobehavioral deficits.

Animals↗
PubMed2005

Autonomic function in children with congenital central hypoventilation syndrome and their families.

STUDY OBJECTIVES: Congenital central hypoventilation syndrome (CCHS) is a genetic disorder characterized by failure of automatic control of breathing in the absence of obvious anatomic lesions. There have been several reports suggesting that CCHS patients display autonomic dysregulation. Pulse arterial tonometry (PAT) is a novel technique that provides noninvasive moment-to-moment measurements of sympathetic tone changes to the cutaneous vascular bed. We hypothesized that autonomic function as measured by PAT would be altered in children with CCHS. DESIGN: Prospective study. SETTING: CCHS Family Conference, Orlando, FL, and the local community in Louisville, KY. PARTICIPANTS: Nineteen CCHS patients and 31 parents as well as 24 control children and 15 adult control subjects. INTERVENTIONS: Children with CCHS and their parents underwent sympathetic challenges (vital capacity sigh and cold hand pressor test) and a test of reactive hyperemia (brachial artery occlusion) while PAT was continuously monitored from the right hand. Control children and control adults underwent the same procedure. MEASUREMENTS AND RESULTS: The maximal change of the PAT signal compared to the preceding baseline was averaged and expressed as percentage change for each of the challenges. The magnitude of sympathetic discharge-induced attenuation of PAT signal following a sigh was reduced in CCHS children compared to control subjects for both the vital capacity sighs and the cold hand pressor test. There were no differences observed in the magnitude of PAT attenuation between parents of children with CCHS and control adults. No differences were observed between either CCHS and control subjects or CCHS parents and adult control subjects for the brachial artery occlusion test. CONCLUSION: CCHS patients show an attenuated response to endogenous sympathetic stimulation, supporting the presence of autonomic nervous system dysfunction as a consistent feature of this condition. No differences were found in parents of children with CCHS compared to control adults, consistent with the finding that CCHS is primarily the result of a de novo gene mutation.

Autonomic Nervous System↗
PubMed2005

Obesity rather than severity of sleep-disordered breathing as the major determinant of insulin resistance and altered lipidemia in snoring children.

OBJECTIVE: Sleep-disordered breathing (SDB) is associated with insulin resistance and dyslipidemia in adults and in obese children. However, the prevalence of such metabolic abnormalities among snoring children is unknown. This study was done to prospectively assess the relative contribution of SDB and obesity to metabolic disturbances in a large cohort of snoring children. METHODS: Measurements of fasting serum glucose, insulin, and lipids were obtained after polysomnographic evaluation in 116 snoring children and in 19 control subjects. Insulin resistance was assessed using the insulin/glucose ratio (I/G ratio) and homeostasis model assessment (HOMA). RESULTS: A total of 135 children (79 boys; mean age: 8.9 +/- 3.5 years) were studied. Sixty-four children had moderate to severe SDB (AHI = 5 per hour of total sleep time [TST]), 52 had mild SDB (AHI = 1 but <5 per hour of TST), and 19 were control subjects (AHI <1 per hour of TST). Seventy of these children were obese. No significant correlations were found between AHI, lowest arterial oxygen saturation, or arousal index and serum insulin, serum glucose, I/G ratio, HOMA, or serum lipids for either the whole group or the obese children only. However, significant positive correlations were found between I/G ratio and relative BMI (relBMI; r = 0.58), HOMA and relBMI (r = 0.52), triglycerides and relBMI (r = 0.30), and high-density lipoprotein and relBMI (r = 0.50). No significant differences were found in relBMI, I/G ratio, and lipid levels between boys and girls. CONCLUSIONS: Among children with suspected SDB, insulin resistance and dyslipidemia seem to be determined primarily by the degree of body adiposity rather than by the severity of SDB.

Adolescent↗
PubMed2004

Glucocorticoid receptor subunit expression in adenotonsillar tissue of children with obstructive sleep apnea.

Tonsillectomy and adenoidectomy (T&A) is a frequent surgical procedure in children with obstructive sleep apnea (OSA). Many symptomatic children who do not fulfill the currently recommended criteria for T&A may benefit from topical intranasal steroid therapy. However, the expression of glucocorticoid receptor (GCR) expression in adenoid and tonsillar tissue is currently unknown. The objective of this study was to assess and compare expression patterns of the human GCR in children who undergo T&A for either recurrent throat infections (RI) or OSA. Adenotonsillar tissues from 36 children with OSA or RI were subjected to quantitative PCR using specific primers for GCR-alpha and GCR-beta and to immunohistochemistry and Western blotting for protein expression of GCR isoforms. mRNA encoding for expression of both GCR-alpha and GCR-beta was detected in the tonsils and adenoids of all children, with markedly higher relative abundance of the GCR-alpha. Furthermore, GCR-alpha mRNA expression was increased in OSA-derived adenoid and tonsil tissues compared with RI, whereas no differences emerged for GCR-beta. Immunoblots confirmed these findings for the protein transcripts of these genes, and immunohistochemistry showed a specific topographic pattern of distribution for both receptors in tonsillar tissue. GCR-alpha and GCR-beta are expressed in pediatric adenotonsillar tissue, are more abundant in OSA patients, and demonstrate a specific topographic pattern of expression. These findings along with the high GCR-alpha:GCR-beta ratio suggest a favorable profile for topical steroid therapy in snoring children with adenotonsillar hypertrophy.

Adenoids↗
PubMed2004

Effect of intermittent hypoxia on long-term potentiation in rat hippocampal slices.

Intermittent hypoxia (IH) during sleep has been shown to induce apoptosis in a time-dependent manner and spatial learning deficits in adult rats. Recently, we have demonstrated that IH induced significant decreases in Ser-133-phosphorylated cAMP-response element-binding protein (pCREB) without changes in total CREB. The expression of cleaved caspase 3 in the hippocampal CA1, a marker of apoptosis, peaked at 3 days of IH and returned to normoxic values at 14 days of IH. In addition, biphasic changes in spatial task learning were correlated with the CREB phosphorylation time course. In the present study, the rat hippocampal slice preparation was used to evaluate the ability to induce and maintain a CA1 population spike long-term potentiation (PS-LTP) in room air (RA)-maintained and IH-exposed rats. A significant decrease in the ability to sustain PS-LTP for 15 min in slices prepared from IH-exposed rats for either 3 days (34% of total) or 7 days (51% of total) as compared to slices prepared from RA-maintained rats (76% of total) was observed. These results suggest that the diminishment in the ability of neuronal tissue to express and sustain PS-LTP is correlated with previously reported biphasic changes in CREB phosphorylation and programmed cell death.

Action Potentials↗
PubMed2004

Health-related quality of life and depressive symptoms in children with suspected sleep-disordered breathing.

STUDY OBJECTIVES: Snoring and sleep-disordered breathing (SDB) are highly prevalent among children. The increasing trends of obesity in the pediatric population further predict an exacerbation of this public health problem. However, the impact of SDB on mood and quality of life and the confounder effect of obesity in this setting are unclear. DESIGN: We studied a group of 85 clinically referred children, aged 8 to 12 years, with snoring and suspected SDB and 35 asymptomatic children (controls). All children completed validated questionnaires for the presence of depression (Children's Depression Inventory) and for health-related quality of life (PedsQL), and parents completed the Parent Report version of the PedsQL. Children referred to the Sleep Medicine Center for sleep-disordered breathing were further subdivided according to their body mass index > 95% for age and sex (n = 44) and with BMI < 95% for age and sex as ClinN1 (n = 41). RESULTS: Parentally reported quality of life and physical health differed between obese and nonobese children. However, both groups with SDB had more-impaired quality of life and depressive symptoms than did controls. CONCLUSIONS: Children with suspected SDB, regardless of the severity of apnea-hypopnea index or the presence of obesity, had more impairments in quality of life and depressive symptoms than did children who did not snore.

Adolescent↗
PubMed2004

Platelet-activating factor receptor and respiratory and metabolic responses to hypoxia and hypercapnia.

Activation of the platelet-activating factor receptor (PAFR) regulates neural transmission. A PAFR blocker reduced the peak hypoxic (pHVR) but not hypercapnic ventilatory (HCVR) responses in rats [Am. J. Physiol. 275 (1998) R604]. To further examine the role of PAFR in respiratory control, genotype-verified PAFR -/- and PAFR +/+ adult male mice underwent hypoxic and hypercapnic challenges. HCVR was similar in the two groups (p-NS). However, pHVR was significantly reduced in PAFR -/- mice (38 +/- 13% baseline [S.D.]) compared to PAFR +/+ mice (78 +/- 16% baseline; P < 0.001, ANOVA), with reduced tidal volume recruitments during pHVR. In addition, hypoxic ventilatory depression was attenuated in PAFR -/- mice (P < 0.01), and was primarily due to attenuation of the time-dependent decreases in oxygen consumption during sustained hypoxia (P < 0.01). Thus, PAFR expression/function modulates components of the acute ventilatory and metabolic adaptations to hypoxia but not to hypercapnia. Imbalances in PAFR activity may lead to maladaptive regulation of the tightly controlled metabolic-ventilatory relationships during hypoxia.

Adaptation, Physiological↗
PubMed2004

Detection of obstructive sleep apnea in pediatric subjects using surface lead electrocardiogram features.

STUDY OBJECTIVES: To investigate the feasibility of detecting obstructive sleep apnea (OSA) in children using an automated classification system based on analysis of overnight electrocardiogram (ECG) recordings. DESIGN: Retrospective observational study. SETTING: A pediatric sleep clinic. PARTICIPANTS: Fifty children underwent full overnight polysomnography. INTERVENTION: N/A. MEASUREMENTS AND RESULTS: Expert polysomnography scoring was performed. The datasets were divided into a training set of 25 subjects (11 normal, 14 with OSA) and a withheld test set of 25 subjects (11 normal, 14 with OSA). Features, calculated from the ECG of the 25 training datasets, were empirically chosen to train a modified quadratic discriminant analysis classification system. The selected configuration used a segment length of 60 seconds and processed mean, SD, power spectral density, and serial correlation measures to classify segments as apneic or normal. By combining per-segment classifications and using receiver-operator characteristic analysis, a per-subject classifier was obtained that had a sensitivity of 85.7%, specificity of 90.9%, and accuracy of 88% on the training datasets. The same decision threshold was applied to the withheld datasets and yielded a sensitivity of 85.7%, specificity of 81.8%, and accuracy of 84%. The positive and negative predictive values were 85.7% and 81.8%, respectively, on the test dataset. CONCLUSIONS: The ability to correctly identify 12 out of 14 cases of OSA (with the 2 false negatives arising from subjects with an apnea-hypopnea index less than 10) indicates that the automated apnea classification system outlined may have clinical utility in pediatric patients.

Adult↗
PubMed2004

Peripheral arterial tonometry events and electroencephalographic arousals in children.

STUDY OBJECTIVES: Peripheral arterial tonometry (PAT) is a sensitive measure of moment-to-moment changes in sympathetic activity and reliably identifies arousals in adult subjects. We investigated whether PAT events during sleep are associated with visually recognizable electroencephalographic arousals in healthy children and in children with sleep-disordered breathing. DESIGN: Prospective cohort. SETTING: Pediatric Sleep Research Laboratory. PARTICIPANTS: Twenty children with obstructive sleep apnea syndrome, 20 children with mild sleep-disordered breathing, and 20 control children with a mean age of 7.6 +/- 2.6 years (range: 5.7-16.5 years); 53% of children were boys. INTERVENTIONS AND MEASUREMENTS: Polysomnographic evaluation in the sleep laboratory with concomitant recording of PAT. PAT events were defined as attenuations from immediately preceding baseline of 20% to 50% (PAT20) and > 50% (PAT50) for at least 5 seconds and the indexes calculated per hour of sleep time that included good-quality PAT signals. Total PAT index (the sum of PAT20 index and PAT50 index) was also calculated. RESULTS: Total PAT index correlated with total arousal index and spontaneous arousal index (r = 0.55, P < .0001, r = 0.64, P < .001, respectively), especially in the group with obstructive sleep apnea syndrome (r = 0.71, P < .0001). The sensitivity and specificity of PAT for identifying electroencephalographic arousals were 95% and 35%, respectively. The PAT device identified pathologic arousals indexes (> or = 16 per hour) (area under the curve 0.79, P = .002). Thirty-five percent of respiratory events (eg, obstructive apnea or hypopnea) were associated with a visual electroencephalographic arousal, compared to 92% being associated with PAT attenuation events. CONCLUSIONS: Arousals in sleeping children are associated with increased sympathetic discharge, as evidenced by attenuations in PAT signal. However, a significant proportion of PAT attenuations were not accompanied by visual electroencephalographic arousals. Thus, the importance of these autonomic arousals has yet to be explored in association with morbidities related to sleep-disordered breathing and, therefore, PAT technology cannot be recommended as an alternative tool for measuring arousals in children. Nevertheless, these data further support the contention that adult criteria for the measurement for arousals may not be adequate in children.

Arousal↗
PubMed2004

Persistent respiratory changes following intermittent hypoxic stimulation in cats and human beings.

Repeated intermittent hypoxia or other stimulation of carotid chemoreceptors produces a consistent long-term increase in respiratory nerve activity in vagotomized, artificially ventilated anesthetized or decerebrate animals, but variable results have been reported in more intact preparations. We sought additional variables that could be measured to help gain an understanding of persistent respiratory responses to intermittent hypoxia. The variance of respiratory phases decreased in 10 of 11 recordings from vagotomized anesthetized cats during long-term facilitation induced by carotid chemoreceptor stimulation. The variance of expiratory time was reduced in 10 awake human beings exposed to repetitive, brief episodes of isocapnic hypoxia (6% O(2) in N(2), 60s). Respiratory frequency was increased in humans and tidal volume decreased so that minute ventilation remained unchanged. The results suggest that there are persistent changes in the output of the respiratory central pattern generator following intermittent peripheral chemoreceptor stimulation or hypoxia.

Animals↗
PubMed2004

Platelet-activating factor receptor modulates respiratory adaptation to long-term intermittent hypoxia in mice.

During hypoxia, release of platelet-activating factor (PAF) and activation of its cognate receptor (PAFR) regulate neural transmission and are required for full expression of peak hypoxic ventilatory response (pHVR) but not hypercapnic ventilatory response. However, it is unclear whether PAFR underlie components of long-term ventilatory adaptations to hypoxia. To examine this issue, adult male PAFR(+/+) and PAFR(-/-) mice were exposed to intermittent hypoxia (IH) consisting of 90 s 21% O(2) and 90 s 10% O(2) for 30 days, and normoxic and hypoxic ventilatory patterns were assessed using whole body plethysmography. Starting at day 14 of IH, normoxic ventilation in PAFR(-/-) was reduced significantly compared with PAFR(+/+) mice (P < 0.001), the latter exhibiting a prominent long-term ventilatory facilitation (LTVF). However, IH-exposed PAFR(-/-) mice had markedly enhanced pHVR and hypoxic ventilatory decline that became similar to those of IH-exposed PAFR(+/+) mice. Thus we postulate that PAFR expression and/or function underlies critical components of IH-induced LTVF but does not play a role in the potentiation of the hypoxic ventilatory response after IH exposures.

Adaptation, Physiological↗
PubMed2004

Temporal trends of cardiac and respiratory responses to ventilatory challenges in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients exhibit respiratory deficits to ventilatory challenges, diminished breathing drive during sleep, and reduction of respiratory-related heart rate variation, but at least partially preserved peripheral chemoreception. We hypothesized that integration of afferent activity with respiratory motor output is deficient in CCHS, rather than chemoreceptor failure, and that examination of trends in heart and breathing rates and variabilities following ventilatory challenges may clarify the deficient mechanisms. Twelve children with CCHS and 12 age- and gender-matched control cases were subjected to hyperoxic hypercapnic, poikylocapnic hypoxic, and hyperoxic challenges while supine. Heart and respiratory rates and variabilities during 60-s baseline and 120-s challenge periods were assessed. Hypoxia and hypercapnia enhanced breathing rate in control subjects; in CCHS cases, the rise differed during hypercapnia and did not occur to hypoxia. Hyperoxia showed initial transient patterns in breathing rate that differed between groups. A heart rate increase to hypoxia and late decline to hyperoxia were muted in CCHS patients. In hypercapnia, heart rate followed similar rising patterns in both groups. Overall CCHS heart rate variability was lower in baseline and challenge periods, principally due to diminished respiratory-related variation, especially during hypercapnia. No heart rate variability group differences emerged in hypoxia, and only a late increase for CCHS cases developed in hyperoxia. The findings indicate retention of aspects of chemoreceptor sensitivity in CCHS cases. The heart rate alterations to ventilatory challenges suggest specific compensatory responses of a slower nature remain intact in CCHS, whereas other rapidly changing components are deficient.

Adolescent↗
PubMed2004

Sleep pressure score: a new index of sleep disruption in snoring children.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS), as measured by objective criteria, is infrequent in snoring children despite a high prevalence of EDS-related behavioral manifestations. We hypothesized that sleep architecture and arousal indexes may be altered relative to the severity of sleep-disordered breathing (SDB). DESIGN: Retrospective and prospective study. SETTING: Questionnaires were distributed through sleep clinic or school program; polysomnograms were performed at Kosair Children's Hospital in Louisville, Kentucky. PARTICIPANTS: To examine this issue, 182 children with SDB, 163 children with primary snoring, and 214 control children with a mean age of 6.9 +/- 2.6 years underwent polysomnographic evaluation in the laboratory. MEASUREMENTS AND RESULTS: Significant increases in slow-wave sleep (percentage of total sleep time) and decreases in rapid eye movement sleep (percentage of total sleep time) occurred in the SDB group (P < .0001). Spontaneous and respiratory arousal indexes and the apnea-hypopnea index (AHI) displayed negative and positive correlations, respectively, suggesting reciprocal interactions. Based on these observations, a sleep pressure score (SPS) was derived as a surrogate numeric measure for disrupted sleep homeostasis. The SPS exhibited linear increases relative to AHI, reaching a plateau at an AHI of 30 to 40 per hour of total sleep time. Furthermore, SPS values were significantly higher among African American and obese children (P < .0001). CONCLUSIONS: Sleep architecture is not preserved in children with SDB. An algorithm allowing for calculation of sleep propensity and disturbed sleep homeostasis in children who snore is proposed and may be of practical value in the assessment of sleepiness.

Body Mass Index↗
PubMed2004

Sleep pressure correlates of cognitive and behavioral morbidity in snoring children.

STUDY OBJECTIVES: Sleep architecture is not preserved in children with sleep-disordered breathing but, rather, undergoes dynamic changes that exhibit significant correlation with severity of sleep-disordered breathing. A sleep pressure score (SPS) with a cutoff value of 0.25 was derived from analysis of a large cohort of snoring and control children. Neurocognitive batteries were applied to examine the potential effect of SPS. DESIGN: Prospective study. PARTICIPANTS: 199 children who underwent a battery of neurobehavioral tests following an overnight sleep study were assigned to SPSHigh (> or = 0.25) or SPSLow (< 0.25) groups, and their neurocognitive performances were compared. RESULTS: Children in the SPSHigh group were significantly more likely to have deficits in memory, language abilities, verbal abilities, and some visuospatial functions than were children in the SPSLow group. These effects remained highly significant after adjusting for confounding variables and exhibited small to moderate effect sizes. CONCLUSIONS: We conclude that a sleep-pressure numerical factor derived from the overnight polysomnogram in snoring children is associated with deficits in neurobehavioral daytime functions that is independent of respiratory disturbance and hypoxemia and suggests a significant role for disturbed sleep homeostasis in pediatric sleep-disordered breathing.

Child↗
PubMed2004

Snoring and sleep-disordered breathing in young children: subjective and objective correlates.

STUDY OBJECTIVES: We sought to assess the predictive validity of parental report of snoring and other behaviors by comparing such reports with objective findings from overnight polysomnography for the evaluation of sleep-disordered breathing in 2 nonclinical samples, namely, at-risk preschoolers and an older group reflective of the general community. Predictive validity of snoring alone and a score based on multiple child behaviors were compared to outcome at different levels of severity of sleep-disordered breathing. DESIGN: Retrospective observational study. SETTING: Questionnaires were distributed through school programs; polysomnography was performed at Kosair Children's Hospital in Louisville, Kentucky. PARTICIPANTS: One hundred twenty-two preschoolers and 172 5- to 7-year-olds, and their parents, participated in both subjective-report and objective-recording portions of the study. MEASUREMENTS AND RESULTS: Compared to the presence of snoring on polysomnography, parental report of frequent snoring was highly sensitive and specific for both age groups. At all but the lowest level of severity of sleep-disordered breathing, predictive ability was higher for both groups when a parental-report score based on multiple measures of child behavior was applied, compared to parental report of snoring alone. The profiles of these predictive child behaviors differed between the 2 groups, as did their sensitivity and specificity, at their high ranges of parental report. CONCLUSIONS: Scores derived from parental-report questionnaires of children's snoring and other sleep and wake behaviors can be used as surrogate predictors of snoring or sleep-disordered breathing in children. However, design and interpretation should consider age, risk status, and the purpose of the screening assessment.

Child↗