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Biomedical subjects

David Gozal

Publications and source records attributed to David Gozal.

At least 127 records · Page 7Linked to original sources
PubMed2003

The effect of stimulants on sleep characteristics in children with attention deficit/hyperactivity disorder.

OBJECTIVE: To investigate the effects of stimulant medications on subjective and objective sleep characteristics of children with attention deficit/hyperactivity disorder (ADHD) compared with control children. METHODS: An observational study in the sleep clinic and the community. Children with characteristics of ADHD, both stimulant-medicated (n=53), and non-medicated (n=34), together with control children (n=53) completed a sleep habits questionnaire prior to undergoing full overnight polysomnographic assessment. RESULTS: Medicated and non-medicated ADHD subjects were reported to have more sleep disturbances compared with controls. Both groups of ADHD children also demonstrated decreased REM sleep percentage compared with controls (P=0.006 for ADHDmed; P=0.02 for ADHDnon). However, the use of stimulant medication (n=53) was not associated with differences in subjective sleep quality or objective sleep measures, compared to ADHD children not taking any medication (n=34; P=n.s.). CONCLUSIONS: Despite the high prevalence of reported sleep disturbance in children with ADHD, stimulant medication appears to have minimal effects on subjective and objective sleep characteristics in children with reported ADHD.

Attention Deficit Disorder with Hyperactivity↗
PubMed2003

Modafinil in the treatment of excessive daytime sleepiness in children.

BACKGROUND: Modafinil is an alerting agent approved for the treatment of narcolepsy in adults. There are no studies examining the long-term effects and safety profile of modafinil in children with excessive daytime somnolence (EDS). OBJECTIVES: To determine the effects of modafinil on clinical manifestations of narcolepsy and idiopathic hypersomnia. METHODS: A systematic chart review was conducted for 13 children (mean age 11.0+/-5.3 years, six males, 10 with narcolepsy and three with idiopathic hypersomnia) receiving modafinil. RESULTS: The mean modafinil dose was 346+/-119 mg/day, with a mean treatment duration of 15.6+/-7.8 months. For approximately 90% of the children treated, parents reported a favorable response with the reduction in sudden sleep attacks, as documented by sleep-wake diaries. One child failed to improve on 400 mg/day modafinil and was switched to methylphenidate. Two other children showed only partial improvement and required additional stimulant medication to control EDS symptoms. Seven children underwent repeated nocturnal polysomnography and multiple sleep latency tests (MSLT). Compared to baseline MSLT measures (mean sleep latency: 6.6+/-3.7 min), modafinil prolonged mean sleep latency (10.2+/-4.8 min, p=0.02) without significant alteration in nocturnal polysomnographic measures. However, a trend towards REM sleep reduction was noted (16.8+/-5.1%TST vs. 11.8+/-6.2%TST). Exacerbation of seizures and psychotic symptoms was reported with modafinil therapy in two children with preexisting conditions. Hematological and hepatic functions assessed every 3 months remained unaltered. CONCLUSION: Modafinil has a modest, yet significant effect on EDS in children and appears to be safe and well tolerated.

Adolescent↗
PubMed2003

Periodic limb movement disorder of sleep in children.

To characterize periodic limb movement disorder (PLMD) in a cohort of prepubertal children we examined sleep-related identifiable differences between children with PLMD and attention-deficit/hyperactivity disorder (ADHD), PLMD alone, and age-matched controls. Children were selected from a chart review of all children referred to a pediatric sleep medicine center and from a community survey of 5-7-year-old-children. Polysomnography (PSG) and parental report data from all children identified as having periodic limb movement index (PLMI) >5 were reviewed and compared with a cohort of age-matched controls. A total of 8.4% of children in the clinic-referred sample, and 11.9% of the children recruited from the community had PLMI >5. Of those, 44.4% were identified as having ADHD. Children with PLMD had significantly lower percentage of rapid eye movement (REM) than control children (P < 0.001). Children in the PLMD/ADHD group had a significantly greater number of arousals associated with PLM (PLMa) than children with PLMD only (P < 0.05). While a relationship between ADHD and PLMD was observed, it was weaker than previous reports (Chervin, R. D. et al. Sleep, 2002; 25: 213; Chervin, R. D. and Archbold, K. H. Sleep, 2001; 24: 313; Picchietti et al. J. Child Neurol., 1999; 13: 588; Picchietti et al. Mov. Disord., 1999; 14: 1000; Picchietti and Walters Sleep, 1999; 22: 297). Children in the PLMD/ADHD group were more likely to have PLMas than were children with PLMD only. We postulate that rather than a direct relationship between ADHD and PLMD, this link may be mediated by the presence of reduced REM sleep and more importantly by the sleep fragmentation associated with PLM-induced arousals.

Attention Deficit Disorder with Hyperactivity↗
PubMed2003

Temporal aspects of spatial task performance during intermittent hypoxia in the rat: evidence for neurogenesis.

Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea, leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in the adult rat. We report that in Sprague-Dawley rats the initial IH-induced impairments in spatial learning are followed by a partial functional recovery over time, despite continuing IH exposure. These functional changes coincide with initial decreases in basal neurogenesis as shown by the number of positively colabelled cells for BrdU and neurofilament in the dentate gyrus of the hippocampus, and are followed by increased expression of neuronal progenitors and mature neurons (nestin and BrdU-neurofilament positively labelled cells, respectively). In contrast, no changes occurred during the course of IH exposures in the expression of the synaptic proteins synaptophysin, SNAP25, and drebrin. Collectively, these findings indicate that the occurrence of IH during the lights on period results in a biphasic pattern of neurogenesis in the hippocampus of adult rats, and may account for the observed partial recovery of spatial function.

Animals↗
PubMed2003

Increased susceptibility to intermittent hypoxia in aging rats: changes in proteasomal activity, neuronal apoptosis and spatial function.

Obstructive sleep apnea (OSA) is a frequent medical condition characterized by intermittent hypoxia (IH) during sleep, and is associated with neurodegenerative changes in several brain regions along with learning deficits. We hypothesized that aging rats exposed to IH during sleep would be particularly susceptible. Young (3-4 months) and aging (20-22 months) Sprague-Dawley rats were therefore exposed to either room air or IH for 14 days. Learning and memory was assessed with a standard place-training version of the Morris water maze. Aging rats exposed to room air (RA) or IH displayed significant spatial learning impairments compared with similarly exposed young rats; furthermore, the decrements in performance between RA and IH were markedly greater in aging compared with young rats (p < 0.01), and coincided with the magnitude of IH-induced decreases in cyclic AMP response element binding (CREB) phosphorylation. Furthermore, decreases in proteasomal activity occurred in both young and aging rats exposed to IH, but were substantially greater in the latter (p < 0.001). Neuronal apoptosis, as shown by cleaved caspase 3 expression, was particularly increased in aging rats exposed to IH (p < 0.01 versus young rats exposed to IH). Collectively, these findings indicate unique vulnerability of the aging rodent brain to IH, which is reflected at least in part, by the more prominent decreases in CREB phosphorylation and a marked inability of the ubiquitin-proteasomal pathway to adequately clear degraded proteins.

Aging↗
PubMed2003

Treatment of obstructive sleep apnea in children: do we really know how?

Obstructive sleep apnea syndrome (OSAS) is a frequent, albeit underdiagnosed problem in children. If left untreated, OSAS may lead to substantial morbidities affecting multiple target organs and systems. The immediate consequences of OSAS in children include behavioral disturbance and learning deficits, pulmonary hypertension, as well as compromised somatic growth. However, if not treated promptly and early in the course of the disease, OSAS may also impose long-term adverse effects on neurocognitive and cardiovascular function, thereby providing a strong rationale for effective treatment of this condition. This review provides a detailed description of the current treatment modalities for pediatric OSAS, and uncovers the potential limitations of the available data on these issues. Furthermore, we postulate that OSAS will persist relatively often after tonsillectomy and adenoidectomy, and that critical studies need to be conducted to identify such patients and refine the clinical management algorithm for pediatric OSAS.

Anti-Inflammatory Agents↗
PubMed2003

Periodic limb movements in sleep and iron status in children.

STUDY OBJECTIVES: To assess potential relationships between serum iron and ferritin levels and the severity of periodic limb movement in sleep (PLMS) in a pediatric population, and to evaluate the response to supplemental iron therapy. DESIGN: A prospective study of all consecutively diagnosed children with PLMS (periodic limb movement index [periodic limb movements per hour of total sleep time, [PLMI] > 5) who underwent overnight polysomnographic evaluation. In all patients, complete blood count and serum iron and ferritin levels were obtained. Patients with serum ferritin concentrations less than 50 microg/L were prescribed iron sulfate at 3 mg/kg of elemental iron per day for 3 months. At the end of treatment, serum iron and ferritin levels and sleep studies were repeated. SETTING: Comprehensive Sleep Medicine Center, Tulane University Health Sciences Center, and Kosair Children's Hospital Sleep Medicine and Apnea Center. PATIENTS: Twenty boys and 19 girls with PLMS with a mean age of 7.5 +/- 3.1 years. INTERVENTION: Iron therapy. RESULTS: Twenty-eight (71.8%) patients had ferritin levels less than 50 microg/L. There was no significant correlation between serum ferritin concentration and PLMS severity as indicated by the PLMI (r = -0.19). The PLMI in patients with serum ferritin levels less than 50 microg/L (29.9 +/- 15.5 PLM/h) was higher than in patients with serum ferritin levels greater than 50 microg/L (21.9 +/- 11.8 PLM/h); however, the difference did not achieve statistical significance (P = 0.09). In contrast, serum iron was significantly correlated with PLMI (r = -0.43, P < 0.01). Indeed, patients with serum iron concentrations less than 50 microg/dL had a higher PLMI compared to patients with serum iron concentrations greater than 50 microg/dL (42.8 +/- 18.3 PLM/h and 23.1 +/- 10.1 PLM/h, respectively; P = 0.02). Twenty-five out of the 28 PLMS patients with serum ferritin levels less than 50 microg/L received treatment with iron sulfate, and 19 (76%) responded favorably. Among the responders to iron therapy, PLMI decreased from 27.6 +/- 14.9 PLM per hour to 12.6 +/- 5.3 PLM per hour after 3 months of iron supplements (P < 0.001) and coincided with increases in serum ferritin levels (pre: 40.8 +/- 27.4 microg/L vs post: 74.1 +/- 13.0 microg/L; P < 0.001). CONCLUSIONS: In children, the presence of PLMS is frequently associated with low serum iron and a tendency toward low serum ferritin levels. In addition, iron therapy is associated with clinical improvement in most of these patients.

Adolescent↗
PubMed2003

Effect of long-term intermittent and sustained hypoxia on hypoxic ventilatory and metabolic responses in the adult rat.

The effects of chronic sustained hypoxia (SH) on ventilation have been thoroughly studied. However, the effects of intermittent hypoxia (IH), a more prevalent condition in health and disease are currently unknown. We hypothesized that the ventilatory consequences of SH and IH may differ and be related to changes in N-methyl-D-aspartate (NMDA) glutamate receptor subunit expression. To examine these issues, Sprague-Dawley adult male rats were exposed to 30 days of either SH (10% O2) or IH (21% and 10% O2 alternations every 90 s) or to normoxia (RA), at the end of which ventilatory and O2 consumption responses to a 20-min acute hypoxic challenge (10% O2) were conducted. In addition, dorsocaudal brain stem tissue lysates were harvested at 1 h, 6 h, 1 day, 3 days, 7 days, 14 days, and 30 days of SH and IH and analyzed for NR1, NR2A, and NR2B NMDA glutamate receptor expression by immunoblotting. Normoxic ventilation was higher after both SH and IH (P < 0.001). Peak hypoxic ventilatory response was higher after SH but not after IH compared with RA. However, hypoxic ventilatory decline was more prominent after SH than IH (P < 0.001). NR1 expression showed a biphasic pattern of expression over time that was essentially identical after IH and SH (P value not significant). However, NR2A and NR2B expression was higher in IH compared with SH and RA (P < 0.01). We conclude that long-lasting exposures to SH and IH enhance normoxic ventilation but are associated with different time domains of ventilation during acute hypoxia that may be accounted in part by changes in NMDA glutamate receptor subunit expression.

Animals↗
PubMed2003

Snoring in preschoolers: associations with sleepiness, ethnicity, and learning.

Sleep-disordered breathing (SDB) in children is associated with poor school performance, with minority children being at increased risk for both conditions. The latter have been attributable to low socio-economic status (SES). To further study these relationships, the contribution of SES to SDB and learning was examined in 1,010 validated questionnaires collected from parents of both white and African-American low-SES preschoolers. Twenty-two percent of disadvantaged preschoolers were reported to be at risk for SDB. These children were more likely to be African American, and had a higher incidence of daytime sleepiness, lower academic performance, and hyperactivity. Maternal education level did not account for these differences.

Black People↗
PubMed2003

Vascular endothelial growth factor in the cerebrospinal fluid of infants who died of sudden infant death syndrome: evidence for antecedent hypoxia.

OBJECTIVES: Recurrent hypoxemia has been proposed as an important pathophysiological mechanism underlying sudden infant death syndrome (SIDS). However, conflicting results emerged when xanthines were used as markers for hypoxia. The vascular endothelial growth factor (VEGF) gene is highly sensitive to changes in tissue partial oxygen tension, and changes in genomic and protein expression occur even after changes in oxygenation within the physiologic range. METHODS: For determining whether hypoxia precedes SIDS, VEGF levels were measured using an enzyme-linked immunosorbent assay in the cerebrospinal fluid (CSF) of 51 SIDS infants and in 33 additional control infants who died of an identifiable cause. In addition, 6 rats that had a chronically implanted catheter in the lateral ventricle were exposed to a short hypoxic challenge, and VEGF concentrations were measured in CSF at various time points for 24 hours. Another set of 6 rats were killed with a pentobarbital overdose, and VEGF CSF levels were obtained at different time points after death. RESULTS: Mean VEGF concentrations in CSF were 308.2 +/- 299.1 pg/dL in the SIDS group and 85.1 +/- 82.9 pg/dL in those who died of known causes. Mean postmortem delay averaged 22 hours for both groups. In rat experiments, hypoxic exposures induced time-dependent increases in VEGF, peaking at 12 hours and returning to baseline at 24 hours. Postmortem duration in the animals was associated with gradual increases in VEGF that reached significance only at 36 hours. CONCLUSIONS: We conclude that VEGF CSF concentrations are significantly higher in infants who die of SIDS. We postulate that hypoxia is a frequent event that precedes the sudden and unexpected death of these infants.

Animals↗
PubMed2003

Sleep and neurobehavioral characteristics of 5- to 7-year-old children with parentally reported symptoms of attention-deficit/hyperactivity disorder.

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.

Age Factors↗
PubMed2002

Proteomic analysis reveals alterations in the renal kallikrein pathway during hypoxia-induced hypertension.

Obstructive sleep apnea syndrome (OSAS), a disorder characterized by episodic hypoxia (EH) during sleep, is associated with systemic hypertension. We used proteomic analysis to examine differences in rat kidney protein expression during EH, and their potential relationship to EH-induced hypertension. Young male Sprague-Dawley rats were exposed to either EH or sustained hypoxia (SH) for 14 (EH14/SH14) and 30 (EH30/SH30) days. Mean arterial blood pressure was significantly increased only in EH30 (p < 0.0002). Kidney proteins were resolved by two-dimensional-PAGE and were identified by MALDI-MS. Renal expression of kallistatin, a potent vasodilator, was down-regulated in all animals. Expression of alpha-1-antitrypsin, an inhibitor of kallikrein activation, was up-regulated in EH but down-regulated in SH. Western blotting showed significant elevation of B(2)-bradykinin receptor expression in all normotensive animals but remained unchanged in hypertensive animals. Proteins relevant to vascular hypertrophy, such as smooth muscle myosin and protein-disulfide isomerase were up-regulated in EH30 but were down-regulated in SH30. These data indicate that EH induces changes in renal protein expression consistent with impairment of vasodilation mediated by the kallikrein-kallistatin pathway and vascular hypertrophy. In contrast, SH-induced changes suggest the kallikrein- and bradykinin-mediated compensatory mechanisms for prevention of hypertension and vascular remodeling. To test the hypothesis suggested by the proteomic data, we measured the effect of EH on blood pressure in transgenic hKLK1 rats that overexpress human kallikrein. Transgenic hKLK1 animals were protected from EH-induced hypertension. We conclude that EH-induced hypertension may result, at least in part, from altered regulation of the renal kallikrein system.

Amino Acid Sequence↗
PubMed2002

Domoic acid lesions in nucleus of the solitary tract: time-dependent recovery of hypoxic ventilatory response and peripheral afferent axonal plasticity.

The nucleus of the solitary tract (NTS) plays a pivotal role in the ventilatory response to hypoxia (HVR). However, the effects of excitotoxic lesions and the potential for functional recovery and plasticity remain unknown. Domoic acid (DA) or vehicle were bilaterally injected within the NTS of adult male Sprague Dawley rats. HVR (10% O(2)) and anatomical changes were assessed at 5-90 d after surgery. DA induced dose-dependent HVR attenuations ( approximately 70% at peak effect) that exhibited saturation at concentrations of 0.75-1.0 mm. However, although sodium cyanide-induced ventilatory responses were virtually abolished, DA did not modify baroreceptor gain. Consistent with ventilatory reductions, NTS neurons showed a significant degeneration 3 d after DA injection. In addition, the projection fields and the density of vagal afferent terminals to the NTS, and the motor neurons in the dorsal motor nucleus of the vagus were substantially reduced at 15 d. At 30 d, no functional or neural recovery were apparent. However, at day 60, the reduction in HVR was only approximately 40% of control, and at 90 d, HVR returned to control levels, paralleling regeneration of vagal afferent terminals within the NTS. The regeneration was particularly prominent in the commissural and dorsomedial subnuclei in the absence of cellular recovery. Thus, the integrity of the NTS is critical for HVR, spontaneous HVR recovery occurs after excitotoxic lesions in the NTS, and vagal-glossopharyngeal terminal sprouting in the NTS may underlie the anatomical substrate for such spontaneous functional recovery. The adult brainstem/NTS has self-repairing capabilities and will compensate for functional losses after structural damage by rewiring of its neural circuitry.

Animals↗
PubMed2002

Circulating vascular endothelial growth factor levels in patients with obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with intermittent hypoxia during sleep. Vascular endothelial growth factor (VEGF) has detectable levels in the circulation and its expression is highly regulated by oxygen tension. We therefore hypothesized that serum VEGF levels will be elevated in patients with OSA. DESIGN: Blood samples were collected at random times during the day from 68 adults and 41 children who were clinically suspected for the presence of OSA, and who underwent overnight polysomnography. SETTING: University hospital sleep laboratory. PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: For both children and adults, serum VEGF levels were significantly higher in polysomnographically confirmed OSA (AHI>15 and AI>5 in adults and children respectively) when compared to those with mild or no disease (p<0.0001). Furthermore, significant correlations were found between VEGF concentrations and respiratory disturbance index and sleep time spent at SpO2 <90%. In addition, VEGF levels in children were higher for any given duration of hypoxia during sleep (p<0.0001). No differences in VEGF emerged between evening and morning samples. However, temporal delays in blood sample processing were associated with spuriously increased VEGF concentrations. Exploratory analysis of the data revealed that serum VEGF concentrations of >150 pg/ml in adults and >100 pg/ml in children were predictive of OSA, when an apnea-hypopnea index >30 and an apnea index >5 were used as disease criteria in adults and children, respectively. CONCLUSIONS: We conclude that circulating VEGF levels are frequently elevated in OSA patients, and may play a role in the regulation of tissue oxygen delivery.

Body Mass Index↗
PubMed2002

Increased mitochondrial antioxidative activity or decreased oxygen free radical propagation prevent mutant SOD1-mediated motor neuron cell death and increase amyotrophic lateral sclerosis-like transgenic mouse survival.

The molecular mechanisms of selective motor neuron degeneration in human amyotrophic lateral sclerosis (ALS) disease remain largely unknown and effective therapies are not currently available. Mitochondrial dysfunction is an early event of motor neuron degeneration in transgenic mice overexpressing mutant superoxide dismutase (SOD)1 gene and mitochondrial abnormality is observed in human ALS patients. In an in vitro cell culture system, we demonstrated that infection of mouse NSC-34 motor neuron-like cells with adenovirus containing mutant G93A-SOD1 gene increased cellular oxidative stress, mitochondrial dysfunction, cytochrome c release and motor neuron cell death. Cells pretreated with highly oxidizable polyunsaturated fatty acid elevated lipid peroxidation and synergistically exacerbated motor neuron-like cell death with mutant G93A-SOD1 but not with wild-type SOD1. Similarly, overexpression of mitochondrial antioxidative genes, MnSOD and GPX4 by stable transfection significantly increased NSC-34 motor neuron-like cell resistance to mutant SOD1. Pre-incubation of cells with spin trapping molecule, 5',5'-dimethylpryrroline-N-oxide (DMPO), prevented mutant SOD1-mediated mitochondrial dysfunction and cell death. Furthermore, treatment of mutant G93A-SOD1 transgenic mice with DMPO significantly delayed paralysis and increased survival. These findings suggest a causal relationship between enhanced oxidative stress and mutant SOD1-mediated motor neuron degeneration, considering that enhanced oxygen free radical production results from the SOD1 structural alterations. Molecular approaches aimed at increasing mitochondrial antioxidative activity or effectively blocking oxidative stress propagation can be potentially useful in the clinical management of human ALS disease.

Amyotrophic Lateral Sclerosis↗