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Biomedical subjects

D Gozal

Publications and source records attributed to D Gozal.

At least 37 records · Page 2Linked to original sources
PubMed2001

Prenatal cigarette smoke exposure selectively alters protein kinase C and nitric oxide synthase expression within the neonatal rat brainstem.

Maternal smoking is a major risk factor for sudden infant death syndrome. Protein kinase C (PKC) and neuronal nitric oxide synthase (NOS) activities within the dorsocaudal brainstem (DB) mediate critical components of respiratory drive and could be implicated in SIDS. Thus, exposure to smoking during fetal life could modify the expression of these kinases in the DB. Rats were exposed to cigarette smoke or room air (Sham) from day 2 to 22 of pregnancy. Immunoblots of DB lysates at 2 days postnatally revealed no differences in PKC-alpha, PKC-beta, and endothelial NOS expression. However, PKC-gamma, PKC-delta, and neuronal NOS immunoreactivities were reduced in the cigarette smoke group. We conclude that gestational smoking is associated with selective reductions in PKC and NOS isoforms within the DB, which could decrease respiratory drive and lead to enhanced hypoxic vulnerability in infants of smoking mothers.

Animals↗
PubMed2001

In vivo PDGF beta receptor activation in the dorsocaudal brainstem of the rat prevents hypoxia-induced apoptosis via activation of Akt and BAD.

Activation of platelet-derived growth factor receptor beta (PDGFR) within the caudal brainstem modulates the hypoxic ventilatory response. Since hypoxia does not induce apoptosis in the caudal brainstem, PDGFR could underlie such protective mechanism via a PI3 kinase-dependent phosphorylation of both Akt and BAD pathways. To further study this issue, caudal brainstem lysates were harvested from Sprague--Dawley rats during hypoxia (10% O(2)) after treatment with either vehicle or CGP 57148B (100 mg/kg), a selective blood-brain barrier-permeable PDGFR antagonist. Time-dependent increases in phosphorylated Akt occurred during hypoxia, peaking at 45' and lasting for up to 6 h, without parallel changes in total Akt protein. CGP 57148B attenuated Akt activation at all time points. Similarly, phosphorylation of BAD at serine136 but not at serine 112 occurred in the caudal brainstem as early as 15' of hypoxia, and was completely blocked by CGP 57148B. Furthermore, CGP 57148B treatment elicited significant increases in single-stranded DNA, caspase-like activity, and cleaved caspase 3 after 24 h of hypoxia that were absent in the caudal brainstem of hypoxic vehicle-treated animals. We conclude that PDGFR-dependent in vivo activation of both Akt and BAD during hypoxia prevents induction of apoptosis, and may contribute to the increased hypoxic tolerance of brainstem neurons.

Animals↗
PubMed2001

Percutaneous image-guided needle biopsy in children--summary of our experience with 57 children.

BACKGROUND: Percutaneous image-guided needle biopsy in children has been slower to gain acceptance than in adults where it is regarded as the standard clinical practice in screening suspicious masses. OBJECTIVES: To report our experience with percutaneous image-guided needle biopsy in the pediatric population and assess its clinical use, efficacy and limitations. MATERIAL AND METHODS: Sixty-nine percutaneous image-guided needle biopsies were performed in 57 children. The age of the children ranged from 4 days to 14 years (mean 5.6 years). We used 16- to-20-gauge cutting-edge needles. Sixty-two biopsies were core-needle biopsies and 7 fine-needle aspiration biopsies. RESULTS: There were 50 malignant lesions, 10 benign lesions and 2 infectious lesions. In 55 (88.7 %) lesions the needle biopsy was diagnostic. In 7 (11.3 %) the biopsy was non-diagnostic and the diagnosis was made by surgery. Core-needle biopsy was diagnostic in 47 of 50 (94 %) of the malignant solid tumors. In 3 out of 5 children with lymphoma, an accurate diagnosis was obtained with needle aspiration. Seven children underwent a repeated core-needle biopsy, (5 for Wilms' tumor and 2 for neuroblastoma) that was diagnostic in all cases. All the biopsies were performed without complications. CONCLUSION: Percutaneous image-guided needle biopsy is a simple, minimally invasive, safe and accurate method for the evaluation of children with suspicious masses. These data suggest that image-guided needle biopsy is an excellent tool for diagnosing solid tumors in the pediatric population. Negative studies should be considered nondiagnostic and followed by excisional surgical biopsies when clinical suspicion of malignancy is high.

Adolescent↗
PubMed2001

Morbidity of obstructive sleep apnea in children: facts and theory.

Sleep-disordered breathing (SDB) is a frequent, albeit underdiagnosed, problem in children. If left untreated, SDB may lead to substantial morbidities affecting multiple target organs and systems. This review provides a detailed and current description of the current status of our understanding of SDB-associated morbidity in children, and provides recommendations of future research directions necessary for increasing our knowledge and awareness on the short- and long-term consequences of SDB during childhood.

Adenoids↗
PubMed2001

Chemoreceptive mechanisms elucidated by studies of congenital central hypoventilation syndrome.

Humans born with the condition of central hypoventilation during non-rapid eye movement sleep, termed congenital central hypoventilation syndrome (CCHS), invariably have absent or greatly diminished central hypercapnic ventilatory chemosensitivity. Genetic and pathological studies of CCHS may enable identification of the genes or areas of the central nervous system involved in the syndrome and thus implicated in central hypercapnic ventilatory chemosensitivity. Functional studies of CCHS permit a more quantitative assessment of the importance of ventilatory chemosensitivity in the regulation of breathing during wakefulness and sleep. The experimental evidence suggests that central hypercapnic ventilatory chemosensitivity is crucial in regulating alveolar ventilation during non-rapid eye movement sleep but not during rapid eye movement sleep or during many of the behaviors occurring during wakefulness. Presumably, other neural drives to breathe supervene to enable adequate ventilation. However, although physiological studies in CCHS subjects have been greatly instructive, their accurate interpretation will have to await future determination of the potential genetic and/or neuroanatomic basis of the syndrome.

Chemoreceptor Cells↗
PubMed2001

Respiratory plasticity following intermittent hypoxia: developmental interactions.

Intermittent hypoxia (IH) is the most frequent form of hypoxia occurring in the developing mammal. On one hand, the maturational process of neural, mechanical, pulmonary, and sleep state-dependent factors will favor the occurrence of IH during early postnatal life. On the other hand, it has also become clear that hypoxia, even when short lasting, can modify subsequent respiratory responses to hypoxia and induce a variety of genes whose consequences will persist for much longer periods than the duration of the hypoxic stimulus itself, i.e., functional and adaptive plasticities. The dynamic interactions between the overall duration and recurring frequency of IH, the severity of IH, and the level of neural maturity at the time of IH will modify the ventilatory, metabolic, and cardiovascular responses to hypoxia. We propose that the earlier IH will occur in the developmental course the more likely that the physiological responses to an ulterior hypoxic challenge will be altered even into adulthood. At this point in time, a critical examination of the field would suggest that the short-term alterations of the hypoxic ventilatory response (HVR) of the developing mammal to IH are qualitatively similar to those of the adult and display a biphasic pattern, namely, initial enhancement of the HVR followed by a reduction in HVR. However, the short- and long-term effects of IH on the modulation of neurotransmitter release, receptor binding and expression, intracellular signaling cascades, transcriptional regulation, and gene expression as a function of animal maturity are almost completely unknown. Further delineation of such complex responses to IH may permit the formulation of interventional strategies aiming at reducing the overall vulnerability of the young infant and child to apnea and sudden death.

Animals↗
PubMed2001

Brainstem nitric oxide tissue levels correlate with anoxia-induced gasping activity in the developing rat.

Gasping is an important mechanism for survival that appears to be developmentally modulated by the glutamate-nitric oxide (NO) pathway. However, the temporal characteristics of NO brain tissue levels during gasping are unknown. We hypothesized that during anoxia-induced gasping, the gasping frequency would be closely correlated with caudal brainstem tissue NO concentrations in developing rats. Brainstem and cortical tissue NO levels were measured during anoxia using a voltammetric electrode in adult rats and 5-day-old pups during control conditions and following pretreatment with the NMDA receptor antagonist MK-801 (1 mg/kg) or the neuronal NO synthase inhibitor 7-nitro-indazole (7-NI; 100 mg/kg). In young animals, NO tissue levels followed a triphasic trajectory coincident with gasp frequency which was markedly altered by MK-801 and 7-NI, albeit with preservation of gasp frequency-NO tissue level relationships. In adult rats, 40-fold higher NO tissue levels occurred and followed a monophasic trajectory coincident with gasp patterning. In the cortex, monophasic increases in NO levels occurred at all ages. We conclude that anoxia-induced gasping neurogenesis is modulated via NMDA-NO mechanisms in the developing rat. We postulate that higher NO brainstem concentrations may favor early autoresuscitation, but limit anoxic tolerance.

Aging↗
PubMed2001

PDGF-beta receptor expression in the dorsocaudal brainstem parallels hypoxic ventilatory depression in the developing rat.

The temporal trajectory of platelet-derived growth factor (PDGF)-beta receptor activation within the dorsocaudal brainstem parallels that of the mild hypoxic ventilatory depression (HVD) seen in adult rats. We hypothesized that enhanced PDGF-beta receptor activity may account for the particularly prominent HVD of developing mammals. To study this issue, 2-, 5-, 10-, and 20-d-old rats underwent hypoxic challenges (10% O(2) for 30 min) after pretreatment with either vehicle (Veh) or the selective PDGF-beta receptor antagonist CGP57148B (intraperitoneal 100 mg/kg). The developmental characteristics and magnitude of the peak hypoxic ventilatory response (HVR) were not modified by the PDGF-beta receptor blocker. However, HVD was markedly attenuated by CGP57148B, and such effect, although still present, gradually abated with increasing postnatal age [p < 0.001, analysis of variance (ANOVA)]. Hypercapnic ventilatory responses were not affected by CGP57148B. The expression of PDGF-beta receptor in the dorsocaudal brainstem was assessed by immunoblotting and confirmed progressively decreasing expression with maturation. We conclude that PDGF-beta receptor activation during hypoxia is an important contributor to HVD at all postnatal ages but more particularly in the immature rat.

Animals↗
PubMed2001

Snoring during early childhood and academic performance at ages thirteen to fourteen years.

OBJECTIVES: Obstructive sleep apnea syndrome in young children is associated with an adverse effect on learning. However, the long-term impact of sleep-disordered breathing (SDB) during early childhood on learning remains unknown. METHODS: Questionnaires were mailed to seventh and eighth graders attending public schools whose class ranking was either in the top 25% (high performance [HP]) or bottom 25% of their class (low performance [LP]), and who were matched for age, gender, race, school, and street of residence. Snoring frequency and loudness at 2 to 6 years of age, tonsillectomy and adenoidectomy (T&A) for snoring or recurrent infection, school grades, and parental smoking and snoring were assessed. RESULTS: The questionnaire response rate was 82.8%. Because of ongoing ring, 13 responders were excluded, such that 1588 questionnaires could be analyzed (797 in LP and 791 in HP group). Frequent and loud snoring during early childhood was reported in 103 LP children (12.9%) compared with 40 HP children (5.1%; odds ratio: 2.79; confidence interval: 1.88-4.15). Furthermore, 24 LP and 7 HP children underwent T&A for snoring (odds ratio: 3.40; confidence interval: 1.47-7.84), while 21 LP and 19 HP children required surgery for recurrent tonsillitis. CONCLUSIONS: Children with lower academic performance in middle school are more likely to have snored during early childhood and to require T&A for snoring compared with better performing schoolmates. These findings support the concept that SDB-associated neurocognitive morbidity may be only partially reversible or that a "learning debt" may develop with SDB during early childhood and hamper subsequent school performance.

Achievement↗
PubMed2001

Objective sleepiness measures in pediatric obstructive sleep apnea.

OBJECTIVES: Excessive daytime sleepiness (EDS) occurs frequently in adult patients with obstructive sleep apnea (OSA). However, the incidence of EDS in children with OSA is unknown. METHODS: To determine overall daytime sleepiness in pediatric OSA, 54 children with OSA, 14 children with primary snoring (PS), and 24 controls (C) underwent an overnight diagnostic polysomnogram followed the next day by a multiple sleep latency test. RESULTS: The mean apnea index was 15.1 +/- 9.5 standard deviation in OSA, 1.1 +/- 0.5 in PS, and 0.1 +/- 0.3 in C. Mean sleep latencies were 23.7 +/- 3.0 minutes in C, 23.7 +/- 3.1 minute in PS, and 20.0 +/- 7.1 minute in OSA patients. However, only 7 children with OSA had mean sleep latencies <10 minutes. In addition, shorter sleep latencies were more likely to occur in more obese OSA patients and those with more severe apnea index, and oxyhemoglobin desaturation. CONCLUSIONS: Shortened sleep latencies occur in children with OSA, but EDS is infrequent and tends to develop among more severe and/or obese patients.

Case-Control Studies↗
PubMed2000

Hypoxia induces activation of a N-methyl-D-aspartate glutamate receptor-protein kinase C pathway in the dorsocaudal brainstem of the conscious rat.

To study in vivo phosphorylation of N-methyl-D-aspartate (NMDA) glutamate receptors and the recruitment of protein kinase C isoforms during acute hypoxia, dorsocaudal brainstem lysates were harvested from conscious rats exposed to either room air or hypoxia (10% O2 for 5 and 15 min). Increased phosphorylation of the NR-1 subunit at serine residue 896 occurred during hypoxia and was blocked by pre-treatment with MK-801. Immunoblots of soluble and particulate fractions revealed subcellular translocation for PKC-beta, -gamma, -delta, -epsilon, and -iota during hypoxia with no changes in PKC-alpha, -mu, and -zeta. Translocation of PKC-beta, -delta and -epsilon was selectively attenuated following MK-801. We demonstrate that hypoxia leads to PKC-mediated activation of NMDA receptors in the brainstem, and that PKC-beta, -delta and -epsilon are the most likely candidates for NR-1 phosphorylation.

Animals↗
PubMed2000

Pulmonary manifestations of neuromuscular disease with special reference to Duchenne muscular dystrophy and spinal muscular atrophy.

Deterioration of respiratory function in patients with neuromuscular disorders is primarily responsible for the high mortality associated with these diseases. A review of Duchenne muscular dystrophy and spinal muscular atrophy, the leading neuromuscular disorders affecting children, will be followed by a critical analysis of the various pathophysiological mechanisms underlying respiratory manifestations in these patients. Among such mechanisms, the role of muscular weakness in preservation of lung function, mucociliary clearance, gas exchange at rest and during exercise, and respiratory control during wakefulness and sleep will be examined in detail. In addition, the potential benefits of respiratory muscle training and of early diagnosis and clinical intervention will be delineated. This review underscores the importance of periodic assessment of pulmonary function during wakefulness and sleep in children affected by neuromuscular diseases as an essential component of multidisciplinary care aimed at improving long-term morbidity, survival, and quality of life.

Humans↗
PubMed2000

Dynamic changes in EEG spectra during obstructive apnea in children.

Children are less likely to demonstrate EEG arousal during obstructive sleep apnea (OSA) than adults. We hypothesized that changes in spectral EEG characteristics occur during REM-associated OSA in the absence of arousal. Eight snoring children underwent overnight polysomnography. OSA events during REM periods not associated with EEG or behavioral arousal were identified. EEG signals from C3A2 and C4A1 leads corresponding to 1) < or =10-sec epochs preceding OSA (PRE), 2) the obstructed period (OSA), and 3) < or =10-sec epochs following airflow resumption (POST) were subjected to fast Fourier transform (FFT) routines. Seventy-two isolated OSA, and 14 clusters of > 4 OSA events were analyzed. In single OSA, delta OSA amplitude was lower than in PRE (P < 0.01) and in POST (P < 0.001). Furthermore, POST delta amplitude was higher than PRE (P < 0.01). In contrast, in OSA clusters, the dynamic differences in delta amplitude disappeared after the second OSA. Reciprocal increases and decreases occurred for the theta frequency domain during OSA and post-OSA, while sigma and beta frequency power did not change. We conclude that during isolated OSA episodes without arousal, significant decreases in power selectively occur for delta frequency, and are followed by a rebound increase upon termination of apnea. The delta changes are progressively attenuated during repeated OSA. We postulate that delta changes may reflect ongoing adaptations in sleep pressure which are necessary to relieve the respiratory compromise, and may represent subtle evidence for arousal and consequent sleep fragmentation in children with OSAS.

Child↗
PubMed2000

Treatment of sleep-disordered breathing in children with myelomeningocele.

The prevalence of moderate to severe sleep-disordered breathing (SDB) in patients with myelomeningocele may be as high as 20%, but little information is available regarding treatment of these patients. To assess the efficacy and complications of treatments for these children, we collected data on 73 patients from seven pediatric sleep laboratories. Obstructive sleep apnea (OSA, n = 30) and central apnea (n = 25) occurred more frequently than central hypoventilation (n = 12). We also describe a sleep-exacerbated restrictive lung disease type of SDB in 6 patients who had hypoxemia during sleep without apnea or central hypoventilation. For each type of SDB, effective treatments were identified in a stepwise process, moving towards more complex and invasive therapies. For OSA, adenotonsillectomy was often ineffective (10/14), whereas nasal continuous positive airway pressure (CPAP) was usually successful (18/21). For central apnea, methylxanthines and/or supplemental oxygen proved sufficient in 2 of 9 and 3 of 6, respectively, but noninvasive positive pressure ventilation was required in 7 children. For central hypoventilation, supplemental oxygen (alone or with methylxanthines), noninvasive positive pressure ventilation, and tracheostomy with positive pressure ventilation were effective in 3, 2, and 2 patients, respectively. Sleep-exacerbated restrictive lung disease always required supplemental oxygen treatment, but in 2 cases also required noninvasive positive pressure ventilation; nutritional and orthopedic procedures also were helpful. Posterior fossa decompression was used for the first three types of SDB, but data were insufficient to delineate specific recommendations for or against its use. In summary, evaluation by an experienced, multidisciplinary team can establish an effective treatment regime for a child with myelomeningocele and SDB.

Adolescent↗
PubMed2000

Signaling pathways of the acute hypoxic ventilatory response in the nucleus tractus solitarius.

The nucleus tractus solitarii (nTS) provides the initial central synaptic relay to peripheral chemoreceptor afferent inputs elicited by changes in oxygen tension. Insofar, the overall cumulative evidence pointing towards the N-methyl-D-aspartate (NMDA) glutamate receptor as the critical receptor underlying the early component of the hypoxic ventilatory response (HVR) is reviewed in detail. In addition, we will present recent findings supporting a role for platelet-derived growth factor (PDGF) beta receptor activation in modulation of the late phase of HVR. This evidence underscores the proposal of a working model for intracellular signaling pathways, downstream to the NMDA glutamate and PDGF-beta receptors in nTS neurons, which may contribute to both the ventilatory characteristics of the acute hypoxic response and to subsequently occurring functional adaptations and synaptic plasticity phenomena.

Acute Disease↗
PubMed2000

Brainstem activation of platelet-derived growth factor-beta receptor modulates the late phase of the hypoxic ventilatory response.

The early phase of the biphasic ventilatory response to hypoxia in mammals is critically dependent on NMDA glutamate receptor activation within the nucleus of the solitary tract. However, the mechanisms underlying the subsequent development of the typical ventilatory roll-off are unclear and could underlie important roles in the functional and molecular adaptation to oxygen deprivation. Because the growth factor platelet-derived growth factor (PDGF)-BB can modulate the open channel probability of NMDA receptors by activating PDGF-beta receptors, its contribution to hypoxic ventilatory roll-off was examined. Administration of PDGF-BB, but not PDGF-AA, in the nucleus of the solitary tract was associated with significant attenuations of the early hypoxic ventilatory response in conscious rats. Furthermore, marked reductions in the magnitude of hypoxic ventilatory roll-off occurred in mice heterozygous for a mutation in the PDGF-beta receptor. Administration of a PDGF-beta receptor antagonist to wild-type littermates elicited similar declines in hypoxic ventilatory roll-off. The relative abundance of PDGF-beta receptors was confirmed in the nucleus of the solitary tract and other nuclei implicated in the hypoxic ventilatory response. In nucleus of the solitary tract lysates, PDGF-beta receptor tyrosine phosphorylation was temporally correlated with hypoxic ventilatory roll-off formation. Increased PDGF-B chain mRNA expression was induced by hypoxia in the nucleus of the solitary tract, and PDGF-B chain immunoreactivity colocalized with approximately 40% of nucleus of the solitary tract neurons, demonstrating hypoxia-induced c-Fos enhancements. Thus, PDGF-BB release and PDGF-beta receptor activation in the nucleus of the solitary tract are critical components of hypoxic ventilatory roll-off and may have important functional implications in processes underlying survival and acclimatization to hypoxic environments.

Animals↗