Biomedical subjects

David Gozal

Publications and source records attributed to David Gozal.

At least 19 recordsLinked to original sources

PubMed2026

Monocarboxylate Transporter 2 (MCT2) Reduction Is Associated with Increased Lung Tumor Growth and Alterations in the Immune Microenvironment in a Subcutaneous Tumor Model.

Monocarboxylate transporter 2 (MCT2; SLC16A7) is a high-affinity pyruvate transporter implicated in cancer metabolism. However, its role in lung cancer progression and the tumor microenvironment remains unclear. This study examined the effects of MCT2 reduction on tumor growth and cell-type-specific transcriptional changes within the tumor microenvironment. MCT2 loxP/loxP mice were crossed with mCre-Tg mice, and MCT2 deletion was induced by tamoxifen. Control (CO) mice received vehicle treatment. TC1 cells (100,000 cells/mouse) were injected subcutaneously, and tumors were harvested after 24 days. Single-nucleus RNA sequencing (snRNA-seq) was performed on isolated tumor nuclei (4000 nuclei/sample; n = 3 per group) using the 10x Genomics Chromium platform. Data were processed with Cell Ranger v3.0.2 and Seurat v5.2.1, followed by differential expression and pathway enrichment analyses integrated with macrophage bulk RNA-seq data. Tumors in mice with systemic MCT2 reduction grew significantly faster than those in control mice, demonstrating an association between host MCT2 reduction and increased tumor growth. Transcriptomic analysis generated high-quality profiles from 6864 CO and 10,055 KO nuclei. Clustering identified 12 cellular populations and cell types. MCT2 reduction altered pathways involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid metabolism across multiple populations. Macrophages showed prominent transcriptional changes, including enrichment of MAPK, PI3K-Akt, IgSF-CAM, ECM, and cytokine-cytokine signaling pathways. These findings were supported by macrophage bulk RNA-seq data. Systemic MCT2 reduction was associated with increased tumor growth and broad transcriptional alterations within the tumor micro-environment. Differences in metabolic and immune-related transcriptional programs, particularly in macrophages, identify potential mechanisms associated with tumor progression that warrant further functional investigation.

Animals↗

PubMed2007

Impaired spatial working memory and altered choline acetyltransferase (CHAT) immunoreactivity and nicotinic receptor binding in rats exposed to intermittent hypoxia during sleep.

Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing (SDB), is associated with cognitive impairment, neurodegeneration, oxidative stress, and inflammatory responses within rodent brain regions such as the basal forebrain. In this region, damage to cholinergic neurons correlates with working memory deficits in a number of neurodegenerative disorders, suggesting that degeneration of cholinergic systems may also contribute to the working memory impairments observed after IH exposures. We therefore examined basal forebrain choline acetyltransferase (CHAT) immunohistochemistry, nicotinic receptor binding in the prefrontal cortex (PFC), and working memory, in male rats tested on a delayed matching to place (DMP) task in the water maze following exposure to either room air (RA) or intermittent hypoxia (IH; alternating 90s epochs of 21% and 10% O(2) during sleep). IH-treated animals displayed impaired working memory with respect to controls, along with significant reductions in CHAT-stained neurons in the medial septal nucleus, in both the vertical and horizontal limbs of the diagonal band, and the substantia inominata after 14 days of IH exposure. In addition, increases in nicotinic binding and receptor affinity in the PFC were observed after 14 days of IH exposure. Thus, a loss of cholinergic neuronal phenotype in the basal forebrain may contribute to the cognitive impairments associated with CIH exposure. However, compensatory mechanisms may also be activated in other brain regions, and may provide potential therapeutic targets for the cognitive impairments associated with SDB.

Animals↗

PubMed2007

Hypoxemia and obesity modulate plasma C-reactive protein and interleukin-6 levels in sleep-disordered breathing.

C-reactive protein (CRP) and interleukin-6 (IL-6) are pro-inflammatory proteins and important risk factors for atherosclerosis. Plasma CRP levels in snoring children may or may not be elevated. Since obesity is prevalent among snoring children and is associated with elevated CRP levels, we aimed to investigate the relative contributions of sleep-disordered breathing (SDB) and obesity to the inflammatory processes in snoring children in this prospective study. Two hundred forty-four children (mean age 8.9 +/- 3.4 years) underwent polysomnographic evaluation. CRP was measured the following morning, and plasma IL-6 levels from 111 randomly selected children were also examined. Plasma CRP and IL-6 levels were elevated in children with SDB. Log plasma CRP levels were higher in the moderate-severe SDB group (apnea/hypopnea index, AHI > or = 5) compared to the mild SDB group (AHI > or = 1 and <5; p < 0.0001) or the control group (AHI < 1; p = 0.0001). Log plasma CRP levels correlated with AHI, arousal index, relative BMI, and SpO(2) nadir (r = 0.30, p < 0.0001; r = 0.21, p = 0.002; r = 0.39, p < 0.0001, r = -0.36, p < 0.0001, respectively). Log plasma CRP levels were lower in children with SpO(2) nadir > or =90 (p < 0.0001). Sub-analysis of the 116 non-obese children in the cohort revealed similar findings. Log plasma IL-6 levels were increased in children with moderate-severe SDB compared to controls (p = 0.03) and correlated with AHI (r = 0.28, p = 0.003) and SpO(2) nadir (r = -0.24, p = 0.02). Children with SDB display significant severity-dependent increases in plasma CRP and IL-6 levels independent of obesity.

Adolescent↗

PubMed2006

Obesity and obstructive sleep apnea in children.

The prevalence and severity of obesity in children and adolescent is dramatically increasing worldwide with a corresponding increase in the prevalence of obesity-associated morbidities particularly those involving OSAS and metabolic and cardiovascular sequelae. Obstructive sleep apnea and obesity hypoventilation syndrome are important and serious consequences of obesity, and may in fact mediate components of the association between obesity and metabolic and cardiovascular morbidities, most likely via potentiation of inflammatory cascades. It is anticipated that the increased prevalence of obesity in children and adolescents in our society will be accompanied by a steady increase in the incidence of OSAS. In this review, we will examine our current understanding of sleep-disordered breathing and associated morbidities in obese children, and summarize the range of therapeutic modalities currently available for this high-risk population.

Adolescent↗

PubMed2006

Respiratory and metabolic responses to early postnatal chronic intermittent hypoxia and sustained hypoxia in the developing rat.

Exposure to sustained hypoxia (SH) differentially modifies the hypoxic ventilatory response (HVR) in adults and developing rats. We examined the possibility that postnatal intermittent hypoxia (IH), a more prevalent clinical condition than SH, may lead to significant modifications of ventilatory patterning during development. Sprague-Dawley rat pups were exposed as of the d 1 of life to either SH (10% O2) or IH [alternating room air (RA) and 10% O2 every 90 s] for up to 30 d; controls were exposed to normoxia. HVR (10% O2 for 20 min) was assessed in unrestrained pups at 5, 10, 15, and 30 d of age using whole-body plethysmography. IH pups displayed higher normoxic ventilation (VE) at all ages (p < 0.001 versus control; n = 12 per group), which was not observed in SH animals until 10 d of exposure (p < 0.001 versus control; n = 12 per group). Furthermore, both SH and IH modified properties of peak HVR (pHVR), as well as those of the ensuing hypoxic ventilatory decline (HVD); however, the ventilatory strategies adopted after SH and IH greatly differed. We conclude that both postnatal IH and SH modify normal ventilatory patterning and induce altered HVR, but differ in the ventilatory strategies adopted to mount HVR responses.

Animals↗

PubMed2006

Effects of progressive and maximal exercise on plasma levels of adhesion molecules in athletes with sickle cell trait with or without alpha-thalassemia.

The aim of the study was to examine the effects of exercise on soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in sickle cell trait (SCT) athletes with or without alpha-thalassemia. Six athletes with SCT, seven athletes with both SCT and alpha-thalassemia (SCTAT), and seven control athletes (Cont) performed an incremental and maximal test on cycloergometer. Levels of sICAM-1 and sVCAM-1 were assessed at rest, immediately after the end of exercise, and 1, 2, and 24 h after exercise. Although Cont and SCTAT groups exhibited similar basal plasma levels of inflammatory and adhesion molecules, the SCT group had higher sVCAM-1 basal concentrations. Incremental exercise resulted in a significant increase of sVCAM-1 in all subjects, which remained elevated only in the SCT group during the recovery period. In conclusion, as sVCAM-1 increased with exercise and during the recovery period, our findings support the concept that SCT athletes might be at risk for microcirculatory disturbances and adhesive phenomena developing at rest and several hours after exercise. alpha-Thalassemia might be considered protective among exercising SCT subjects.

Adult↗

PubMed2006

Hypoxia differentially regulates the expression of neuroglobin and cytoglobin in rat brain.

Neuroglobin (Ngb) and Cytoglobin (Cygb) are new members of the globin family and display heterotopic expression patterns. To examine the effect of different hypoxia profiles on expression of Ngb and Cygb in rodent brain, rats were exposed to either sustained hypoxia (SH; 10% O(2)) or intermittent hypoxia (IH; 10% and 21% O(2) alternating every 90 s) for 1, 3, 7 and 14 days, and mRNA and protein expression of Ngb and Cygb were assessed in brain cortex. SH increased Ngb mRNA and protein expression throughout the exposure, while IH only elicited slight increases in Ngb expression at day 1. Neither SH nor IH elicited increases in Cygb expression. Thus, hypoxic stimulus presentation is a major determinant of the regulation of hypoxic sensitive genes such as Ngb. Furthermore, disparities between Ngb and Cygb responses to hypoxia further suggest that these two globins may play divergent roles in brain.

Animals↗

PubMed2006

Sleep apnea in children--treatment considerations.

The prevalence of obstructive sleep apnea (OSA) is clearly increasing in the pediatric population. However, the polysomnographic criteria for treatment still remain to be defined by appropriate scientific methodology. Furthermore, the overall efficacy of currently available interventions such as surgical removal of enlarged tonsils and adenoids (T&A) is unknown, such that we are currently unable to precisely define who the high risk patients are, and the cost and benefits associated with any given treatment. Here, we review the available approaches to the management of OSA in the pediatric population, and examine the potential complementary role of anti-inflammatory therapy, mask ventilation, and intra-oral appliances in the context of mild OSA or residual OSA following T&A.

Child↗

PubMed2006

Sleep studies: which technologies?

The demand for sleep services for young patients has escalated due to the increased recognition of pediatric sleep disorders over the past two decades. In this overview, we will highlight the essentials of pediatric sleep monitoring and stress particular issues that require the awareness of clinicians evaluating children for sleep disorders. While many techniques used in the "adult" sleep centers may suffice for the older adolescent patient, specific tailoring of the design of the sleep center to younger children and their families, and attention to the age-sensitive components of sleep data acquisition and interpretation are increasingly important in younger children. Several promising newer technologies and their potential for future clinical utility will be also reviewed.

Blood Pressure Determination↗

PubMed2006

Anatomical changes in selected cardio-respiratory brainstem nuclei following early post-natal chronic intermittent hypoxia.

Early post-natal environmental exposures, including chronic intermittent hypoxia (CIH), may lead to long-term alterations in cardio-respiratory control, such as reductions in baroreflex sensitivity and acute hypoxic ventilatory responses in adult rats. Although the mechanisms underlying CIH-induced functional metaplasticity are unclear, anatomical alterations within selected brainstem nuclei may develop after CIH. To examine this issue, male rats were exposed to CIH (RAIH) or room air (RARA) for the first 30 days of life and were microinjected unilaterally in the right nodose ganglion with the neuronal tracer tetramethylrhodamine-dextran (TMR-D) to label brainstem neurons receiving vagal and glossopharyngeal projections. Substantial reductions in labeled afferents within the nucleus tractus solitarii (nTS) and significant increases in the total number of labeled neurons within the ventrolateral medulla (VLM), principally in the nucleus ambiguus (Namb; p<0.01) occurred in RAIH. Furthermore, 5-bromo-2'deoxyuridine labeling revealed enhanced neurogenesis within the Namb in RAIH and could partially account for the increased neuronal population in Namb. Thus, CIH-associated cardio-respiratory metaplasticity is accompanied by substantial structural changes within both the nTS and Namb.

Afferent Pathways↗

PubMed2006

Differential metabolic adaptation to acute and long-term hypoxia in rat primary cortical astrocytes.

Brain astrocytes provide structural and metabolic support to surrounding cells during ischemia. Glucose and oxygen are critical to brain function, and glucose uptake and metabolism by astrocytes are essential to their metabolic coupling to neurons. To examine astrocyte metabolic response to hypoxia, cell survival and metabolic parameters were assessed in rat primary cortical astrocytes cultured for 3 weeks in either normoxia or in either 1 day or 3 weeks sustained hypoxia (5% O2). Although cell survival and proliferation were not affected by the mildly hypoxic environment, substantial differences in glucose consumption and lactate release after either acute or prolonged hypoxia suggest that astrocyte metabolism may contribute to their adaptation. Hypoxia over a period of 1 day increased glucose uptake, lactate release, and glucose transporter 1 (GLUT1) and monocarboxylate transporter 1 (MCT1) expression, whereas hypoxia over a period of 3 weeks resulted in a decrease of all parameters. Furthermore, increased glucose uptake at 1 day of hypoxia was not inhibited by cytochalasin B suggesting the involvement of additional glucose transporters. We uncovered hypoxia-regulated expression of sodium-dependent glucose transporters (SGLT1) in astrocytes indicating a novel adaptive strategy involving both SGLT1 and GLUT1 to regulate glucose intake in response to hypoxia. Overall, these findings suggest that although increased metabolic response is required for the onset of astrocyte adaptation to hypoxia, prolonged hypoxia requires a shift to an energy conservation mode. These findings may contribute to the understanding of the relative tolerance of astrocytes to hypoxia compared with neurons and provide novel therapeutic strategies aimed at maintaining brain function in cerebral pathologies involving hypoxia.

Adaptation, Physiological↗

PubMed2006

Sleep habits and risk factors for sleep-disordered breathing in infants and young toddlers in Louisville, Kentucky.

INTRODUCTION: Snoring affects biobehavioral development among preschool and early school-age children. The goals of the present study were to survey the parents of a large community sample of infants and young toddlers to evaluate (a) naturalistic sleep duration and location; (b) snoring prevalence; and (c) demographic measures and sleep behaviors related to the presence of snoring either 2 or >or=3 days/week. METHODS: Questionnaires were completed by parents of children ages 2 weeks to 2 years attending well-baby checkups and were also mailed to the homes of six-month-old infants. RESULTS: Data from 944 children were available for analyses. No age differences were reported for total sleep duration, co-sleeping, or snoring. Average daily sleep duration was 12.5+/-1.8h (standard deviation (SD)), with daytime naps accounting for an increased proportion of total sleep duration among younger infants. Co-sleeping was reported by 15% of families. Snoring 2 days/week was reported in 11.8% and> days/week in 5.3% of participants. Survey items indicating risk for sleep-disordered breathing (SDB) clustered into factors related to the child, their environment, and their family; restless sleep was exclusively related to snoring 2 days/week and ethnicity, sweating during sleep, and noisy breathing exclusive to snoring >or=3 days/week. CONCLUSIONS: Young infants appear to sleep less than currently recommended. Co-sleeping is relatively common and not age-dependent through the first 2 years of life. Items relating to the child's sleep behaviors, environment, and parents' perceptions were predictive of positive report of snoring, with snoring rates consistent with a significant risk for SDB being similar to those reported for older children.

Catchment Area, Health↗

PubMed2006

Reciprocal interactions between spontaneous and respiratory arousals in adults with suspected sleep-disordered breathing.

BACKGROUND AND PURPOSE: Excessive daytime sleepiness (EDS) is a major consequence of sleep-disordered breathing (SDB) in adults. In snoring children, spontaneous and respiratory arousals display reciprocal interactions, allowing for development of a new quantitative measure, the sleep pressure score (SPS), which provides intra-polysomnographic estimates of sleep pressure/disruption. The aim of the present study was to assess the interactions between respiratory and spontaneous arousals in adults with suspected SDB, and to examine whether the SPS and the Epworth sleepiness scale (ESS) are correlated. PATIENTS AND METHODS: Retrospective chart review of 530 adult patients who underwent polysomnographic evaluation for suspected SDB in two medical centers was performed. Polysomnographic studies reports, patients' demographics and ESS scores were reviewed. RESULTS: Spontaneous and respiratory arousal indices and the apnea-hypopnea index (AHI) displayed negative and positive correlations respectively (r=-0.25, r=0.97, P<0.0001) indicating reciprocal interactions between respiratory and spontaneous arousals during sleep. The AHI corresponding to the SPS at which the respiratory arousal/total arousal fraction exceeded the spontaneous arousal/total arousal fraction occurred at approximately 14/h of total sleep time (TST) (compared to 7/h TST in children) (P<0.001). No correlation was found between SPS values and ESS scores. CONCLUSIONS: As in children, snoring adults exhibit reciprocal interactions between respiratory and spontaneous arousals that can also be expressed as a single quantitative measure, the SPS, which is highly dependent on the severity of SDB and could possibly serve as a more reliable index of sleep disruption, considering that the ESS is unrelated to either SPS or AHI.

Adult↗

PubMed2006

Urinary protein expression patterns in children with sleep-disordered breathing: preliminary findings.

BACKGROUND: Obstructive sleep apnea (OSA) is the most common form of sleep-disordered breathing, with almost 15 million Americans affected and many more at risk. Current diagnostic approach to OSA requires polysomnography, which is laborious, onerous, and time-consuming. There is ample evidence that inflammatory responses to the perturbations associated with OSA trigger a variety of genes and signaling cascades that ultimately lead to end-organ injury and changes in kidney function and protein expression. The aim of this study was therefore to analyze proteins in human urine and assess whether differential expression of particular proteins is associated with the presence of OSA. METHODS: Eleven OSA and 11 control children between the ages of three and 14 (males=17; females=5) underwent overnight sleep studies followed by a first-morning urine sample. Proteomic analysis of urine samples yielded a unique map of proteins, of which, five spots were selected for further analysis due to their significant intensity differences between OSA and control groups. RESULTS: Mass spectrometry followed by peptide mass fingerprinting conclusively identified four of the five spots as gelsolin, perlecan (a heparan sulfate proteoglycan), albumin, and immunoglobulin (P<0.05 and protein scores>67). CONCLUSIONS: Overall, increased expression of gelsolin and perlecan in the urinary proteome of children with OSA suggests that the episodic hypoxia associated with OSA may lead to changes in protein permeability or alternatively to increased catabolism of these proteins and their excretion in urine.

Body Mass Index↗

PubMed2006

Changes in ventilatory adaptations associated with long-term intermittent hypoxia across the age spectrum in the rat.

Intermittent hypoxia (IH) induces alterations in respiratory control that reflect various types of ventilatory plasticity. In freely behaving rats, acute exposure to IH elicits enhancements in normoxic minute ventilation (VE), termed ventilatory long-term facilitation. Exposure to longer time periods of IH induces unique ventilatory adaptations to intermittent hypoxia (VAIH). We hypothesized that long-term IH-induced ventilatory plasticity may be developmentally regulated and thus, IH exposures at progressively later post-natal ages may elicit differential effects on the magnitude of VAIH. To examine this issue, male Sprague-Dawley rats were exposed to 30 continuous days of IH beginning at post-natal ages 1, 10, 30, 60, 180, 360, and 540 days. Control animals were exposed to normoxic conditions with room air. Normoxic VE was significantly higher in IH-exposed rats (p < 0.01) except for the group in which IH was initiated at post-natal age 540 days (p = NS). The magnitude of VAIH was greatest in rats exposed in the immediate post-natal period and gradually diminished with advancing post-natal age. Enhanced normoxic VE was due to significant contributions from both frequency (p < 0.01) and tidal volume (p < 0.01), and could not be accounted for by changes in metabolic rate. We conclude that the magnitude of IH-induced ventilatory plasticity is age-dependent with progressive declines becoming apparent with advancing post-natal age.

Acclimatization↗

PubMed2006

Impaired control of renal sympathetic nerve activity following neonatal intermittent hypoxia in rats.

Apneas and recurring oxygen desaturations can occur in preterm infants and young children. To investigate long-term effects of neonatal intermittent hypoxia on baroreflex control of sympathetic nerve activity, we studied 5-7-month-old (adult) Sprague-Dawley rats exposed to chronic intermittent hypoxia (CIH, n=9; 8% O2 for 90 s alternating with 90 s 21% O2, 12h/day) for their first 30 postnatal days or controls exposed to normoxia (C, n=9). In adult CIH and C rats, baseline heart rate, mean arterial pressure, and plasma concentration of epinephrine and norepinephrine were similar. Baroreflex sensitivity was evaluated in anesthetized rats by changes in renal sympathetic nerve activity (RSNA) in response to i.v. infusions of phenylephrine (PE,1.5 microg/min/100g) and sodium nitroprusside (SNP, 1.5 microg/min/100g). Acute intermittent hypoxia (AIH, 18 min) induced elevations in RSNA by over 30% of baseline about three times more often in the CIH group than in the C group. After AIH, the gain of the baroreflex sympatho-excitatory response increased by approximately two times in C and did not change in CIH rats. The gain of sympatho-inhibitory responses to SNP at the maximum decrease in MAP was similar in the two groups in normoxia and was not affected by AIH. We conclude that postnatal intermittent hypoxia causes long-lasting impairment in chemoreceptor and baroreceptor control of renal nerve activity.

Adrenergic alpha-Agonists↗

PubMed2006

Oxidant stress and inflammation in the snoring child: confluent pathways to upper airway pathogenesis and end-organ morbidity.

Snoring in children is increasingly being recognized as a highly prevalent condition, and indicates the presence of heightened upper airway resistance during sleep. In this paper, we present evidence to support the hypothesis that local inflammatory processes within the upper airway contribute to the pathophysiology of adenotonsillar hypertrophy and altered reflexes potentially leading to increased propensity for upper airway obstruction during sleep. Furthermore, the cumulative evidence supporting multiorgan morbidity for sleep-disordered breathing (SDB) is reviewed, and a unified hypothesis of a triple risk model proposing oxidative-inflammatory mechanisms as mediating the morbid consequences of SDB is presented. This hypothetical working model incorporates both dose-dependent disease severity components, as well as environmental and genetic elements of susceptibility.

Adenoids↗

PubMed2006

Early postnatal chronic intermittent hypoxia modifies hypoxic respiratory responses and long-term phrenic facilitation in adult rats.

Acute isocapnic intermittent hypoxia elicits time-dependent, serotonin-dependent enhancement of phrenic motor output in anesthetized rats (phrenic long-term facilitation, pLTF). In adult rats, pLTF is enhanced by chronic intermittent hypoxia (CIH). To test the hypothesis that early postnatal CIH induces persistent modifications of ventilation and pLTF, we exposed male Sprague-Dawley rat pups on their first day of life to a CIH profile consisting of alternating room air and 10% oxygen every 90 s for 30 days during daylight hours (RAIH) or to comparable exposures consisting of room air throughout (RARA). One month after cessation of CIH, respiratory responses were recorded using whole body plethysmography, and integrated phrenic nerve activity was recorded in urethane-anesthetized, vagotomized, paralyzed, and ventilated rats at baseline and after exposures to three 5-min hypoxic episodes [inspired O2 fraction (FiO2)=0.11] separated by 5 min of hyperoxia (FiO2=0.5). RAIH rats displayed greater normoxic ventilation and also increased burst frequency compared with RARA rats (P<0.01). Ventilatory responses to hypoxia and short-term phrenic responses during acute hypoxic challenges were reduced in RAIH rats (P<0.01). Although pLTF was present in both RAIH and RARA rats, it was diminished in RAIH rats (minute activity: 74+/-2% in RARA vs. 55+/-5% in RAIH at 60 min; P<0.01). Thus we conclude that early postnatal CIH modifies normoxic and hypoxic ventilatory and phrenic responses that persist at 1 mo after cessation of CIH (i.e., metaplasticity) and markedly differ from previously reported increased neural plasticity changes induced by CIH in adult rats.

Animals↗