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Biomedical subjects

Karen A Waters

Publications and source records attributed to Karen A Waters.

17 recordsLinked to original sources
PubMed2006

Obesity increases the risk for persisting obstructive sleep apnea after treatment in children.

OBJECTIVE: To evaluate the impact of obesity at diagnosis on treatment outcomes in paediatric obstructive sleep apnea (OSA). METHODS: Children were included if they had both diagnostic and follow-up studies for OSA. Anthropological and polysomnographic data were collected at the time of both studies. Polysomnograms were scored using standard criteria and OSA was defined as a respiratory disturbance index (RDI) >or=5. Obesity was defined as a body mass index standard deviation (z-)score (BMIsds) greater than 2, adjusted for age and gender. RESULTS: For 69 children (49 males), mean age was 7.1+/-4.2 years and 29 (42%) children were obese. There was no significant difference in RDI between obese and non-obese children at diagnostic study. Following adenotonsillectomy the obese children had a significantly higher mean RDI (10.7+/-15.6 versus 3.7+/-4.3; p=0.01). Disease resolution occurred in 77.5% of non-obese compared to 45% of obese children (p=0.011). The odds ratio (OR) for persistent OSA in obese compared to non-obese children was 4.2 (95% CI: 1.5-11.9; p=0.005). Using initial RDI as a covariate, these data show that obesity in children has an adjusted OR for persistent OSA after adenotonsillectomy 3.7 (95% CI: 1.3-10.8, p=0.016). CONCLUSION: For children, obesity at the time of diagnosis is a major risk for persisting OSA after treatment, regardless of the severity of initial disease.

Adenoidectomy↗
PubMed2006

Follow-up on metabolic markers in children treated for obstructive sleep apnea.

RATIONALE: In adults, obstructive sleep apnea (OSA) is associated with metabolic dysfunction that improves with treatment of OSA. No equivalent studies exist in children. OBJECTIVE: To examine the relationship between metabolic markers and OSA with time and treatment in children. METHODS: Metabolic markers measured on a fasting morning blood sample at diagnostic polysomnography and follow-up 1.3 +/- 0.6 yr later. MEASUREMENTS AND MAIN RESULTS: Forty-five children (34 males), aged 6.9 +/- 3.5 yr, and including 12 obese subjects, were in the final analysis. There were no differences in metabolic markers between children with and without OSA at initial study; however, obese children had significantly higher insulin (106.1 +/- 72.1 vs. 66.7 +/- 37.6 pmol/L; p = 0.028), insulin/glucose ratio (23.7 +/- 14.3 vs. 14.7 +/- 8.0; p = 0.02), and significantly lower high-density lipoprotein cholesterol (1.3 +/- 0.2 vs. 1.6 +/- 0.4 nmol/L; p = 0.005) than nonobese children. Twenty children underwent surgical removal of adenotonsillar tissue, whereas 12 children with OSA elected not to have treatment. OSA persisted after treatment in five children, and resolved in 27. Thirteen children did not have OSA on initial or follow-up studies. At follow-up, there was a small but significant improvement in total cholesterol in those children whose OSA was resolved (4.8 +/- 0.8 to 4.7 +/- 0.6 nmol/L; p = 0.005) and a trend for obese children with persisting OSA to have elevated insulin levels compared with obese children without OSA (p = 0.07). CONCLUSION: Obesity appears to be the major influence on metabolic dysfunction in children with OSA, but these preliminary data also suggest that resolution or persistence of OSA may affect changes in metabolic function over time.

Blood Glucose↗
PubMed2006

Inflammatory measures in children with obstructive sleep apnoea.

AIM: To evaluate a range of inflammatory measures in children with obstructive sleep apnoea (OSA). METHODS: In total, 44 children with polysomnographically defined OSA (30 boys; mean age: 7.3 +/- 3.7 years) and 69 control subjects (44 boys; mean age: 7.6 +/- 4 years) were recruited. Controls were screened for symptoms of OSA by questionnaire at the time of elective surgery that was unrelated to the upper airway. Blood samples were analysed for C-reactive protein, and cytokines IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, GM-CSF, IFN-gamma and TNF-alpha. RESULTS: The majority of the children had mild OSA (32/44). Children with OSA (respiratory disturbance index 5.3 +/- 6.5 events/h) had significantly higher IFN-gamma and IL-8 levels than controls (P < 0.001 and 0.003, respectively), although correction for age, sex and body mass index reduced these differences (IFN-gammaP = 0.002, and IL-8 P = 0.051). There were no significant correlations between inflammatory measures and body mass index, respiratory disturbance index, or other sleep, desaturation, or arousal parameters including respiratory or spontaneous arousal indices, desaturation index or severity, sleep efficiency, or apnoea/hypopnoea duration in the OSA group. CONCLUSION: Children with OSA, even of mild severity, have significantly elevated IFN-gamma levels and a trend towards elevated IL-8 levels compared with asymptomatic controls, consistent with a pro-inflammatory effect of OSA. These changes seen in mild OSA may precede changes in other pro-inflammatory cytokines found in studies of adults with more severe and long-standing disease, implying a potential benefit from early disease identification and intervention.

Adolescent↗
PubMed2005

Role of NMDA receptors in development of respiratory control.

The N-methyl-D-aspartate (NMDA) receptor has many functions throughout the central nervous system (CNS) including its role within the centers controlling respiration. Although NMDA receptors are important for normal breathing, they are specifically active under conditions of stress, such as hypoxia. Consistent with its role in other neurological functions, the NMDA receptor is also important to the prenatal development of normal neurological pathways for the control of ventilation. The importance of NMDA receptors to both normal breathing and stress responses is demonstrated by recent observations of antenatal effects of disturbances to the NMDA receptor which disrupts normal breathing as well as causing reduced ventilatory responses during stress in newborns. These characteristics fit with the known NMDA influences on neuronal development and plasticity. The methods used to evaluate these functions have mainly included pharmacological agents for activation (agonists) or depression (antagonists) of NMDA receptors. NMDA receptor expression has also been measured histologically, and more recently knockout animal models have been used to provide additional functional information.

Animals↗
PubMed2005

8. Investigation and treatment of upper-airway obstruction: childhood sleep disorders I.

Always take a history of snoring and sleep disturbance when reviewing children in primary care, as there is evidence that episodes of hypoxia and arousal during sleep may result in deficits in memory, attention and behaviour, in addition to the well known sequelae of growth failure, developmental delay and cor pulmonale. Check for changes in behaviour affecting school progress. To investigate for possible obstructive sleep apnoea syndrome (OSAS), clinical examination, lateral neck x-ray (adenoidal hypertrophy) and overnight oximetry (desaturation episodes) are useful screening tests, but oximetry is best used in conjunction with polysomnography. A negative oximetry test does not exclude OSAS. Polysomnography is the best method for detecting and assessing the severity of OSAS in children, and is especially helpful for prioritising treatment and evaluating the risk of perioperative complications of adenotonsillectomy. Adenotonsillectomy is thought to "cure" (ie, symptoms disappear and overnight respiratory parameters are corrected) in about 80% of children with OSAS. The remaining 20% need ongoing evaluation and treatment. Further research is needed to determine the "true" prevalence of OSAS; what degrees of severity of upper-airway obstruction lead to morbidity requiring treatment; and whether the deficits in neurocognitive function associated with sleep-disordered breathing are fully correctable.

Adenoidectomy↗
PubMed2005

Habituation of arousal responses after intermittent hypercapnic hypoxia in piglets.

RATIONALE: Clinical studies have demonstrated arousal deficits in infants suffering obstructive sleep apnea, and some infant deaths have been attributed to such an arousal deficit. OBJECTIVES: To evaluate whether arousal deficits can be induced by intermittent asphyxia during normal development. METHODS AND MEASUREMENTS: Young piglets were exposed to intermittent hypercapnic hypoxia for 4 days from age 9.55 +/- 0.5 days. Arousal responses were compared between control animals and animals exposed to intermittent hypercapnic hypoxia. Outcome measures included time to arouse after onset of the respiratory stimulus and frequency of arousals during recovery. MAIN RESULTS: Arousal deficits emerged after successive exposures to hypercapnic hypoxia on Day 1, and were exacerbated on Day 4, although after overnight recovery, the deficit only became evident during the second and subsequent episode of hypercapnic hypoxia. On Day 1, time to arouse increased from 16.9 +/- 7.1 seconds in the first epoch to 41.7 +/- 28.6 seconds in the fourth epoch (p = 0.004 between cycles, one-way analysis of variance). In the recovery periods after hypercapnic hypoxia, there were 64% fewer arousals than baseline on Day 1 and 90% fewer arousals on Day 4. Respiratory effort, measured by VT across 10 breaths before the arousal, increased from 25.7 +/- 7.6 on Day 1 to 29.1 +/- 6.8 ml/kg on Day 4 (p < 0.001, two-way analysis of variance, Day 4 vs. Day 1, respectively). CONCLUSIONS: These studies demonstrate that acute and chronic arousal deficits can be induced by intermittent asphyxia, on a background of otherwise normal postnatal development.

Animals↗
PubMed2003

Increased neuronal cell death after intermittent hypercapnic hypoxia in the developing piglet brainstem.

We examined the immunohistochemical expression of caspase-3 (CASP3), active caspase-3 and TUNEL in the normal piglet brainstem at 13-14 days of age and evaluated the effects of exposure to 2 vs. 4 days of intermittent hypercapnic hypoxia (IHH) on their expression. Eight nuclei from the level of the caudal medulla were studied. In control piglets, CASP3 was present in approximately 45% of neurons while active caspase-3 and TUNEL were present in approximately 5%, indicating that approximately half the neuronal population of the piglet medulla express caspase-3 in a latent state and that only approximately 5% undergo 'normal' programmed cell death. After 2 days of IHH, CASP3 increased in the nucleus of the solitary tract (NTS), gracile and cuneate nuclei (P<0.05 for all). Active caspase-3 increased in the dorsal motor nucleus of the vagus (DMNV) (P<0.05) but decreased in the lateral reticular nucleus (LRt) (P<0.05), while TUNEL increased in both the DMNV and LRt (P<0.05 for both). After 4 days of IHH, CASP3 remained elevated in the cuneate nucleus (P<0.01) but decreased in the hypoglossal and DMNV (P<0.05) when compared to controls. Active caspase-3 levels were not changed, whereas TUNEL was increased in the DMNV, LRt, and inferior olivary nucleus (P<0.05 for all). These results show that IHH induces neuronal cell death within certain nuclei in the piglet caudal medulla that are functionally important in cardiorespiratory, sleep and arousal control. This could have important implications for clinical conditions including obstructive apnea and prone sleeping as a risk for SIDS.

Aging↗
PubMed2003

Responses to hypoxia during early development.

Sustained hypoxia evokes a predictable cascade of ventilatory, neurochemical, and metabolic responses. Responses in immature animals are characterized by earlier and more marked depression of ventilation than fully mature animals. Ventilation during hypoxia reflects a collective system output, incorporating a number of compensatory mechanisms (stimulation or depression) from multiple systems. The time course of these responses is clearly developmentally regulated. When hypercapnia interacts with hypoxia, the ventilatory responses are enhanced but other responses are apparently unchanged. We propose a model in which responses to intermittent stimuli vary according to the point within the sequence of a single response where the stimulus interruption occurs. An intermittent stimulus may be seen as 'continuous' if the recurrence frequency exceeds a certain threshold, whereas application of slower cycles below such threshold may elicit discordant recruitment of the compensatory responses. Indeed, experimental observations on intermittent (hypercapnic or poikylocapnic) hypoxia show excitatory or depressant effects that are dictated by the cycle duration. Subject to further testing, this model may help explain how detrimental effects of hypoxic events in infancy only affect selected groups.

Animals↗
PubMed2003

Influence of sleep state on frequency of swallowing, apnea, and arousal in human infants.

Apnea and arousal are modulated with sleep stage, and swallowing may interfere with respiratory rhythm in infants. We hypothesized that swallowing itself would display interaction with sleep state. Concurrent polysomnography and measurement of swallowing allowed time-matched analysis of 3,092 swallows, 482 apneas, and 771 arousals in 17 infants aged 1-34 wk. The mean rates of swallowing, apnea, and arousal were significantly different, being 23.3 +/- 8.5, 9.4 +/- 8.8, and 15.5 +/- 10.6 h(-1), respectively (P < 0.001 ANOVA). Swallows occurred before 25.2 +/- 7.9% and during 74.8 +/- 6.3% of apneas and before 39.8 +/- 6.0% and during 60.2 +/- 6.0% of arousals. The frequencies of apneas and arousals were both strongly influenced by sleep state (active sleep > indeterminate > quiet sleep, P < 0.001), whether or not the events coincided with swallowing, but swallowing rate showed minimal independent interaction with sleep state. Interactions between swallowing and sleep state were predominantly influenced by the coincidence of swallowing with apnea or arousal.

Arousal↗
PubMed2003

Effect of stimulus cycle time on acute respiratory responses to intermittent hypercapnic hypoxia in unsedated piglets.

To determine whether stimulus frequency affects physiological compensation to an intermittent respiratory stimulus, we studied piglets (n = 43) aged 14.8 +/- 2.4 days. A 24-min total hypercapnic hypoxia (HH) (10% O(2)-6% CO(2)-balance N(2) = HH) was delivered in 24-, 8-, 4-, or 2-min cycles alternating with air. Controls (n = 10) breathed air continuously. Minute ventilation and temperature were not different between the 2-min and 24-min groups, with neither different from controls during recovery. Piglets exposed to 8-min cycles had ventilatory stimulation, whereas those exposed to 4-min cycles had significant depression of ventilation. Despite this, piglets in these intermediate intermittent HH (IHH) groups (8- and 4-min cycles) showed more severe acidosis and attenuated temperature changes (P < 0.001 and P < 0.01 for pH and temperature vs. 24 min, respectively). Cycle time affected the ability of young piglets to tolerate IHH. More severe respiratory acidosis developed when IHH was delivered in intermediate (4 min or 8 min) cycles compared with the same total dose as a single episode or in short (2 min) cycles.

Adaptation, Physiological↗
PubMed2003

NMDA receptor 1 expression in the brainstem of human infants and its relevance to the sudden infant death syndrome (SIDS).

The N-methyl-D-aspartate (NMDA) glutamatergic receptor is widely expressed in the brain during the early postnatal period and, among other functions is involved in cardiorespiratory control and in cell death by excitotoxic mechanisms. This study examined NMDA receptor-1 (NR1) expression in the human infant brainstem and assessed whether expression differed between non-SIDS and SIDS infants. NRI mRNA was identified using non-radioactive in situ hybridization and quantified by optical density. NRI protein was identified by immunohistochemistry and quantified by cellular counting. Eight nuclei of the mid-medulla and 2 nuclei of the rostral pons were studied. NRI mRNA and protein were expressed in all nuclei studied, confirming that the NMDA receptor is widely distributed in the human infant brainstem. Compared to non-SIDS infants (n = 10). SIDS infants (n = 15) had increased mRNA in 6 nuclei of the mid-medulla (p < 0.05 for all) while protein was increased in the dorsal motor nucleus of the vagus (p = 0.04) and decreased in the nucleus of the spinal trigeminal tract (p = 0.03). No differences were observed in the rostral pons. This preliminary study suggests that abnormalities of the glutamatergic system are present in SIDS victims. Further studies will be required to delineate these abnormalities and to investigate potential underlying mechanisms and sequelae.

Analysis of Variance↗
PubMed2002

Distribution and quantification of NMDA R1 mRNA and protein in the piglet brainstem and effects of intermittent hypercapnic hypoxia (IHH).

The first aim of this study was to determine the cellular distribution of NR1 in the piglet brainstem. Documentation of NR1 mRNA was by non-radioactive in situ hybridisation (non-RISH) and of NR1 protein by immunohistochemistry. We found that all neurons expressed mRNA but not all had NR1 protein. Application of non-RISH has permitted us, for the first time, to document the cellular localization of NR1 mRNA showing that it was present in the cytoplasm and nucleolus of motor neurons but dispersed throughout the cellular compartments of sensory neurons. NR1 protein on the other hand, was localized to the cytoplasm only. The second aim of this study was to quantify the distribution of NR1 mRNA and protein. Using image analysis software, we used optical density (OD) to quantify the non-RISH signal for mRNA and cellular counting for protein (expressed as % positive). Results show that NR1 expression is greater in motor than sensory nuclei; for mRNA: 0.46+/-0.04 vs. 0.31+/-0.02 OD units (P<0.001), for protein: 75.9+/-3.1 vs. 58.4+/-2.5% positive (P<0.001). The third aim of this study was to determine the effects of intermittent hypercapnic hypoxia (IHH) on NR1 expression. Chronic IHH exposure caused differential changes in mRNA and protein expression. NR1 mRNA expression increased while the number of neurons expressing NR1 protein showed no change. This finding suggests that NMDA pathways are activated by exposure to IHH.

Animals↗
PubMed2002

Retrieval of mRNA from paraffin-embedded human infant brain tissue for non-radioactive in situ hybridization using oligonucleotides.

In situ hybridization (ISH) is used to examine the spatiotemporal distribution of gene expression in a range of tissues. Neuroscience research in human brain tissue requires techniques that can be used in formalin fixed and paraffin-embedded tissue rather than frozen tissue which is recommended, but difficult to obtain. This study presents a method for non-radioactive (DIG) ISH for detecting NR1 gene expression, in human infant brain tissue. We compared three pre-treatment effects, protease digestion, autoclaving (in citrate and Tris/EDTA buffer) and microwaving (in citrate and Tris/EDTA buffer). Tissue had been fixed in formalin for 2-12 weeks. Results were compared for the hybridization and background signal intensities, and tissue morphology. We found that optimum results were obtained using 12-min microwave pre-treatment in Tris/EDTA buffer. This method produced optimum signal to background ratio in infant and adult tissue, preserved tissue morphology, and was suitable for use across a broad range of fixation times.

Aged↗
PubMed2002

Metabolic correlates with obstructive sleep apnea in obese subjects.

OBJECTIVE: To examine links between obstructive sleep apnea (OSA), insulin resistance, and dyslipidemia. STUDY DESIGN: Obese (body mass index [BMI] >95th percentile for age and gender) children who snored (n = 62, 46 males, age 10.89 [5-16 years] underwent polysomnography and metabolic studies. RESULTS: Respiratory disturbance index (RDI) was 9.23 (0-95), with 23 children (39%) recommended for treatment. Fasting insulin levels were 154.6 pmol/L +/- 79.8 (52-486), and fasting glucose levels were high in 7 children (11%). Fasting insulin levels correlated with sleep variables, including log transformed RDI (log(10)RDI) (P =.01), desaturation events (P =.05), arousal index (P =.01), and sleep-time with oxygen saturation in arterial blood <90% (P =.03) (adjusted r (2) = 0.21, F = 3.9, P =.005), but not with age, or BMI Z score. Log(10)RDI correlated with fasting insulin (P =.001) and BMI Z score (P =.03) (adjusted r (2) = 0.12, F = 3.9, P =.005), but not age or other metabolic variables. The correlation between log(10)RDI and fasting insulin persisted in models combining sleep and metabolic variables: log(10)RDI, adjusted r (2) = 0.75, F = 35.2, P <.001, and for fasting insulin, adjusted r (2) = 0.42, F = 6.1, and P <.001. CONCLUSIONS: The severity of OSA (log(10)RDI) correlated with fasting insulin levels, independent of BMI. Insulin levels may be further elevated as a consequence of OSA in obese children.

Adolescent↗
PubMed2002

Effects of OSA, inhalational anesthesia, and fentanyl on the airway and ventilation of children.

To assess effects of anesthesia and opioids, we studied 13 children with obstructive sleep apnea (OSA, age 4.0 +/- 2.2 yr, mean +/- SD) and 24 age-matched control subjects (5.8 +/- 4.0 yr). Apnea indexes of children with OSA were 29.4 +/- 18 h-1, median 30 h-1. Under inhalational anesthetic, closing pressure at the mask was 2.2 +/- 6.9 vs. -14.7 +/- 7.8 cmH2O, OSA vs. control (P < 0.001). After intubation, spontaneous ventilation was 115.5 +/- 56.9 vs. 158.7 +/- 81.6 ml x kg-1 small middle dot min-1, OSA vs. control (P = 0.02), despite elevated PCO2 (49.3 vs. 42.1 Torr, OSA vs. control, P < 0.001). Minute ventilation fell after fentanyl (0.5 microg/kg iv), with central apnea in 6 of 13 OSA cases vs. 1 of 23 control subjects (P < 0.001). Consistent with the finding of reduced spontaneous ventilation, apnea was most likely when end-tidal CO2 exceeded 50 Torr during spontaneous breathing under anesthetic. Thus children with OSA had depressed spontaneous ventilation under anesthesia, and opioids precipitated apnea in almost 50% of children with OSA who were intubated but breathing spontaneously under inhalational anesthesia.

Analgesics, Opioid↗
PubMedDate not supplied

NMDA receptors in the developing brain and effects of noxious insults.

This review covers normal expression of the NMDA receptor in the fetus and newborn, and then the response of the NMDA receptors within the central nervous system (CNS) during early development, to noxious stimuli. In the research setting, hypoxia is a commonly studied noxious stimulus that has been studied in a variety of contexts, including isolated hypoxia, or hypoxia combined with ischemia or hypercapnia, and delivered in single or repeated doses (intermittent stimuli). We review differences and commonalities between these experimental paradigms, and the sequelae of a common outcome, which is cell death, possibly through excitotoxic mechanisms. Finally, based on current literature, we will examine potential directions for clinical therapeutic interventions. By highlighting knowledge gaps in this field, we hope to encourage future research focusing on clinically relevant problems and outcomes in this area.

Animals↗